An atypical presentation of mpox transmitted between transgender males through oral sex
The current multicountry outbreak of mpox in 2022 is the first occurrence of widespread transmission in nonendemic countries. Prior cases in the United States involved exposure through foreign travel or direct contact with infected rodents. Reports of the current outbreak have predominately described spread through sexual encounters between cis-gender men who have sex with men. We report a unique case of mpox in which the transmission occurred through oral sex between 2 transgender men, with a short incubation period and progressive asynchronous emergence of lesions. Continued analysis of transmission routes and awareness will improve timely prevention, diagnosis and treatment.
Authors: Wick, Jenna M;Pelliccione, Alex;Lee-Rodriguez, Christian;Tran, H Nicole;McCleskey, Patrick E;Nichol, Aran;Skarbinski, Jacek
Sex Transm Dis. 2023 Oct 01;50(10):685-686. Epub 2023-05-12.
Prevalence of Self-Inflicted Injuries Among Transgender and Gender Diverse Adolescents and Young Adults Compared to Their Peers: An Examination of Interaction with Mental Health Morbidity
Compare occurrence of self-inflicted injuries among transgender and gender diverse (TGD) youth to that of their cisgender peers while accounting for mental health diagnoses. Review of electronic health records from three integrated health care systems identified 1087 transfeminine and 1431 transmasculine adolescents and young adults. Poisson regression was used to calculate prevalence ratios comparing the proportion of TGD participants with at least one self-inflicted injury (a surrogate for suicide attempt) before index date (first evidence of TGD status) to the corresponding proportions in presumed cisgender male and female referents matched on age, race/ethnicity, and health plan. Interactions between gender identities and mental health diagnoses were assessed on multiplicative and additive scales. TGD adolescents and young adults were more likely to have a self-inflicted injury, various mental health diagnoses, and multiple mental health diagnoses than their cisgender peers. The prevalence of self-inflicted injuries among TGD adolescents and young adults was high even in the absence of mental health diagnoses. Results were consistent with positive additive interaction and negative multiplicative interaction. Universal suicide prevention efforts for all youth, including those with no mental health diagnoses, and more intensive suicide prevention efforts for TGD adolescents and young adults and those with at least one mental health diagnosis are warranted.
Authors: Pampati, Sanjana; Silverberg, Michael J; Goodman, Michael; et al.
Ann Epidemiol. 2023 May;81:40-46.e2. Epub 2023-03-11.
Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies
The life expectancy of people with HIV taking antiretroviral therapy (ART) has increased substantially over the past 25 years. Most previous studies of life expectancy were based on data from the first few years after starting ART, when mortality is highest. However, many people with HIV have been successfully treated with ART for many years, and up-to-date prognosis data are needed. We aimed to estimate life expectancy in adults with HIV on ART for at least 1 year in Europe and North America from 2015 onwards. We used data for people with HIV taking ART from the Antiretroviral Therapy Cohort Collaboration and the UK Collaborative HIV Cohort Study. Included participants started ART between 1996 and 2014 and had been on ART for at least 1 year by 2015, or started ART between 2015 and 2019 and survived for at least 1 year; all participants were aged at least 16 years at ART initiation. We used Poisson models to estimate the associations between mortality and demographic and clinical characteristics, including CD4 cell count at the start of follow-up. We also estimated the remaining years of life left for people with HIV aged 40 years who were taking ART, and stratified these estimates by variables associated with mortality. These estimates were compared with estimates for years of life remaining in a corresponding multi-country general population. Among 206 891 people with HIV included, 5780 deaths were recorded since 2015. We estimated that women with HIV at age 40 years had 35·8 years (95% CI 35·2-36·4) of life left if they started ART before 2015, and 39·0 years (38·5-39·5) left if they started ART after 2015. For men with HIV, the corresponding estimates were 34·5 years (33·8-35·2) and 37·0 (36·5-37·6). Women with CD4 counts of fewer than 49 cells per μL at the start of follow-up had an estimated 19·4 years (18·2-20·5) of life left at age 40 years if they started ART before 2015 and 24·9 years (23·9-25·9) left if they started ART after 2015. The corresponding estimates for men were 18·2 years (17·1-19·4) and 23·7 years (22·7-24·8). Women with CD4 counts of at least 500 cells per μL at the start of follow-up had an estimated 40·2 years (39·7-40·6) of life left at age 40 years if they started ART before 2015 and 42·0 years (41·7-42·3) left if they started ART after 2015. The corresponding estimates for men were 38·0 years (37·5-38·5) and 39·2 years (38·7-39·7). For people with HIV on ART and with high CD4 cell counts who survived to 2015 or started ART after 2015, life expectancy was only a few years lower than that in the general population, irrespective of when ART was started. However, for people with low CD4 counts at the start of follow-up, life-expectancy estimates were substantially lower, emphasising the continuing importance of early diagnosis and sustained treatment of HIV. US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.
Authors: Trickey, Adam; Silverberg, Michael J; Sterne, Jonathan A C; et al.
Lancet HIV. 2023 May;10(5):e295-e307. Epub 2023-03-20.
Age group differences in substance use, social support, and physical and mental health concerns among people living with HIV two years after receiving primary care-based alcohol treatment
Objectives: People living with HIV (PWH) have seen reduction in HIV-associated morbidity and increase in near-normal life expectancy, yet unhealthy alcohol use poses substantial risks to older as well as younger adults. Further research regarding age-associated physical and mental health concerns among PWH who drink alcohol is needed to inform services, given the expanding age range of patients in care.Methods: We compared age group differences (18-34, 35-44, 45-54, ≥55 years old) in two-year patient-reported outcomes and HIV viral control among PWH enrolled in a primary care-based behavioral alcohol intervention trial; with 90% follow up from baseline.Results: Of 553 PWH, 50 (9%) were 18-34, 85 (15%) were 35-44, 197 (36%) were 45-54, and 221 (40%) were ≥55 years old. Most were men (97%) and White (64%). At two years, PWH ≥55 reported less substance use in the prior 30 days, fewer social contacts, and more pain; younger PWH had lower antiretroviral therapy (ART) adherence. In adjusted analyses, PWH ages 18-34 had higher odds of unhealthy alcohol use, tobacco, cannabis, or other substances compared to those ≥55; with higher odds of anxiety among PWH 35-44 compared with those ≥55; and physical quality of life was worse among those ≥55 compared with younger groups.Conclusions: While older PWH report less substance use than younger PWH and have better ART adherence post-treatment, they are more likely to experience limited social support and worse physical quality of life. Findings can inform interventions to address varying needs of PWH across the lifespan.
Authors: Satre, Derek D; Sarovar, Varada; Leyden, Wendy A; Leibowitz, Amy S; Lam, Jennifer O; Hojilla, J Carlo; Davy-Mendez, Thibaut; Hare, Charles B; Silverberg, Michael J
Aging Ment Health. 2023 May;27(5):1011-1019. Epub 2022-06-29.
Immunogenicity and Safety of a Third COVID-19 BNT162b2 mRNA Vaccine Dose in 5-11-Year-Olds
In this ongoing study, substantially increased ancestral SARS-CoV-2 neutralizing responses were observed 1 month after a third 10-µg BNT162b2 dose given to 5 to 11-year olds versus neutralizing responses post-dose 2. After dose 3, increased neutralizing responses against Omicron BA.1 and BA.4/BA.5 strains were also observed. The safety/tolerability profile was acceptable. (NCT04816643).
Authors: Simões, Eric A F; Klein, Nicola P; C4591007 Clinical Trial Group,; et al.
J Pediatric Infect Dis Soc. 2023 Apr 28;12(4):234-238.
Protection of 2 and 3 mRNA Vaccine Doses Against Severe Outcomes Among Adults Hospitalized with COVID-19 – VISION Network, August 2021 – March 2022
We assessed coronavirus disease 2019 (COVID-19) vaccination impact on illness severity among adults hospitalized with COVID-19, August 2021-March 2022. We evaluated differences in intensive care unit (ICU) admission, in-hospital death, and length of stay among vaccinated (2 or 3 mRNA vaccine doses) versus unvaccinated patients aged ≥18 years hospitalized for ≥24 hours with COVID-19-like illness and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular testing. We calculated odds ratios (ORs) for ICU admission and death and subdistribution hazard ratios (SHR) for time to hospital discharge adjusted for age, geographic region, calendar time, and local virus circulation. We included 27 149 SARS-CoV-2-positive hospitalizations. During both Delta- and Omicron-predominant periods, protection against ICU admission was strongest among 3-dose vaccinees compared with unvaccinated patients (Delta OR, 0.52 [95% CI, .28-.96]; Omicron OR, 0.69 [95% CI, .54-.87]). During both periods, risk of in-hospital death was lower among vaccinated compared with unvaccinated patients but ORs overlapped across vaccination strata. We observed SHR >1 across all vaccination strata in both periods indicating faster discharge for vaccinated patients. COVID-19 vaccination was associated with lower rates of ICU admission and in-hospital death in both Delta and Omicron periods compared with being unvaccinated.
Authors: DeSilva, Malini B; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; Gaglani, Manjusha; et al.
J Infect Dis. 2023 Apr 18;227(8):961-969.
Evaluation of the effectiveness of maternal immunization against pertussis in Alberta using agent-based modeling: A Canadian immunization research network study
The re-emergence of pertussis has occurred in the past two decades in developed countries. The highest morbidity and mortality is seen among infants. Vaccination in pregnancy is recommended to reduce the pertussis burden in infants. We developed and validated an agent-based model to characterize pertussis epidemiology in Alberta. We computed programmatic effectiveness of pertussis vaccination during pregnancy (PVE) in relation to maternal vaccine coverage and pertussis disease reporting thresholds. We estimated the population preventable fraction (PFP) of different levels of maternal vaccine coverage against counterfactual “no-vaccination” scenario. We modeled the effect of immunological blunting and measured protection through interruption of exposure pathways. PVE was inversely related to duration of passive immunity from maternal immunization across most simulations. In the scenario of 50% maternal vaccine coverage, PVE was 87% (95% quantiles 82-91%), with PFP of 44% (95% quantiles 41-45%). For monthly age intervals of 0-2, 2-4, 4-6 and 6-12, PVE ranged between 82 and 99%, and PFP ranged between 41 and 49%. At 75% maternal vaccine coverage, PVE and PFP were 90% (95% quantiles 86-92%) and 68% (95% quantiles 65-69%), respectively. At 50% maternal vaccine coverage and 10% blunting, PVE and PFP were 86% (95% quantiles 77-87%) and 43% (95% quantiles 39-44%), respectively, while at 50% blunting, the corresponding values of PVE and PFP were 76% (95% quantiles 70-81%) and 38% (95% quantiles 35-40%). PVE attributable to interruption of exposure pathways was 54-57%. Our model predicts significant reduction in future pertussis cases in infants due to maternal vaccination, with immunological blunting slightly moderating its effectiveness. The model is most sensitive to maternal vaccination coverage. The interruption of exposure pathways plays a role in the reduction of pertussis burden in infants due to maternal immunization. The effect of maternal immunization on population other than infants remains to be elucidated.
Authors: Hempel, Karsten; McDonald, Wade; Osgood, Nathaniel D; Fisman, David; Halperin, Scott A; Crowcroft, Natasha; Klein, Nicola P; Rohani, Pejman; Doroshenko, Alexander
Vaccine. 2023 Apr 06;41(15):2430-2438. Epub 2023-02-10.
Provider- and Facility-Level Variation in Pre-Cancerous Cervical Biopsy Diagnoses
Reproducibility of cervical biopsy diagnoses is low and may vary based on where the diagnostic test is performed and by whom. Our objective was to measure multilevel variation in diagnoses across colposcopists, pathologists, and laboratory facilities. We cross-sectionally examined variation in cervical biopsy diagnoses within the 5 sites of the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium within levels defined by colposcopists, pathologists, and laboratory facilities. Patients aged 18 to 65 years with a colposcopy with biopsy performed were included, with diagnoses categorized as normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), and grade 3 (CIN3). Using Markov Chain Monte-Carlo methods, we fit mixed-effects logistic regression models for biopsy diagnoses and presented median odds ratios (MORs), which reflect the variability within each level. Median odds ratios can be interpreted as the average increased odds a patient would have for a given outcome (e.g., CIN2 or CIN3 vs normal or CIN1) when switching to a provider with higher odds of diagnosing that outcome. The MOR is always 1 or greater, and a value of 1 indicates no variation in outcome for that level, with higher values indicating greater variation. A total of 130,110 patients were included who received care across 82 laboratory facilities, 2,620 colposcopists, and 489 pathologists. Substantial variation in biopsy diagnoses was found at each level, with the most occurring between laboratory facilities, followed by pathologists and colposcopists. Substantial variation in biopsy diagnoses of CIN2 or CIN3 (vs normal or CIN1) was present between laboratory facilities (MOR: 1.26; 95% credible interval = 1.19-1.36). Improving consistency in cervical biopsy diagnoses is needed to reduce underdiagnosis, overdiagnosis, and unnecessary treatment resulting from variation in cervical biopsy diagnoses.
Authors: Del Vecchio, Natalie J; Corley, Douglas A; Silverberg, Michael; et al.
J Low Genit Tract Dis. 2023 Apr 01;27(2):113-119. Epub 2023-01-17.
Safety of measles, mumps, and rubella vaccine in adolescents and adults in the vaccine safety Datalink
Measles, mumps, and rubella vaccine (MMR) is routinely administered to children; however, adolescents and adults may receive MMR for various reasons. Safety studies in adolescents and adults are limited. We report on safety of MMR in this age group in the Vaccine Safety Datalink. We included adolescents (aged 9-17 years) and adults (aged ≥ 18 years) who received ≥ 1 dose of MMR from January 1, 2010-December 31, 2018. Pre-specified outcomes were identified by diagnosis codes. Clinically serious outcomes included anaphylaxis, encephalitis/myelitis, Guillain-Barré syndrome, immune thrombocytopenia, meningitis, and seizure. Non-serious outcomes were allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, non-specific reaction, parotitis, rash, and syncope. All serious outcomes underwent medical record review. Outcome-specific incidence was calculated in pre-defined post-vaccination windows. A self-controlled risk interval design was used to determine the relative risk of each outcome in a risk window after vaccination compared to a more distal control window. During the study period, 276,327 MMR doses were administered to adolescents and adults. Mean age of vaccinees was 34.8 years; 65.8 % were female; 53.2 % of doses were administered simultaneously with ≥ 1 other vaccine. Serious outcomes were rare, with incidence ≤ 6 per 100,000 doses for each outcome assessed, and none had a significant elevation in incidence during the risk window compared to the control window. Incidence of non-serious outcomes per 100,000 doses ranged from 3.4 for parotitis to 263.0 for arthropathy. Other common outcomes included injection site reaction and rash (157.0 and 112.9 per 100,000 doses, respectively). Significantly more outcomes were observed during the risk window compared to the control window for all non-serious outcomes except parotitis. Some variability was observed by sex and age group. Serious outcomes after MMR are rare in adolescents and adults, but vaccinees should be counseled regarding anticipated local and systemic non-serious adverse events.
Authors: Hanson, Kayla E; Klein, Nicola P; McLean, Huong Q; et al.
Vaccine X. 2023 Apr;13:100268. Epub 2023-02-04.
Satisfaction with current hormone therapy and goals of additional gender-affirming care in transgender adults
Many transgender persons seek hormone therapy to reduce gender dysphoria and improve quality of life, but little is known about patient satisfaction with current gender-affirming hormone therapy. To examine patient satisfaction with current gender-affirming hormone therapy and patients’ goals of additional hormone therapy. Transgender adults in the validated multicenter STRONG cohort (Study of Transition, Outcomes, and Gender) were asked to complete a cross-sectional survey about current and planned hormone therapy and the effects that they experienced or hoped to gain. The proportion of respondents reporting overall satisfaction with hormone therapy were compared with χ2 or Fisher exact test. Cochran-Mantel-Haenszel analysis was used to compare the covariates of interest while controlling for age at the time of survey completion. Patient satisfaction across hormone therapies, each measured with a 5-point scale, was averaged and dichotomized. Out of 2136 eligible transgender adults, 696 (33%) completed the survey: 350 transfeminine (TF) and 346 transmasculine (TM) respondents. Most participants (80%) were satisfied or very satisfied with their current hormone therapies. TF participants and older participants were less likely to report being satisfied with their current hormone therapies than TM participants and younger participants, respectively. However, TM and TF categories were not associated with patient satisfaction after controlling for age at the time of survey completion. More TF persons planned to take additional treatment. The most frequent goals for additional hormone therapy for TF persons included breast size growth, feminine body fat distribution, and facial feature softening; for TM persons, goals included diminishing dysphoria, greater muscle mass, and masculine body fat distribution. Multidisciplinary care beyond provision of hormone therapy-such as involvement of surgical, dermatologic, reproductive health, mental health, and/or gender expression care-may be important to help achieve unmet gender-affirming care goals. This study had a modest response rate and included only respondents with private insurance, limiting generalizability. Understanding patient satisfaction and goals of care will assist shared decision making and counseling in patient-centered gender-affirming therapy.
Authors: Siira, Meron; Getahun, Darios; Silverberg, Michael J; Tangpricha, Vin; Goodman, Michael; Yeung, Howa
J Sex Med. 2023 Mar 31;20(4):568-572.
Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022
During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness.† VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 32% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 59% compared with no vaccination, 42% compared with monovalent vaccination only with last dose 5-7 months earlier, and 48% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.
Authors: Tenforde, Mark W; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Link-Gelles, Ruth; et al.
MMWR Morb Mortal Wkly Rep. 2023 Mar 17;71(53):1637-1646. Epub 2023-03-17.
COVID-19 Vaccine Safety Surveillance in Early Pregnancy in the United States: Design Factors Affecting the Association Between Vaccine and Spontaneous Abortion
In the Vaccine Safety Datalink (VSD), we previously reported no association between COVID-19 vaccination in early pregnancy and spontaneous abortion (SAB). The current study aims to understand how time since vaccine roll-out or other methodologic factors could affect results. Using a case-control design and generalized estimating equations, we estimated the odds ratios (OR) of COVID-19 vaccination in the 28 days before a SAB or last date of the surveillance period (index date) in ongoing pregnancies and occurrence of SAB, across cumulative 4-week periods from December 2020 through June 2021. Using data from a single site, we evaluated alternate methodologic approaches: increasing the exposure window to 42 days, modifying the index date from the last day to the midpoint of the surveillance period, and constructing a cohort design with a time-dependent exposure model. A protective effect (OR 0.78; 95% Confidence Interval (CI): 0.69-0.89), observed with 3-cumulative periods ending March 8, 2021, was attenuated when surveillance extended to June 28, 2021 (OR: 1.02; 95% CI: 0.96-1.08). We observed a lower OR for a 42-day as compared to a 28-day window. The time-dependent model showed no association. Timing of the surveillance appears to be an important factor affecting the observed vaccine-SAB association.
Authors: Vazquez-Benitez, Gabriela; Klein, Nicola P; Kharbanda, Elyse O; et al.
Am J Epidemiol. 2023 Mar 16.
Optimizing Treatment for Human Immunodeficiency Virus to Improve Clinical Outcomes Using Precision Medicine
In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz (EFV)-based regimen compared to an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009 to 2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of AIDS-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an EFV- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval, 8.6% to 11.3%), corresponding to an absolute risk reduction of 2.3% (0.9% to 3.8%) when compared to recommending an EFV-based regimen for all patients and 2.6% (1.0% to 4.2%) when compared to recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome as compared to assigning all patients the same drug regimen.
Authors: Jetsupphasuk, Michael; Silverberg, Michael J; Eron, Joseph J; et al.
Am J Epidemiol. 2023 Mar 15.
Safety of 9-valent human papillomavirus vaccine administered to males and females in routine use
The nine-valent human papillomavirus vaccine (HPV9, Gardasil®9) was licensed in the USA in December 2014. This study was a multiyear post-licensure study to assess HPV9 safety following routine administration. This retrospective cohort study compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a later interval. Kaiser Permanente Northern California (KPNC) members aged ≥ 9 years who received ≥ 1 HPV9 dose between 10/1/2015-9/30/2017 were included. Outcomes were grouped into predefined diagnostic categories. We compared the odds of events in postvaccination risk intervals (days 0-14, days 1-60) with odds of events during control intervals (days 61-75, days 61-120) using conditional logistic regression. We characterized prespecified events on the day of vaccination (allergic reaction and syncope) and all deaths in the study period. The study included 215,965 individuals receiving ≥ 1 dose of HPV9, of whom 140,628 had no prior HPV vaccination. We observed similar numbers of males and females and racial/ethnic diversity consistent with the underlying population. At first dose median age was 12-13 years and 77% received ≥ 1 concomitant vaccine. Eighteen event categories were significantly elevated, including skin disorders (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.00, 3.53) and ill-defined conditions (OR 1.36, 95% CI 1.13, 1.64; category includes abdominal pain, allergic reactions, syncope, etc.). On review, most findings were previously known, preceded vaccination, or had other causes. Allergic reactions and syncope at vaccination were infrequent but many were potentially related. No deaths (n = 37) were considered related to HPV9 and were consistent with the background rate. We did not identify new safety concerns related to HPV9. The results are consistent with the HPV9 safety profile as established from previous studies/surveillance. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS13151, protocol V503-028).
Authors: Hansen, John;Yee, Arnold;Lewis, Ned;Li, Se;Velicer, Christine;Saddier, Patricia;Klein, Nicola P
Vaccine. 2023 Mar 10;41(11):1819-1825. Epub 2022-11-14.
Human Immunodeficiency Virus Status, Tenofovir Exposure, and the Risk of Poor Coronavirus Disease 19 (COVID-19) Outcomes: Real-World Analysis From 6 United States Cohorts Before Vaccine Rollout
People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection. Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only). Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81]). Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH.
Authors: Lea, Alexandra N; Marafino, Ben J; Skarbinski, Jacek; Silverberg, Michael J; et al.
Clin Infect Dis. 2023 Mar 02.
Estimation of COVID-19 mRNA Vaccine Effectiveness and COVID-19 Illness and Severity by Vaccination Status During Omicron BA.4 and BA.5 Sublineage Periods
Recent SARS-CoV-2 Omicron variant sublineages, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 after vaccination. To evaluate the estimated vaccine effectiveness (VE) of 2, 3, or 4 doses of COVID-19 mRNA vaccination among immunocompetent adults during a period of BA.4 or BA.5 predominant circulation; and to evaluate the relative severity of COVID-19 in hospitalized patients across Omicron BA.1, BA.2 or BA.2.12.1, and BA.4 or BA.5 sublineage periods. This test-negative case-control study was conducted in 10 states with data from emergency department (ED) and urgent care (UC) encounters and hospitalizations from December 16, 2021, to August 20, 2022. Participants included adults with COVID-19-like illness and molecular testing for SARS-CoV-2. Data were analyzed from August 2 to September 21, 2022. mRNA COVID-19 vaccination. The outcomes of interest were COVID-19 ED or UC encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. VE associated with protection against medically attended COVID-19 was estimated, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as the reference group). Among hospitalized patients with COVID-19, demographic and clinical characteristics and in-hospital outcomes were compared across sublineage periods. During the BA.4 and BA.5 predominant period, there were 82 229 eligible ED and UC encounters among patients with COVID-19-like illness (median [IQR] age, 51 [33-70] years; 49 682 [60.4%] female patients), and 19 114 patients (23.2%) had test results positive for SARS-CoV-2; among 21 007 hospitalized patients (median [IQR] age, 71 [58-81] years; 11 209 [53.4%] female patients), 3583 (17.1 %) had test results positive for SARS-CoV-2. Estimated VE against hospitalization was 25% (95% CI, 17%-32%) for receipt of 2 vaccine doses at 150 days or more after receipt, 68% (95% CI, 50%-80%) for a third dose 7 to 119 days after receipt, and 36% (95% CI, 29%-42%) for a third dose 120 days or more (median [IQR], 235 [204-262] days) after receipt. Among patients aged 65 years or older who had received a fourth vaccine dose, VE was 66% (95% CI, 53%-75%) at 7 to 59 days after vaccination and 57% (95% CI, 44%-66%) at 60 days or more (median [IQR], 88 [75-105] days) after vaccination. Among hospitalized patients with COVID-19, ICU admission or in-hospital death occurred in 21.4% of patients during the BA.1 period vs 14.7% during the BA.4 and BA.5 period (standardized mean difference: 0.17). In this case-control study of COVID-19 vaccines and illness, VE associated with protection against medically attended COVID-19 illness was lower with increasing time since last dose; estimated VE was higher after receipt of 1 or 2 booster doses compared with a primary series alone.
Authors: Link-Gelles, Ruth; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; Tenforde, Mark W; et al.
JAMA Netw Open. 2023 Mar 01;6(3):e232598. Epub 2023-03-01.
Influenza Vaccination Uptake and Associated Factors Among Adults With and Without HIV in a Large, Integrated Health Care System
Influenza vaccination is recommended for adults regardless of HIV status. There may be facilitators or barriers to vaccinating people with HIV (PWH) that differ from people without HIV (PWoH). We sought to describe the uptake of influenza vaccination by HIV status and identify factors associated with vaccination. We abstracted data from the electronic health records of PWH and PWoH in Kaiser Permanente Northern California during six influenza seasons (2013-2018). We determined vaccination uptake and used Poisson regression models to evaluate factors associated with vaccination in PWH and PWoH. 9,272 PWH and 194,393 PWoH matched by age, sex, and race/ethnicity were included (mean age: 48 vs 49 years; men: 91% vs 90%; white race: 53%). PWH were more likely to receive the influenza vaccine (65%-69% across years for PWH and 37%-41% for PWoH) with an adjusted risk ratio for all years of 1.48 (95% CI: 1.46-1.50). For PWH, lower vaccination uptake was associated with several factors that suggested more complex health needs, such as lower CD4 cell counts, higher HIV viral loads, prior depression diagnoses, having Medicare insurance, and having a higher number of comorbidities. Associations with vaccination uptake were attenuated in PWH, compared with PWoH, for smoking, alcohol, and demographic factors. PWH had an almost 50% higher uptake of influenza vaccination than PWoH, possibly reflecting greater engagement with the healthcare system. We also found that PWH with more complex health needs had reduced vaccination uptake. Findings may inform outreach strategies to increase influenza vaccination in PWH.
Authors: Imp, Brandon M; Levine, Tory; Satre, Derek D; Skarbinski, Jacek; Luu, Mitchell N; Sterling, Stacy A; Silverberg, Michael J
Clin Infect Dis. 2023 Mar 01.
Maternal SARS-CoV-2 vaccination and infant protection against SARS-CoV-2 during the first six months of life
We examined the effectiveness of maternal vaccination against SARS-CoV-2 infection in 30,311 infants born at Kaiser Permanente Northern California from December 15, 2020, to May 31, 2022. Using Cox regression, the effectiveness of ≥2 doses of COVID-19 vaccine received during pregnancy was 84% (95% confidence interval [CI]: 66, 93), 62% (CI: 39, 77) and 56% (CI: 34,71) during months 0-2, 0-4 and 0- 6 of a child’s life, respectively, in the Delta variant period. In the Omicron variant period, the effectiveness of maternal vaccination in these three age intervals was 21% (CI: -21,48), 14% (CI: -9,32) and 13% (CI: -3,26), respectively. Over the entire study period, the incidence of hospitalization for COVID-19 was lower during the first 6 months of life among infants of vaccinated mothers compared with infants of unvaccinated mothers (21/100,000 person-years vs. 100/100,000 person-years). Maternal vaccination was protective, but protection was lower during Omicron than during Delta. Protection during both periods decreased as infants aged.
Authors: Zerbo, Ousseny; Ray, G Thomas; Fireman, Bruce; Layefsky, Evan; Goddard, Kristin; Lewis, Edwin; Ross, Pat; Omer, Saad; Greenberg, Mara; Klein, Nicola P
Nat Commun. 2023 Feb 28;14(1):894. Epub 2023-02-28.
Risk of venous thromboembolism in non-respiratory and respiratory presentations of COVID-19 in critically ill patients
Authors: Roubinian, Nareg H; Vinson, David R; Pai, Ashok P; Myers, Laura C; Skarbinski, Jacek; Lee, Catherine; Mark, Dustin G; Liu, Vincent X
Chest. 2023 Feb 12.
Effect of adopting the new race-free 2021 CKD-EPI eGFR creatinine equation on racial differences in kidney disease progression among people with HIV; an observational study
The impact of adopting a race-free estimated glomerular filtration rate (eGFR) creatinine (eGFRcr) equation on racial differences in chronic kidney disease (CKD) progression among people with human immunodeficiency virus (PWH) is unknown. We defined eGFR stages using the original race-adjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRcr equation and the new race-free CKD-EPI eGFRcr equation. We then estimated 5-year probabilities of transitioning from baseline kidney function to more advanced eGFR stages and examined the association of race (black vs white) with rates of CKD progression using Markov models. With the race-adjusted eGFRcr equation, black participants (n = 31 298) had a lower risk of progressing from eGFR stage 1 to 2 (hazard ratio [HR], 0.77; 95% confidence interval [CI], .73-.82), an equal risk of progressing from stage 2 to 3 (1.00; .92-.07) and a 3-fold risk of progressing from stage 3 to 4 or 5 (3.06; 2.60-3.62), compared with white participants (n = 27 542). When we used the race-free eGFRcr equation, 16% of black participants were reclassified into a more severe eGFR stage at baseline. The reclassified black individuals had a higher prevalence of CKD risk factors than black PWH who were not reclassified. With the race-free eGFRcr equation, black participants had a higher risk of disease progression across all eGFR stages than white participants. The original eGFRcr equation systematically masked a subgroup of black PWH who are at high-risk of CKD progression. The new race-free eGFRcr equation unmasks these individuals and may allow for earlier detection and management of CKD.
Authors: Muiru, Anthony N; Silverberg, Michael J; Estrella, Michelle M; et al.
Clin Infect Dis. 2023 Feb 08;76(3):461-468.
The prevalence of mental health disorders in people with HIV and the effects on the HIV care continuum
To describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHDs). Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design. PWH (≥18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008 to 2018 based on International Classification of Diseases code mapping. Mental health (MH) multimorbidity was defined as having two or more MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care (≥1 visit/year) and viral suppression (HIV RNA ≤200 copies/ml) by presence vs. absence of each MHD between 2016 and 2018. Among 122 896 PWH, 67 643 (55.1%) were diagnosed with one or more MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008 and 2018, whereas bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016 to 2018 (N = 64 684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR = 0.98 [0.98-0.99]) as did PWH with MH multimorbidity (aPR = 0.99 [0.99-1.00]) compared with PWH without MHD. The prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity.
Authors: Lang, Raynell; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA),; et al.
AIDS. 2023 Feb 01;37(2):259-269. Epub 2022-11-10.
The changing prevalence of anemia and risk factors in people with HIV in North America who have initiated ART, 2007-2017
To characterize the prevalence of anemia and risk factors between 2007 and 2017 for moderate/severe anemia among people with HIV (PWH) in North America who have initiated antiretroviral therapy (ART). Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We estimated the annual prevalence between 1 January 2007 and 31 December 2017 of mild (11.0-12.9 g/dl men, 11.0-11.9 g/dl women), moderate (8.0-10.9 g/dl regardless of sex) and severe (<8.0 g/dl regardless of sex) anemia. Poisson regression models with robust variance and general estimating equations estimated crude and adjusted prevalence ratios (aPR) with 95% confidence intervals ([-]) comparing risk factors for moderate/severe vs. no/mild anemia between 2007 and 2017. Among 73 898 PWH we observed 366 755 hemoglobin measurements following ART initiation, 37 301 (50%) had one or more measures of anemia during follow-up (mild = 17 743 [24%]; moderate = 13 383[18%]; severe = 6175 [8%]). Moderate/severe anemia was more prevalent among women, non-Hispanic Black and Hispanic PWH (vs. non-Hispanic white), those with underweight body mass index (<18.5 kg/m2) and with comorbidities and coinfections. Older age had increased prevalence of moderate/severe anemia among males and decreased prevalence among females. Prevalence of moderate/severe anemia was greater among those with lower CD4+ cell count (≤200 cells/μl) [aPR = 2.11 (2.06-2.17)] unsuppressed HIV viral load (>200 copies/ml) [aPR = 1.26 (1.23-1.29)] and within the first 6 months of ART initiation (vs. >1 year of ART) [aPR = 1.66 (1.61-1.72)]. The prevalence of anemia among PWH is reduced after ART initiation but remains high. Risk factors differ by sex and include comorbidities and HIV disease severity. The persistent, substantial prevalence of anemia among PWH merits further investigation, targeted screening, and clinical interventions.
Authors: Lang, Raynell; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research, Design (NA-ACCORD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA),; et al.
AIDS. 2023 Feb 01;37(2):287-298. Epub 2022-11-10.
Active Post-Licensure Safety Surveillance for Recombinant Zoster Vaccine Using Electronic Health Record Data
Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster (shingles) and its complications in older adults. In this prospective, postlicensure Vaccine Safety Datalink study using electronic health records, we sequentially monitored a real-world population of adults aged ≥50 years who received care in multiple US Vaccine Safety Datalink health systems to identify potentially increased risks of 10 prespecified health outcomes, including stroke, anaphylaxis, and Guillain-Barré syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative to either historical (2013-2017) recipients of zoster vaccine live, a live attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccine recipients who had an annual well-person visit during the 2018-2019 study period. We confirmed prelicensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.
Authors: Nelson, Jennifer C; Klein, Nicola P; Jackson, Lisa A; et al.
Am J Epidemiol. 2023 Feb 01;192(2):205-216.
Gaps in the screening process for women diagnosed with cervical cancer in four diverse US health care settings
Potential care gaps in the cervical cancer screening process among women diagnosed with cervical cancer in an era with increased human papillomavirus (HPV) testing have not been extensively evaluated. Women diagnosed with cervical cancer between ages 21 and 65 at four study sites between 2010 and 2014 were included. Screening histories were ascertained from 0.5 to 4 years prior to cervical cancer diagnosis. We identified potential care gaps in the screening history for each woman and classified them into one of three mutually exclusive types: lack of a screening test, screening test failure, and diagnostic/treatment care gap. Distributions of care gaps were tabulated by stage, histology, and study site. Multivariable nominal logistic regression was used to examine the associations between demographic and cancer characteristics and type of care gap. Of 499 women evaluated, 46% lacked a screening test in the time window examined, 31% experienced a screening test failure, and 22% experienced a diagnostic/treatment care gap. More than half of the women with advanced cancer and squamous cell carcinoma lacked a screening test compared to 31% and 24% of women with localized cancer and adenocarcinoma, respectively. Women aged 21-29 at diagnosis were more likely to experience screening test failure and diagnostic/treatment care gap, while those aged 50-65 were more likely to lack a screening test, compared to women aged 30-39. Our findings demonstrate a continuing need to develop interventions targeting unscreened and under-screened women and improve detection and diagnosis of adenocarcinoma in women undergoing cervical cancer screening and diagnostic follow-up.
Authors: Chao, Chun R; Silverberg, Michael J; Corley, Douglas A; Wheeler, Cosette M; et al.
Cancer Med. 2023 Feb;12(3):3705-3717. Epub 2022-09-15.
Vaccine effectiveness against influenza-associated urgent care, emergency department, and hospital encounters during the 2021-2022 season, VISION Network
Following historically low influenza activity during the 2020-2021 season, the United States saw an increase in influenza circulating during the 2021-2022 season. Most viruses belonged to the influenza A(H3N2) 3C.2a1b 2a.2 subclade. We conducted a test-negative case-control analysis among adults ≥18 years of age at three sites within the VISION Network. Encounters included emergency department/urgent care (ED/UC) visits or hospitalizations with ≥1 acute respiratory illness (ARI) discharge diagnosis codes and molecular testing for influenza. Vaccine effectiveness (VE) was calculated by comparing the odds of influenza vaccination ≥14 days before the encounter date between influenza-positive cases (type A) and influenza-negative and SARS-CoV-2-negative controls, applying inverse probability-to-be-vaccinated weights, and adjusting for confounders. 86,732 ED/UC ARI-associated encounters (7,696 [9%] cases) and 16,805 hospitalized ARI-associated encounters (649 [4%] cases) were included. VE against influenza-associated ED/UC encounters was 25% (95% confidence interval (CI): 20-29%) and 25% (95%CI: 11-37%) against influenza-associated hospitalizations. VE against ED/UC encounters was lower in adults ≥65 years of age (7%; CI: -5-17%) or with immunocompromising conditions (4%, CI:-45-36%). During an influenza A(H3N2)-predominant influenza season, modest VE was observed. These findings highlight the need for improved vaccines, particularly for A(H3N2) viruses that are historically associated with lower VE.
Authors: Tenforde, Mark W; Fireman, Bruce; Zerbo, Ousseny; Klein, Nicola P; et al.
J Infect Dis. 2023 Jan 23.
A safety study evaluating non-COVID-19 mortality risk following COVID-19 vaccination
The safety of COVID-19 vaccines plays an important role in addressing vaccine hesitancy. We conducted a large cohort study to evaluate the risk of non-COVID-19 mortality after COVID-19 vaccination while adjusting for confounders including individual-level demographics, clinical risk factors, health care utilization, and community-level socioeconomic risk factors. The retrospective cohort study consisted of members from seven Vaccine Safety Datalink sites from December 14, 2020 through August 31, 2021. We conducted three separate analyses for each of the three COVID-19 vaccines used in the US. Crude non-COVID-19 mortality rates were reported by vaccine type, age, sex, and race/ethnicity. The counting process model for survival analyses was used to analyze non-COVID-19 mortality where a new observation period began when the vaccination status changed upon receipt of the first dose and the second dose. We used calendar time as the basic time scale in survival analyses to implicitly adjust for season and other temporal trend factors. A propensity score approach was used to adjust for the potential imbalance in confounders between the vaccinated and comparison groups. For each vaccine type and across age, sex, and race/ethnicity groups, crude non-COVID-19 mortality rates among COVID-19 vaccinees were lower than those among comparators. After adjusting for confounders with the propensity score approach, the adjusted hazard ratios (aHRs) were 0.46 (95% confidence interval [CI], 0.44-0.49) after dose 1 and 0.48 (95% CI, 0.46-0.50) after dose 2 of the BNT162b2 vaccine, 0.41 (95% CI, 0.39-0.44) after dose 1 and 0.38 (95% CI, 0.37-0.40) after dose 2 of the mRNA-1273 vaccine, and 0.55 (95% CI, 0.51-0.59) after receipt of Ad26.COV2.S. While residual confounding bias remained after adjusting for several individual-level and community-level risk factors, no increased risk was found for non-COVID-19 mortality among recipients of three COVID-19 vaccines used in the US.
Authors: Xu, Stanley; Klein, Nicola P; Fireman, Bruce; Qian, Lei; et al.
Vaccine. 2023 Jan 16;41(3):844-854. Epub 2022-12-20.
Characterization of parental intention to vaccinate elementary school aged children in the state of California
In October 2021, Emergency Use Authorization of Coronavirus Disease 2019 (COVID-19) vaccines was granted for children aged 5-11. To ensure vaccine uptake in children upon approval, California will implement a state-wide executive order mandating COVID-19 vaccination for school children following full US FDA approval. This study uses survey data collected between November 6th, 2020 and December 14th, 2020 (n = 2091) to identify how sociodemographic characteristics and attitudes towards childhood vaccines among California parents were associated with their intentions to vaccinate their child against COVID-19. About one quarter (26 %) of surveyed California parents did not intend to vaccinate their child, suggesting skepticism towards the COVID-19 vaccine for children and the potential for pushback to a COVID-19 vaccine school-entry mandate. However, 17 % were unsure of their decision, suggesting the potential for public health messaging to make a positive impact on COVID-19 vaccine confidence and uptake. This study identifies characteristics of hesitant parents in California to prioritize for research and outreach. These data also provide a baseline for parental attitudes towards vaccinating children against COVID-19 in California, which will be useful for characterizing changes in attitudes towards childhood COVID-19 vaccination over time.
Authors: Dudley, Matthew Z; Klein, Nicola P; Salmon, Daniel A; et al.
Vaccine. 2023 Jan 16;41(3):630-635. Epub 2022-12-19.
Risk of posthospital venous thromboembolism in patients with COVID-19 varies by SARS-CoV-2 period and vaccination status
Authors: Roubinian, Nareg H;Vinson, David R;Knudson-Fitzpatrick, Tess Wheeler;Mark, Dustin G;Skarbinski, Jacek;Lee, Catherine;Liu, Vincent X;Pai, Ashok P
Blood Adv. 2023 Jan 10;7(1):141-144.
Association of Race and Ethnicity With Initial Prescription of Antiretroviral Therapy Among People With HIV in the US
Integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) is currently the guideline-recommended first-line treatment for HIV. Delayed prescription of INSTI-containing ART may amplify differences and inequities in health outcomes. To estimate racial and ethnic differences in the prescription of INSTI-containing ART among adults newly entering HIV care in the US and to examine variation in these differences over time in relation to changes in treatment guidelines. Retrospective observational study of 42 841 adults entering HIV care from October 12, 2007, when the first INSTI was approved by the US Food and Drug Administration, to April 30, 2019, at more than 200 clinical sites contributing to the North American AIDS Cohort Collaboration on Research and Design. Combined race and ethnicity as reported in patient medical records. Probability of initial prescription of ART within 1 month of care entry and probability of being prescribed INSTI-containing ART. Differences among non-Hispanic Black and Hispanic patients compared with non-Hispanic White patients were estimated by calendar year and time period in relation to changes in national guidelines on the timing of treatment initiation and recommended initial treatment regimens. Of 41 263 patients with information on race and ethnicity, 19 378 (47%) as non-Hispanic Black, 6798 (16%) identified as Hispanic, and 13 539 (33%) as non-Hispanic White; 36 394 patients (85%) were male, and the median age was 42 years (IQR, 30 to 51). From 2007-2015, when guidelines recommended treatment initiation based on CD4+ cell count, the probability of ART initiation within 1 month of care entry was 45% among White patients, 45% among Black patients (difference, 0% [95% CI, -1% to 1%]), and 51% among Hispanic patients (difference, 5% [95% CI, 4% to 7%]). From 2016-2019, when guidelines strongly recommended treating all patients regardless of CD4+ cell count, this probability increased to 66% among White patients, 68% among Black patients (difference, 2% [95% CI, -1% to 5%]), and 71% among Hispanic patients (difference, 5% [95% CI, 1% to 9%]). INSTIs were prescribed to 22% of White patients and only 17% of Black patients (difference, -5% [95% CI, -7% to -4%]) and 17% of Hispanic patients (difference, -5% [95% CI, -7% to -3%]) from 2009-2014, when INSTIs were approved as initial therapy but were not yet guideline recommended. Significant differences persisted for Black patients (difference, -6% [95% CI, -8% to -4%]) but not for Hispanic patients (difference, -1% [95% CI, -4% to 2%]) compared with White patients from 2014-2017, when INSTI-containing ART was a guideline-recommended option for initial therapy; differences by race and ethnicity were not statistically significant from 2017-2019, when INSTI-containing ART was the single recommended initial therapy for most people with HIV. Among adults entering HIV care within a large US research consortium from 2007-2019, the 1-month probability of ART prescription was not significantly different across most races and ethnicities, although Black and Hispanic patients were significantly less likely than White patients to receive INSTI-containing ART in earlier time periods but not after INSTIs became guideline-recommended initial therapy for most people with HIV. Additional research is needed to understand the underlying racial and ethnic differences and whether the differences in prescribing were associated with clinical outcomes.
Authors: Zalla, Lauren C; Silverberg, Michael J; Edwards, Jessie K; et al.
JAMA. 2023 Jan 03;329(1):52-62.
All Older Adults Benefit From Pneumococcal Vaccinations-The Case for Evaluating Vaccine Effectiveness Using All-Cause Pneumonia
Authors: Hsiao, Amber; Klein, Nicola P
JAMA Intern Med. 2023 Jan 01;183(1):48-49.
Association Between Aluminum Exposure From Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months
To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months. A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and ?2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization. The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum�exposure was�4.07�mg (SD�0.60) and 3.98�mg (SD�0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25). In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.
Authors: Daley, Matthew F; Klein, Nicola P; DeStefano, Frank; et al.
Acad Pediatr. 2023 Jan-Feb;23(1):37-46. Epub 2022-09-28.
COVID-19 vaccination protects children and adolescents
Authors: Irving, Stephanie A; Klein, Nicola P
Lancet Infect Dis. 2023 Jan;23(1):5-6. Epub 2022-09-09.
Sexually Transmitted Infection Screening in Key Populations of Persons Living with HIV
Annual screening for bacterial sexually transmitted infections (STI), including gonorrhea/chlamydia (GC/CT) and syphilis, is recommended for persons with HIV (PWH). We used the prevention index to quantify the extent to which STI screening was completed at guideline-recommended frequency in African American and Latinx persons, women, persons with alcohol (AUD) and substance (SUD) use disorders. Data from PWH at Kaiser Permanente Northern California were collected from electronic health records. We defined receipt of GC/CT and syphilis screening consistent with recommendations as a prevention index score ≥ 75%. Among 9655 PWH (17.7% Latinx; 16.2% African American; 9.6% female; 12.4% AUD; 22.1% SUD), prevention index scores for GC/CT and syphilis increased from 2015 to 2019. African American PWH had lower odds of receiving an annual syphilis screen (aOR 0.87 [95% CI 0.79-0.97]). Female sex was associated with lower odds of GC/CT (aOR 0.30 [95% CI 0.27-0.34]) and syphilis (aOR 0.27 [95% CI 0.24-0.310) screening. AUD and SUD were not associated with differences in annual GC/CT or syphilis screening. Key PWH subgroups experience ongoing challenges to annual STI screening despite comparable healthcare access.
Authors: Hojilla, J Carlo; Sarovar, Varada; Lam, Jennifer O; Park, Ina U; Vincent, Wilson; Hare, C Bradley; Silverberg, Michael J; Satre, Derek D
AIDS Behav. 2023 Jan;27(1):96-105. Epub 2022-08-02.
Extended surveillance to assess safety of 9-valent human papillomavirus vaccine
The safety of 9-valent HPV vaccine (9vHPV) has been established with regard to common and uncommon adverse events. However, investigation of rare and severe adverse events requires extended study periods to capture rare outcomes. This observational cohort study investigated the occurrence of three rare and serious adverse events following 9-valent human papillomavirus (9vHPV) vaccination compared to other vaccinations, in US individuals 9-26?years old, using electronic health record data from the Vaccine Safety Datalink (VSD). We searched for occurrences of Guillain-Barr� syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and stroke following 9vHPV vaccination from October 4, 2015, through January 2, 2021. We compared the risks of GBS, CIDP, and stroke following 9vHPV vaccination to risks of those outcomes following comparator vaccines commonly given to this age group (Td, Tdap, MenACWY, hepatitis A, and varicella vaccines) from January 1, 2007, through January 2, 2021. We observed 1.2 cases of stroke, 0.3 cases of GBS, and 0.1 cases of CIDP per 100,000 doses of 9vHPV vaccine. After observing more than 1.8 million doses of 9vHPV, we identified no statistically significant increase in risks associated with 9vHPV vaccination for any of these adverse events, either combined or stratified by age (9-17?years of age vs. 18-26?years of age) and sex (males vs. females). Our findings provide additional evidence supporting 9vHPV vaccine safety, over longer time frames and for more serious and rare adverse events.
Authors: Sundaram, Maria E; Klein, Nicola P; Donahue, James G; et al.
Hum Vaccin Immunother. 2022 Dec 30;18(7):2159215. Epub 2022-12-28.
Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults – VISION Network, Nine States, September-November 2022
During June-October 2022, the SARS-CoV-2 Omicron BA.5 sublineage accounted for most of the sequenced viral genomes in the United States, with further Omicron sublineage diversification through November 2022.* Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5 sublineages. On September 1, 2022, a single bivalent booster dose was recommended for adults who had completed a primary vaccination series (with or without subsequent booster doses), with the last dose administered ≥2 months earlier (1). During September 13-November 18, the VISION Network evaluated vaccine effectiveness (VE) of a bivalent mRNA booster dose (after 2, 3, or 4 monovalent doses) compared with 1) no previous vaccination and 2) previous receipt of 2, 3, or 4 monovalent-only mRNA vaccine doses, among immunocompetent adults aged ≥18 years with an emergency department/urgent care (ED/UC) encounter or hospitalization for a COVID-19-like illness.† VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated ED/UC encounters was 56% compared with no vaccination, 31% compared with monovalent vaccination only with last dose 2-4 months earlier, and 50% compared with monovalent vaccination only with last dose ≥11 months earlier. VE of a bivalent booster dose (after 2, 3, or 4 monovalent doses) against COVID-19-associated hospitalizations was 57% compared with no vaccination, 38% compared with monovalent vaccination only with last dose 5-7 months earlier, and 45% compared with monovalent vaccination only with last dose ≥11 months earlier. Bivalent vaccines administered after 2, 3, or 4 monovalent doses were effective in preventing medically attended COVID-19 compared with no vaccination and provided additional protection compared with past monovalent vaccination only, with relative protection increasing with time since receipt of the last monovalent dose. All eligible persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose. Persons should also consider taking additional precautions to avoid respiratory illness this winter season, such as masking in public indoor spaces, especially in areas where COVID-19 community levels are high.
Authors: Tenforde, Mark W; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Link-Gelles, Ruth; et al.
MMWR Morb Mortal Wkly Rep. 2022 Dec 30;71(5152):1616-1624. Epub 2022-12-30.
Statins utilization in adults with HIV: The treatment gap and predictors of statin initiation
We characterized trends in statin eligibility and subsequent statin initiation among people with HIV (PWH) from 2001 to 2017 and identified predictors of statin initiation between 2014 and 2017. PWH participating in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) enrolled in 12 US cohorts collecting data on statin eligibility criteria/prescriptions from 2001 to 2017. We determined the annual proportion eligible for statins, initiating statins, and median waiting time (from statin eligibility to initiation). Eligibility was defined using ATP III guidelines (2001-2013) and ACC/AHA guidelines (2014-2017). We assessed initiation predictors in 2014-2017 among statin-eligible PWH using Poisson regression, estimating adjusted prevalence ratios (aPRs) with 95% confidence intervals (95% CIs). Among 16,409 PWH, 7386 (45%) met statin eligibility criteria per guidelines (2001-2017). From 2001 to 2013, statin eligibility ranged from 22% to 25%. Initiation increased from 13% to 45%. In 2014, 51% were statin-eligible, among whom 25% initiated statins, which increased to 32% by 2017. Median waiting time to initiation among those we observed declined over time. Per 10-year increase in age, initiation increased 46% (aPR 1.46, 95% CI: 1.29 to 1.67). Per 1-year increase in calendar year from 2014 to 2017, there was a 41% increase in the likelihood of statin initiation (aPR 1.41, 95% CI: 1.25 to 1.58). There is a substantial statin treatment gap, amplified by the 2013 ACC/AHA guidelines. Measures are warranted to clarify reasons we observe this gap, and if necessary, increase statin use consistent with guidelines including efforts to help providers identify appropriate candidates.
Authors: Coburn, Sally B; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA,; et al.
J Acquir Immune Defic Syndr. 2022 12 15;91(5):469-478.
Impact of the Coronavirus Disease 2019 Pandemic on Antiretroviral Therapy Initiation and Care Delivery for People With Newly Diagnosed HIV in an Integrated Healthcare System
The coronavirus disease 2019 (COVID-19) pandemic disrupted health systems. For patients newly diagnosed with human immunodeficiency virus, starting immediate antiretroviral therapy (ART) is recommended. For periods before and during the COVID-19 pandemic, Kaiser Permanente Northern California found similar rates of rapid ART initiation and time to viral suppression, concurrent with an increase in telemedicine.
Authors: Mohr, Kurtis B; Lee-Rodriguez, Christian; Samiezade-Yazd, Zahra; Lam, Jennifer O; Imp, Brandon M; Luu, Mitchell N
Open Forum Infect Dis. 2022 Dec;9(12):ofac639. Epub 2022-11-24.
Kawasaki Disease Following the 13-valent Pneumococcal Conjugate Vaccine and Rotavirus Vaccines
Temporal associations between Kawasaki disease (KD) and childhood vaccines have been reported. Limited data on KD following 13-valent pneumococcal conjugate (PCV13) and rotavirus vaccines are available. We conducted a self-controlled risk interval study using Vaccine Safety Datalink electronic health record data to investigate the risk of KD following PCV13 and rotavirus vaccines in children <2 years of age who were born from 2006 to 2017. All hospitalized KD cases identified by International Classification of Diseases diagnosis codes that fell within predefined risk (days 1-28 postvaccination) and control (days 29-56 for doses 1 and 2, and days 43-70 for doses 3 and 4) intervals were confirmed by manual chart review. During the study period, 655 cases of KD were identified by International Classification of Diseases codes. Of these, 97 chart-confirmed cases were within risk or control intervals. In analyses, the age-adjusted relative risk for KD following any dose of PCV13 was 0.75 (95% confidence interval, 0.47-1.21). Similarly, the age-adjusted relative risk for KD following any dose of rotavirus vaccine was 0.66 (95% CI, 0.40-1.09). Overall, there was no evidence of an elevated risk of KD following PCV13 or rotavirus vaccines by dose. In addition, no statistically significant temporal clustering of KD cases was identified during days 1 to 70 postvaccination. PCV13 and rotavirus vaccination were not associated with an increased risk of KD in children <2 years of age. Our findings provide additional evidence for the overall safety of PCV13 and rotavirus vaccines.
Authors: Kamidani, Satoshi; Zerbo, Ousseny; Weintraub, Eric S; et al.
Pediatrics. 2022 Dec 01;150(6).
Incidence of Myocarditis/Pericarditis Following mRNA COVID-19 Vaccination Among Children and Younger Adults in the United States
Authors: Goddard, Kristin; Hanson, Kayla E; Lewis, Ned; Weintraub, Eric; Fireman, Bruce; Klein, Nicola P
Ann Intern Med. 2022 Dec;175(12):1169-1771. Epub 2022-10-04.
Longitudinal HIV care outcomes by gender identity in the United States
Describe engagement in HIV care over time after initial engagement in HIV care, by gender identity. Observational, clinical cohort study of people with HIV engaged in routine HIV care across the United States. We followed people with HIV who linked to and engaged in clinical care (attending ≥2 visits in 12 months) in cohorts in the North American Transgender Cohort Collaboration, 2000-2018. Within strata of gender identity, we estimated the 7-year (84-month) restricted mean time spent: lost-to-clinic (stratified by pre/postantiretroviral therapy (ART) initiation); in care prior to ART initiation; on ART but not virally suppressed; virally suppressed (≤200 copies/ml); or dead (pre/post-ART initiation). Transgender women ( N = 482/101 841) spent an average of 35.5 out of 84 months virally suppressed (this was 30.5 months for cisgender women and 34.4 months for cisgender men). After adjustment for age, race, ethnicity, history of injection drug use, cohort, and calendar year, transgender women were significantly less likely to die than cisgender people. Cisgender women spent more time in care not yet on ART, and less time on ART and virally suppressed, but were less likely to die compared with cisgender men. Other differences were not clinically meaningful. In this sample, transgender women and cisgender people spent similar amounts of time in care and virally suppressed. Additional efforts to improve retention in care and viral suppression are needed for all people with HIV, regardless of gender identity.
Authors: Lesko, Catherine R; Silverberg, Michael J; Poteat, Tonia C; et al.
AIDS. 2022 11 01;36(13):1841-1849. Epub 2022-07-21.
Negative Control Exposures: Causal effect Identifiability and Use in Probabilistic-Bias and Bayesian Analyses with Unmeasured Confounders
Probabilistic bias and Bayesian analyses are important tools for bias correction, particularly when required parameters are nonidentifiable. Negative controls are another tool; they can be used to detect and correct for confounding. Our goals are to present conditions that assure identifiability of certain causal effects and to describe and illustrate a probabilistic bias analysis and related Bayesian analysis that use a negative control exposure. Using potential-outcome models, we characterized assumptions needed for identification of causal effects using a dichotomous, negative control exposure when residual confounding exists. We defined bias parameters, characterized their relationships with the negative control and with specified causal effects, and described the corresponding probabilistic-bias and Bayesian analyses. We present analytic examples using data on hormone therapy and suicide attempts among transgender people. To address possible confounding by healthcare utilization, we used prior tetanus-diphtheria-pertussis (TdaP) vaccination as a negative control exposure. Hormone therapy was weakly associated with risk (risk ratio [RR] = 0.9). The negative control exposure was associated with risk (RR = 1.7), suggesting confounding. Based on an assumed prior distribution for the bias parameter, the 95% simulation interval for the distribution of confounding-adjusted RR was (0.17, 1.6), with median 0.5; the 95% credibility interval was similar. We used dichotomous negative control exposure to identify causal effects when a confounder was unmeasured under strong assumptions. It may be possible to relax assumptions and the negative control exposure could prove helpful for probabilistic bias analyses and Bayesian analyses.
Authors: Flanders, W D; Waller, L A; Zhang, Q; Getahun, D; Silverberg, M; Goodman, M
Epidemiology. 2022 Nov 01;33(6):832-839. Epub 2022-07-27.
Retrospective cohort study to assess the association between treatment with tocilizumab and mortality among mechanically ventilated patients with COVID-19
Assess the association between tocilizumab administration and clinical outcomes among mechanically ventilated patients with COVID-19 pneumonia. Retrospective cohort study. Large integrated health system with 9 million members in California, USA. 4185 Kaiser Permanente members hospitalised with COVID-19 pneumonia requiring invasive mechanical ventilation (IMV). Receipt of tocilizumab within 10 days of initiation of IMV. Using a retrospective cohort of consecutive patients hospitalised with COVID-19 pneumonia who required IMV in a large integrated health system in California, USA, we assessed the association between tocilizumab administration and 28-day mortality, time to extubation from IMV and time to hospital discharge. Among 4185 patients, 184 received tocilizumab and 4001 patients did not receive tocilizumab within 10 days of initiation of IMV. After inverse probability weighting, baseline characteristics were well balanced between groups. Patients treated with tocilizumab had a similar risk of death in the 28 days after intubation compared with patients not treated with tocilizumab (adjusted HR (aHR), 1.21, 95% CI 0.98 to 1.50), but did have a significantly longer time-to-extubation (aHR 0.71; 95% CI 0.57 to 0.88) and time-to-hospital-discharge (aHR 0.66; 95% CI 0.50 to 0.88). However, patients treated with tocilizumab ≤2 days after initiation of IMV had a similar risk of mortality (aHR 1.47; 95% CI 0.96 to 2.26), but significantly shorter time-to-extubation (aHR 0.37; 95% CI 0.23 to 0.58) and time-to-hospital-discharge (aHR 0.31; 95% CI CI 0.17 to 0.56) compared with patients treated with tocilizumab 3-10 days after initiation of IMV. Among mechanically ventilated patients with COVID-19, the risk of death in the 28-day follow-up period was similar, but time-to-extubation and time-to-hospital-discharge were longer in patients who received tocilizumab within 10 days of initiation of IMV compared with patients who did not receive tocilizumab.
Authors: Skarbinski, Jacek; Fireman, Bruce H; Tartof, Sara Y; et al.
BMJ Open. 2022 10 31;12(10):e060358. Epub 2022-10-31.
Prescribing for different antibiotic classes across age groups in the Kaiser Permanente Northern California population in association with influenza incidence, 2010-2018
There is limited information on the volume of antibiotic prescribing that is influenza-associated, resulting from influenza infections and their complications (such as streptococcal pharyngitis). We estimated that for the Kaiser Permanente Northern California population during 2010-2018, 3.4% (2.8%-4%) of all macrolide prescriptions (fills), 2.7% (2.3%-3.2%) of all aminopenicillin prescriptions, 3.1% (2.4%-3.9%) of all 3rd generation cephalosporins prescriptions, 2.2% (1.8%-2.6%) of all protected aminopenicillin prescriptions and 1.3% (1%-1.6%) of all quinolone prescriptions were influenza-associated. The corresponding proportions were higher for select age groups, e.g. 4.3% of macrolide prescribing in ages over 50 years, 5.1% (3.3%-6.8%) of aminopenicillin prescribing in ages 5-17 years and 3.3% (1.9%-4.6%) in ages <5 years was influenza-associated. The relative contribution of influenza to antibiotic prescribing for respiratory diagnoses without a bacterial indication in ages over 5 years was higher than the corresponding relative contribution to prescribing for all diagnoses. Our results suggest a modest benefit of increasing influenza vaccination coverage for reducing prescribing for the five studied antibiotic classes, particularly for macrolides in ages over 50 years and aminopenicillins in ages <18 years, and the potential benefit of other measures to reduce unnecessary antibiotic prescribing for respiratory diagnoses with no bacterial indication, both of which may contribute to the mitigation of antimicrobial resistance.
Authors: Goldstein, Edward; Fireman, Bruce H; Klein, Nicola P; Lipsitch, Marc; Ray, G Thomas
Epidemiol Infect. 2022 Oct 26;150:e180. Epub 2022-10-26.
Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults During SARS-CoV-2 Omicron Predominance – VISION Network, 10 States, December 2021-August 2022
Persons with moderate-to-severe immunocompromising conditions might have reduced protection after COVID-19 vaccination, compared with persons without immunocompromising conditions (1-3). On August 13, 2021, the Advisory Committee on Immunization Practices (ACIP) recommended that adults with immunocompromising conditions receive an expanded primary series of 3 doses of an mRNA COVID-19 vaccine. ACIP followed with recommendations on September 23, 2021, for a fourth (booster) dose and on September 1, 2022, for a new bivalent mRNA COVID-19 vaccine booster dose, containing components of the BA.4 and BA.5 sublineages of the Omicron (B.1.1.529) variant (4). Data on vaccine effectiveness (VE) of monovalent COVID-19 vaccines among persons with immunocompromising conditions since the emergence of the Omicron variant in December 2021 are limited. In the multistate VISION Network,§ monovalent 2-, 3-, and 4-dose mRNA VE against COVID-19-related hospitalization were estimated among adults with immunocompromising conditions¶ hospitalized with COVID-19-like illness,** using a test-negative design comparing odds of previous vaccination among persons with a positive or negative molecular test result (case-patients and control-patients) for SARS-CoV-2 (the virus that causes COVID-19). During December 16, 2021-August 20, 2022, among SARS-CoV-2 test-positive case-patients, 1,815 (36.3%), 1,387 (27.7%), 1,552 (31.0%), and 251 (5.0%) received 0, 2, 3, and 4 mRNA COVID-19 vaccine doses, respectively. Among test-negative control-patients during this period, 6,928 (23.7%), 7,411 (25.4%), 12,734 (43.6%), and 2,142 (7.3%) received these respective doses. Overall, VE against COVID-19-related hospitalization among adults with immunocompromising conditions hospitalized for COVID-like illness during Omicron predominance was 36% ≥14 days after dose 2, 69% 7-89 days after dose 3, and 44% ≥90 days after dose 3. Restricting the analysis to later periods when Omicron sublineages BA.2/BA.2.12.1 and BA.4/BA.5 were predominant and 3-dose recipients were eligible to receive a fourth dose, VE was 32% ≥90 days after dose 3 and 43% ≥7 days after dose 4. Protection offered by vaccination among persons with immunocompromising conditions during Omicron predominance was moderate even after a 3-dose monovalent primary series or booster dose. Given the incomplete protection against hospitalization afforded by monovalent COVID-19 vaccines, persons with immunocompromising conditions might benefit from updated bivalent vaccine booster doses that target recently circulating Omicron sublineages, in line with ACIP recommendations. Further, additional protective recommendations for persons with immunocompromising conditions, including the use of prophylactic antibody therapy, early access to and use of antivirals, and enhanced nonpharmaceutical interventions such as well-fitting masks or respirators, should also be considered.
Authors: Britton, Amadea; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; Tenforde, Mark W; et al.
MMWR Morb Mortal Wkly Rep. 2022 Oct 21;71(42):1335-1342. Epub 2022-10-21.
Maternal SARS-CoV-2 Vaccination and Infant Protection Against SARS-CoV-2 During the First 6 Months of Life
We examined the effectiveness of maternal vaccination against SARS-CoV-2 infection in 30,288 infants born at Kaiser Permanente Northern California from December 15, 2020, to May 31, 2022. Using Cox regression, the effectiveness of maternal vaccination was 85% (95% confidence interval [CI]: 67, 93), 64% (CI: 43, 78) and 57% (CI: 36,71) during the first 2, 4 and 6 months of life, respectively, in the Delta variant period. In the Omicron variant period, the effectiveness of maternal vaccination in these three age intervals was 22% (CI: -18,48), 14% (CI: -10,32) and 12% (CI: -4,26), respectively. Over the entire study period, the incidence of hospitalization for COVID-19 was lower during the first 6 months of life among infants of vaccinated mothers compared with infants of unvaccinated mothers (21/100,000 person-years vs. 100/100,000 person-years). Maternal vaccination was protective, but protection was lower during Omicron than during Delta. Protection during both periods decreased as infants aged.
Authors: Zerbo, Ousseny; Ray, G Thomas; Fireman, Bruce; Layefsky, Evan; Goddard, Kristin; Lewis, Edwin; Ross, Pat; Omer, Saad; Greenberg, Mara; Klein, Nicola
Res Sq. 2022 Oct 18.
Evaluating the Cardiovascular Risk in an Aging Population of People With HIV: The Impact of Hepatitis C Virus Coinfection
Background People with HIV (PWH) are at an increased risk of cardiovascular disease (CVD) with an unknown added impact of hepatitis C virus (HCV) coinfection. We aimed to identify whether HCV coinfection increases the risk of type 1 myocardial infarction (T1MI) and if the risk differs by age. Methods and Results We used data from NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) from January 1, 2000, to December 31, 2017, PWH (aged 40-79 years) who had initiated antiretroviral therapy. The primary outcome was an adjudicated T1MI event. Those who started direct-acting HCV antivirals were censored at the time of initiation. Crude incidence rates per 1000 person-years were calculated for T1MI by calendar time. Discrete time-to-event analyses with complementary log-log models were used to estimate adjusted hazard ratios and 95% CIs for T1MI among those with and without HCV. Among 23 361 PWH, 4677 (20%) had HCV. There were 89 (1.9%) T1MIs among PWH with HCV and 314 (1.7%) among PWH without HCV. HCV was not associated with increased T1MI risk in PWH (adjusted hazard ratio, 0.98 [95% CI, 0.74-1.30]). However, the risk of T1MI increased with age and was amplified in those with HCV (adjusted hazard ratio per 10-year increase in age, 1.85 [95% CI, 1.38-2.48]) compared with those without HCV (adjusted hazard ratio per 10-year increase in age,1.30 [95% CI, 1.13-1.50]; P<0.001, test of interaction). Conclusions HCV coinfection was not significantly associated with increased T1MI risk; however, the risk of T1MI with increasing age was greater in those with HCV compared with those without, and HCV status should be considered when assessing CVD risk in aging PWH.
Authors: Lang, Raynell; Silverberg, Michael J; Althoff, Keri N; et al.
J Am Heart Assoc. 2022 10 04;11(19):e026473. Epub 2022-09-21.
Analysis of Severe Illness After Postvaccination COVID-19 Breakthrough Among Adults With and Without HIV in the US
Understanding the severity of postvaccination SARS-CoV-2 (ie, COVID-19) breakthrough illness among people with HIV (PWH) can inform vaccine guidelines and risk-reduction recommendations. To estimate the rate and risk of severe breakthrough illness among vaccinated PWH and people without HIV (PWoH) who experience a breakthrough infection. In this cohort study, the Corona-Infectious-Virus Epidemiology Team (CIVET-II) collaboration included adults (aged ≥18 years) with HIV who were receiving care and were fully vaccinated by June 30, 2021, along with PWoH matched according to date fully vaccinated, age group, race, ethnicity, and sex from 4 US integrated health systems and academic centers. Those with postvaccination COVID-19 breakthrough before December 31, 2021, were eligible. HIV infection. The main outcome was severe COVID-19 breakthrough illness, defined as hospitalization within 28 days after a breakthrough SARS-CoV-2 infection with a primary or secondary COVID-19 discharge diagnosis. Discrete time proportional hazards models estimated adjusted hazard ratios (aHRs) and 95% CIs of severe breakthrough illness within 28 days of breakthrough COVID-19 by HIV status adjusting for demographic variables, COVID-19 vaccine type, and clinical factors. The proportion of patients who received mechanical ventilation or died was compared by HIV status. Among 3649 patients with breakthrough COVID-19 (1241 PWH and 2408 PWoH), most were aged 55 years or older (2182 patients [59.8%]) and male (3244 patients [88.9%]). The cumulative incidence of severe illness in the first 28 days was low and comparable between PWoH and PWH (7.3% vs 6.7%; risk difference, -0.67%; 95% CI, -2.58% to 1.23%). The risk of severe breakthrough illness was 59% higher in PWH with CD4 cell counts less than 350 cells/μL compared with PWoH (aHR, 1.59; 95% CI, 0.99 to 2.46; P = .049). In multivariable analyses among PWH, being female, older, having a cancer diagnosis, and lower CD4 cell count were associated with increased risk of severe breakthrough illness, whereas previous COVID-19 was associated with reduced risk. Among 249 hospitalized patients, 24 (9.6%) were mechanically ventilated and 20 (8.0%) died, with no difference by HIV status. In this cohort study, the risk of severe COVID-19 breakthrough illness within 28 days of a breakthrough infection was low among vaccinated PWH and PWoH. PWH with moderate or severe immune suppression had a higher risk of severe breakthrough infection and should be included in groups prioritized for additional vaccine doses and risk-reduction strategies.
Authors: Lang, Raynell; Silverberg, Michael J; Skarbinski, Jacek; Corona-Infectious-Virus Epidemiology Team (CIVETs) of the NA-ACORD of IeDEA,; et al.
JAMA Netw Open. 2022 10 03;5(10):e2236397. Epub 2022-10-03.
Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study
To estimate the effectiveness of mRNA vaccines against moderate and severe covid-19 in adults by time since second, third, or fourth doses, and by age and immunocompromised status. Test negative case-control study. Hospitals, emergency departments, and urgent care clinics in 10 US states, 17 January 2021 to 12 July 2022. 893 461 adults (≥18 years) admitted to one of 261 hospitals or to one of 272 emergency department or 119 urgent care centers for covid-like illness tested for SARS-CoV-2. The main outcome was waning of vaccine effectiveness with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine during the omicron and delta periods, and the period before delta was dominant using logistic regression conditioned on calendar week and geographic area while adjusting for age, race, ethnicity, local virus circulation, immunocompromised status, and likelihood of being vaccinated. 45 903 people admitted to hospital with covid-19 (cases) were compared with 213 103 people with covid-like illness who tested negative for SARS-CoV-2 (controls), and 103 287 people admitted to emergency department or urgent care with covid-19 (cases) were compared with 531 168 people with covid-like illness who tested negative for SARS-CoV-2. In the omicron period, vaccine effectiveness against covid-19 requiring admission to hospital was 89% (95% confidence interval 88% to 90%) within two months after dose 3 but waned to 66% (63% to 68%) by four to five months. Vaccine effectiveness of three doses against emergency department or urgent care visits was 83% (82% to 84%) initially but waned to 46% (44% to 49%) by four to five months. Waning was evident in all subgroups, including young adults and individuals who were not immunocompromised; although waning was morein people who were immunocompromised. Vaccine effectiveness increased among most groups after a fourth dose in whom this booster was recommended. Effectiveness of mRNA vaccines against moderate and severe covid-19 waned with time after vaccination. The findings support recommendations for a booster dose after a primary series and consideration of additional booster doses.
Authors: Ferdinands, Jill M; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; et al.
BMJ. 2022 10 03;379:e072141. Epub 2022-10-03.
Variation in Heart Failure Risk by HIV Severity and Sex in People With HIV Infection
HIV is an independent risk factor for heart failure (HF). However, the association of HIV severity with incident HF and the potential interaction with sex are incompletely understood. Integrated health care system. We conducted a cohort study of people with HIV (PWH) and matched people without HIV (PWoH), all aged ≥ 21 years and with no previous HF. Poisson regression was used to compare incident HF by HIV status, with PWH stratified by severity of HIV infection [defined by recent (<6 months) CD4 count, nadir CD4 count, or recent HIV RNA level]. Models were adjusted for sociodemographic characteristics, substance use, and HF risk factors. Analyses were conducted for men and women combined, then by sex. The study included 38,868 PWH and 386,569 PWoH (mean baseline age = 41.0 ± 10.8 years; 88% men). Compared with PWoH, incident HF risk was higher among PWH with lower recent CD4 [200-499 cells/µL, adjusted rate ratio (aRR) = 1.82, 95% confidence interval (CI) = 1.50 to 2.21 and <200 cells/µL, aRR = 3.26 (2.47 to 4.30)] and a low nadir CD4 [<200 cells/µL, aRR = 1.56 (1.37 to 1.79)] but not among PWH with normal CD4 [≥500 cells/µL, aRR = 1.14 (0.90 to 1.44)]. Higher incident HF risk was observed among PWH at all HIV RNA levels, with greater HF risk at higher HIV RNA levels. The excess HF risk associated with low CD4 (recent or nadir) and high HIV RNA was stronger among women than men (P interactions=0.05, 0.08, and 0.01, respectively). Given the association of HIV severity with HF, optimizing HIV treatment and management may be important for HF prevention among PWH.
Authors: Lam, Jennifer O; Ambrosy, Andrew P; Go, Alan S; Silverberg, Michael J; et al.
J Acquir Immune Defic Syndr. 2022 Oct 01;91(2):175-181.
Characterizing Unhealthy Alcohol Use Patterns and Their Association with Alcohol Use Reduction and Alcohol Use Disorder During Follow-Up in HIV Care
Outcomes of PWH with unhealthy alcohol use, such as alcohol use reduction or progression to AUD, are not well-known and may differ by baseline patterns of unhealthy alcohol use. Among 1299 PWH screening positive for NIAAA-defined unhealthy alcohol use in Kaiser Permanente Northern California, 2013-2017, we compared 2-year probabilities of reduction to low-risk/no alcohol use and rates of new AUD diagnoses by baseline use patterns, categorized as exceeding: only daily limits (72% of included PWH), only weekly limits (17%), or both (11%), based on NIAAA recommendations. Overall, 73.2% (95% CI 70.5-75.9%) of re-screened PWH reduced to low-risk/no alcohol use over 2 years, and there were 3.1 (95% CI 2.5-3.8%) new AUD diagnoses per 100 person-years. Compared with PWH only exceeding daily limits at baseline, those only exceeding weekly limits and those exceeding both limits were less likely to reduce and likelier to be diagnosed with AUD during follow-up. PWH exceeding weekly drinking limits, with or without exceeding daily limits, may have a potential need for targeted interventions to address unhealthy alcohol use.
Authors: Davy-Mendez, Thibaut; Sterling, Stacy A; Weisner, Constance M; Silverberg, Michael J; Satre, Derek D; et al.
AIDS Behav. 2022 Sep 28.
Mortality for adults entering HIV care under universal early treatment compared to the general US population
Mortality among adults with human immunodeficiency virus (HIV) remains elevated over those in the US general population, even in the years after entry into HIV care. We explore whether the elevation in 5-year mortality would have persisted if all adults with HIV had initiated antiretroviral therapy within 3 months of entering care. Among 82 766 adults entering HIV care at North American AIDS Cohort Collaboration clinical sites in the United States, we computed mortality over 5 years since entry into HIV care under observed treatment patterns. We then used inverse probability weights to estimate mortality under universal early treatment. To compare mortality with those for similar individuals in the general population, we used National Center for Health Statistics data to construct a cohort representing the subset of the US population matched to study participants on key characteristics. For the entire study period (1999-2017), the 5-year mortality among adults with HIV was 7.9% (95% confidence interval [CI]: 7.6%-8.2%) higher than expected based on the US general population. Under universal early treatment, the elevation in mortality for people with HIV would have been 7.2% (95% CI: 5.8%-8.6%). In the most recent calendar period examined (2011-2017), the elevation in mortality for people with HIV was 2.6% (95% CI: 2.0%-3.3%) under observed treatment patterns and 2.1% (.0%-4.2%) under universal early treatment. Expanding early treatment may modestly reduce, but not eliminate, the elevation in mortality for people with HIV.
Authors: Edwards, Jessie K; Silverberg, Michael J; Eron, Joseph J; et al.
Clin Infect Dis. 2022 Sep 14;75(5):867-874.
Estimation of COVID-19 mRNA Vaccine Effectiveness Against Medically Attended COVID-19 in Pregnancy During Periods of Delta and Omicron Variant Predominance in the United States
Pregnant people are at high risk for severe COVID-19 but were excluded from mRNA vaccine trials; data on COVID-19 vaccine effectiveness (VE) are needed. To evaluate the estimated effectiveness of mRNA vaccination against medically attended COVID-19 among pregnant people during Delta and Omicron predominance. This test-negative, case-control study was conducted from June 2021 to June 2022 in a network of 306 hospitals and 164 emergency department and urgent care (ED/UC) facilities across 10 US states, including 4517 ED/UC encounters and 975 hospitalizations among pregnant people with COVID-19-like illness (CLI) who underwent SARS-CoV-2 molecular testing. Two doses (14-149 and ≥150 days prior) and 3 doses (7-119 and ≥120 days prior) of COVID-19 mRNA vaccine (≥1 dose received during pregnancy) vs unvaccinated. Estimated VE against laboratory-confirmed COVID-19-associated ED/UC encounter or hospitalization, based on the adjusted odds ratio (aOR) for prior vaccination; VE was calculated as (1 - aOR) × 100%. Among 4517 eligible CLI-associated ED/UC encounters and 975 hospitalizations, 885 (19.6%) and 334 (34.3%) were SARS-CoV-2 positive, respectively; the median (IQR) patient age was 28 (24-32) years and 31 (26-35) years, 537 (12.0%) and 118 (12.0%) were non-Hispanic Black and 1189 (26.0%) and 240 (25.0%) were Hispanic. During Delta predominance, the estimated VE against COVID-19-associated ED/UC encounters was 84% (95% CI, 69% to 92%) for 2 doses within 14 to 149 days, 75% (95% CI, 5% to 93%) for 2 doses 150 or more days prior, and 81% (95% CI, 30% to 95%) for 3 doses 7 to 119 days prior; estimated VE against COVID-19-associated hospitalization was 99% (95% CI, 96% to 100%), 96% (95% CI, 86% to 99%), and 97% (95% CI, 79% to 100%), respectively. During Omicron predominance, for ED/UC encounters, the estimated VE of 2 doses within 14 to 149 days, 2 doses 150 or more days, 3 doses within 7 to 119 days, and 3 doses 120 or more days prior was 3% (95% CI, -49% to 37%), 42% (95% CI, -16% to 72%), 79% (95% CI, 59% to 89%), and -124% (95% CI, -414% to 2%), respectively; for hospitalization, estimated VE was 86% (95% CI, 41% to 97%), 64% (95% CI, -102% to 93%), 86% (95% CI, 28% to 97%), and -53% (95% CI, -1254% to 83%), respectively. In this study, maternal mRNA COVID-19 vaccination, including booster dose, was associated with protection against medically attended COVID-19. VE estimates were higher against COVID-19-associated hospitalization than ED/UC visits and lower against the Omicron variant than the Delta variant. Protection waned over time, particularly during Omicron predominance.
Authors: Schrag, Stephanie J; Zerbo, Ousseny; Klein, Nicola P; Fireman, Bruce; Naleway, Allison L; et al.
JAMA Netw Open. 2022 09 01;5(9):e2233273. Epub 2022-09-01.
Incidence of respiratory syncytial virus lower respiratory tract infections during the first 2 years of life: A prospective study across diverse global settings
The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175.
Authors: Langley, Joanne M; Klein, Nicola P; Cohen, Rachel A; et al.
J Infect Dis. 2022 Aug 26;226(3):374-385.
Discrimination And Calibration Of The Vacs Index 2.0 For Predicting Mortality Among People With Hiv In North America
The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)-specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age <50 or ≥50 years, race/ethnicity, HIV-1 RNA ≤500 or >500 copies/mL, CD4 count <350 or ≥350 cells/µL, and years 1999-2009 or 2010-2018. Because mortality rates have decreased over time, the final model was limited to 2010-2018. Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830-.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809-.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.
Authors: McGinnis, Kathleen A; Silverberg, Michael J; Veterans Aging Cohort Study,; et al.
Clin Infect Dis. 2022 Aug 25;75(2):297-304.
Risk of myocarditis and pericarditis following BNT162b2 and mRNA-1273 COVID-19 vaccination
Evidence indicates that mRNA COVID-19 vaccination is associated with risk of myocarditis and possibly pericarditis, especially in young males. It is not clear if risk differs between mRNA-1273 versus BNT162b2. We assessed if risk differs using comprehensive health records on a diverse population. Members 18-39 years of age at eight integrated healthcare-delivery systems were monitored using data updated weekly and supplemented with medical record review of myocarditis and pericarditis cases. Incidence of myocarditis and pericarditis events that occurred among vaccine recipients 0 to 7 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by conditional Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. Head-to-head comparison directly assessed risk following mRNA-1273 versus BNT162b2 during 0-7 days post-vaccination. From December 14, 2020 – January 15, 2022 there were 41 cases after 2,891,498 doses of BNT162b2 and 38 cases after 1,803,267 doses of mRNA-1273. Cases had similar demographic and clinical characteristics. Most were hospitalized for ≤1 day; none required intensive care. During days 0-7 after dose 2 of BNT162b2, the incidence was 14.3 (CI: 6.5-34.9) times higher than the comparison interval, amounting to 22.4 excess cases per million doses; after mRNA-1273 the incidence was 18.8 (CI: 6.7-64.9) times higher than the comparison interval, amounting to 31.2 excess cases per million doses. In head-to-head comparisons 0-7 days after either dose, risk was moderately higher after mRNA-1273 than after BNT162b2 (RR: 1.61, CI 1.02-2.54). Both vaccines were associated with increased risk of myocarditis and pericarditis in 18-39-year-olds. Risk estimates were modestly higher after mRNA-1273 than after BNT162b2.
Authors: Goddard, Kristin; Fireman, Bruce; Zerbo, Ousseny; Klein, Nicola P; et al.
Vaccine. 2022 Aug 19;40(35):5153-5159. Epub 2022-07-12.
Safety of COVID-19 Vaccination in US Children Ages 5-11 Years
Limited postauthorization safety data for the Pfizer-BioNTech coronavirus disease 2019 vaccination among children ages 5 to 11 years are available, particularly for the adverse event myocarditis, which has been detected in adolescents and young adults. We describe adverse events observed during the first 4 months of the United States coronavirus disease 2019 vaccination program in this age group. We analyzed data from 3 United States safety monitoring systems: v-safe, a voluntary smartphone-based system that monitors reactions and health effects; the Vaccine Adverse Events Reporting System (VAERS), the national spontaneous reporting system comanaged by the Centers for Disease Control and Prevention and Food and Drug Administration; and the Vaccine Safety Datalink, an active surveillance system that monitors electronic health records for prespecified events, including myocarditis. Among 48 795 children ages 5 to 11 years enrolled in v-safe, most reported reactions were mild-to-moderate, most frequently reported the day after vaccination, and were more common after dose 2. VAERS received 7578 adverse event reports; 97% were nonserious. On review of 194 serious VAERS reports, 15 myocarditis cases were verified; 8 occurred in boys after dose 2 (reporting rate 2.2 per million doses). In the Vaccine Safety Datalink, no safety signals were detected in weekly sequential monitoring after administration of 726 820 doses. Safety findings for Pfizer-BioNTech vaccine from 3 United States monitoring systems in children ages 5 to 11 years show that most reported adverse events were mild and no safety signals were observed in active surveillance. VAERS reporting rates of myocarditis after dose 2 in this age group were substantially lower than those observed among adolescents ages 12 to 15 years.
Authors: Hause, Anne M; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Shimabukuro, Tom T; et al.
Pediatrics. 2022 08 01;150(2).
Toward Ending the HIV Epidemic: Temporal Trends and Disparities in Early ART Initiation and Early Viral Suppression Among People Newly Entering HIV Care in the United States, 2012-2018
In 2012, the US Department of Health and Human Services updated their HIV treatment guidelines to recommend antiretroviral therapy (ART) for all people with HIV (PWH) regardless of CD4 count. We investigated recent trends and disparities in early receipt of ART prescription and subsequent viral suppression (VS). We examined data from ART-naïve PWH newly presenting to HIV care at 13 North American AIDS Cohort Collaboration on Research and Design clinical cohorts in the United States during 2012-2018. We calculated the cumulative incidence of early ART (within 30 days of entry into care) and early VS (within 6 months of ART initiation) using the Kaplan-Meier survival function. Discrete time-to-event models were fit to estimate unadjusted and adjusted associations of early ART and VS with sociodemographic and clinical factors. Among 11 853 eligible ART-naïve PWH, the cumulative incidence of early ART increased from 42% in 2012 to 82% in 2018. The cumulative incidence of early VS among the 8613 PWH who initiated ART increased from 83% in 2012 to 93% in 2018. In multivariable models, factors independently associated with delayed ART and VS included non-Hispanic/Latino Black race, residence in the South census region, being a male with injection drug use acquisition risk, and history of substance use disorder (SUD; all P ≤ .05). Early ART initiation and VS have substantially improved in the United States since the release of universal treatment guidelines. Disparities by factors related to social determinants of health and SUD demand focused attention on and services for some subpopulations.
Authors: Li, Jun; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS,; et al.
Open Forum Infect Dis. 2022 Aug;9(8):ofac336. Epub 2022-07-22.
Adults hospitalized with breakthrough COVID-19 have lower mortality than matched unvaccinated adults
Coronavirus disease 2019 (COVID-19) breakthrough infections are common. Evaluate in-hospital mortality of patients with COVID-19 by vaccination status using retrospective cohort study. We generated propensity scores for receipt of full vaccination in adults requiring supplemental oxygen hospitalized at Kaiser Permanente Northern California (1 April 2021 to 30 November 2021) with positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction tests. Optimal matching of fully vaccinated/unvaccinated patients was performed comparing in-hospital mortality. Of 7305 patients, 1463 (20.0%) were full, 138 (1.9%) were partial, and 5704 (78.1%) were unvaccinated. Fully vaccinated were older than partial or unvaccinated (71.0, 63.0, and 54.0 years, respectively, p < 0.001) with more comorbidities (Comorbidity Point Scores 33.0, 22.0, and 10.0, p < 0.001) and immunosuppressant (11.5%, 8.7%, and 3.0%, p < 0.001) or chemotherapy exposure (2.8%, 0.7%, and 0.4%, p < 0.001). Fewer fully vaccinated patients died compared to matched unvaccinated (9.0% vs. 16.3%, p < 0.0001). Fully vaccinated patients are less likely to die compared to matched unvaccinated patients.
Authors: Myers, Laura C; Kipnis, Patricia; Greene, John; Lawson, Brian; Escobar, Gabriel J; Fireman, Bruce H; Klein, Nicola P; Liu, Vincent X
J Intern Med. 2022 08;292(2):377-384. Epub 2022-05-17.
Effectiveness of 2, 3, and 4 COVID-19 mRNA Vaccine Doses Among Immunocompetent Adults During Periods when SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 Sublineages Predominated – VISION Network, 10 States, December 2021-June 2022
The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network† examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19-like illness§ diagnosis among 10 states during December 18, 2021-June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19-associated hospitalization 7-119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%-93%) and 85% (95% CI = 81%-89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%-76%) and 52% (95% CI = 44%-59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19-associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%-62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%-85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible.¶.
Authors: Link-Gelles, Ruth; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Tenforde, Mark W; et al.
MMWR Morb Mortal Wkly Rep. 2022 Jul 22;71(29):931-939. Epub 2022-07-22.
Safety of Live-Attenuated Vaccines in Children Exposed to Biologic Response Modifiers in Utero
Authors: Zerbo, Ousseny; Klein, Nicola P; et al.
Pediatrics. 2022 07 01;150(1).
SARS-CoV-2 testing and positivity among persons with and without HIV in 6 United States cohorts
It is not definitively known if persons with HIV (PWH) are more likely to be SARS-CoV-2 tested or test positive than persons without HIV (PWoH). We describe SARS-CoV-2 testing and positivity in 6 large geographically and demographically diverse cohorts of PWH and PWoH in the United States. The Corona Infectious Virus Epidemiology Team comprises 5 clinical cohorts within a health system (Kaiser Permanente Northern California, Oakland, CA; Kaiser Permanente Mid-Atlantic States, Rockville, MD; University of North Carolina Health, Chapel Hill, NC; Vanderbilt University Medical Center, Nashville, TN; and Veterans Aging Cohort Study) and 1 interval cohort (Multicenter AIDS Cohort Study/Women’s Interagency HIV Study Combined Cohort Study). We calculated the proportion of patients SARS-CoV-2 tested and the test positivity proportion by HIV status from March 1 to December 31, 2020. The cohorts ranged in size from 1675 to 31,304 PWH and 1430 to 3,742,604 PWoH. The proportion of PWH who were tested for SARS-CoV-2 (19.6%-40.5% across sites) was significantly higher than PWoH (14.8%-29.4%) in the clinical cohorts. However, among those tested, the proportion of patients with positive SARS-CoV-2 tests was comparable by HIV status; the difference in proportion of SARS-CoV-2 positivity ranged from 4.7% lower to 1.4% higher. Although PWH had higher testing proportions compared with PWoH, we did not find evidence of increased positivity in 6 large, diverse populations across the United States. Ongoing monitoring of testing, positivity, and COVID-19-related outcomes in PWH are needed, given availability, response, and durability of COVID-19 vaccines; emergence of SARS-CoV-2 variants; and latest therapeutic options.
Authors: Park, Lesley S; Silverberg, Michael J; Skarbinski, Jacek; Althoff, Keri N; et al.
J Acquir Immune Defic Syndr. 2022 07 01;90(3):249-255.
Hepatitis C coinfection and extrahepatic cancer incidence among people living with HIV
We assessed the incidence of extrahepatic cancer among people with HIV/HCV coinfection and the potential impact of direct-acting antivirals (DAAs) on extrahepatic cancer risk among people with HIV/HCV coinfection. Our study cohort included adults who initiated HIV care at a CNICS site in the US during 1995-2017, excluding those with previous cancer and without HCV testing. We used Cox regression to estimate hazard ratios for extrahepatic cancer incidence among patients with HIV/HCV coinfection compared with those with HIV monoinfection. Standardized morbidity ratio (SMR) weights were used to create a ‘pseudopopulation’ in which all patients were treated with antiretroviral therapy (ART), and to compare extrahepatic cancer incidence among patients with untreated HIV/HCV coinfection with the incidence that would have been observed if they had been successfully treated for HCV. Of 18 422 adults, 1775 (10%) had HCV RNA and 10 899 (59%) were on ART at baseline. Incidence rates of any extrahepatic cancer among patients with HIV/HCV coinfection and HIV monoinfection were 1027 and 771 per 100 000 person-years, respectively. In SMR-weighted analyses, the risk of any extrahepatic cancer among patients with untreated HCV coinfection at baseline was similar to the risk if they had been successfully treated for HCV. Patients with untreated HCV coinfection at baseline had higher incidence of kidney, lung and inflammation-related cancers than if their HCV had been successfully treated, but these associations were not statistically significant. We did not find evidence that treating HCV coinfection with DAAs would reduce the incidence of extrahepatic cancers among people with HIV receiving ART.
Authors: Willis, Sarah J; Silverberg, Michael J; Marcus, Julia L; et al.
HIV Med. 2022 07;23(6):620-628. Epub 2021-12-23.
Lessons from a mature acellular pertussis vaccination program and strategies to overcome suboptimal vaccine effectiveness
Despite high vaccination coverage among children and adolescents, pertussis remains a public health problem, with large outbreaks occurring periodically in the US and other developed countries. We examine lessons learned more than 20 years after implementation of programs which use only acellular pertussis vaccines and propose avenues for possible effective use of acellular pertussis vaccine to prevent large outbreaks. Acellular pertussis vaccines were introduced more than 20 years ago, yet the incidence of pertussis has been increasing over the past decade, with periodic large outbreaks marked by notable shifts in disease burden from infants and young children toward fully vaccinated adolescents and young adults. This age shift is mainly driven by the waning of vaccine immunity. To better protect adolescents against pertussis, modification of the current acellular pertussis vaccination schedule or adoption of new vaccination strategies should be considered. For infants not yet eligible to be vaccinated, maternal vaccination against pertussis during pregnancy is an effective way to protect infants from infection, severe disease and death. Implementation of maternal vaccination programs should be encouraged in countries without one or efforts to improve coverage should be supported in countries with existing program.
Authors: Zerbo, Ousseny; Fireman, Bruce; Klein, Nicola P
Expert Rev Vaccines. 2022 07;21(7):899-907. Epub 2021-10-08.
Sampling Validation Data to Achieve a Planned Precision of the Bias-Adjusted Estimate of Effect
Data collected from a validation substudy permit calculation of a bias-adjusted estimate of effect that is expected to equal the estimate that would have been observed had the gold standard measurement been available for the entire study population. In this paper, we develop and apply a framework for adaptive validation to determine when sufficient validation data have been collected to yield a bias-adjusted effect estimate with a prespecified level of precision. Prespecified levels of precision are decided a priori by the investigator, based on the precision of the conventional estimate and allowing for wider confidence intervals that would still be substantively meaningful. We further present an applied example of the use of this method to address exposure misclassification in a study of transmasculine/transfeminine youth and self-harm. Our method provides a novel approach to effective and efficient estimation of classification parameters as validation data accrue, with emphasis on the precision of the bias-adjusted estimate. This method can be applied within the context of any parent epidemiologic study design in which validation data will be collected and modified to meet alternative criteria given specific study or validation study objectives.
Authors: Collin, Lindsay J; MacLehose, Richard F; Ahern, Thomas P; Gradus, Jaimie L; Getahun, Darios; Silverberg, Michael J; Goodman, Michael; Lash, Timothy L
Am J Epidemiol. 2022 Jun 27;191(7):1290-1299.
Risk of severe clinical outcomes among persons with SARS-CoV-2 infection with differing levels of vaccination during widespread Omicron (B.1.1.529) and Delta (B.1.617.2) variant circulation in Northern California: A retrospective cohort study
The incidence of and risk factors for severe clinical outcomes with the Omicron (B.1.1.529) SARS-CoV-2 variant have not been well-defined. We conducted a retrospective cohort study to assess risks of severe clinical outcomes within 21 days after SARS-CoV-2 diagnosis in a large, diverse, integrated health system. Among 118,078 persons with incident SARS-CoV-2 infection, 48,101 (41%) were during the Omicron period and 69,977 (59%) during the Delta (B.1.617.2) period. Cumulative incidence of any hospitalization (2.4% versus 7.8%; adjusted hazard ratio [aHR] 0.55; 95% confidence interval [CI] (0.51-0.59), with low-flow oxygen support (1.6% versus 6.4%; aHR 0.46; CI 0.43-0.50), with high-flow oxygen support (0.6% versus 2.8%; aHR 0.47; CI 0.41-0.54), with invasive mechanical ventilation (0.1% versus 0.7%; aHR 0.43; CI 0.33-0.56), and death (0.2% versus 0.7%; aHR 0.54; CI 0.42-0.70) were lower in the Omicron than the Delta period. The risk of hospitalization was higher among unvaccinated persons (aHR 8.34; CI 7.25-9.60) and those who completed a primary COVID-19 vaccination series (aHR 1.72; CI 1.49-1.97) compared with those who completed a primary vaccination series and an additional dose. The strongest risk factors for all severe clinical outcomes were older age, higher body mass index and select comorbidities. Persons with SARS-CoV-2 infection were significantly less likely to develop severe clinical outcomes during the Omicron period compared with the Delta period. COVID-19 primary vaccination and additional doses were associated with reduced risk of severe clinical outcomes among those with SARS-CoV-2 infection. National Cancer Institute and The Permanente Medical Group.
Authors: Skarbinski, Jacek; Wood, Mariah S; Chervo, Tyler C; Schapiro, Jeffrey M; Elkin, Eric P; Valice, Emily; Amsden, Laura B; Hsiao, Crystal; Quesenberry, Charles; Corley, Douglas A; Kushi, Lawrence H
Lancet Reg Health Am. 2022 Jun 16:100297.
CD4/CD8 Ratio and Cancer Risk among Adults with HIV
Independent of CD4 cell count, a low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the United States and Canada. We examined all cancer-free PWH with 1 or more CD4/CD8 values from North American AIDS Cohort Collaboration on Research and Design observational cohorts with validated cancer diagnoses between 1998 and 2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines. Models were adjusted for age, sex, race and ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness. Among 83 893 PWH, there were 5628 incident cancers, including lung cancer (n = 755), Kaposi sarcoma (n = 501), non-Hodgkin lymphoma (n = 497), and anal cancer (n = 439). The median age at cohort entry was 43 years. The overall median 6-month lagged CD4/CD8 ratio was 0.52 (interquartile range = 0.30-0.82). Compared with a 6-month lagged CD4/CD8 of 0.80, a CD4/CD8 of 0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval = 1.14 to 1.35]). The CD4/CD8 ratio was also inversely associated with non-Hodgkin lymphoma, Kaposi sarcoma, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all 2-sided P < .05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values. A low CD4/CD8 ratio up to 24 months before cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.
Authors: Castilho, Jessica L; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA),; et al.
J Natl Cancer Inst. 2022 06 13;114(6):854-862.
Influenza Vaccination Among Pregnant Women: Self-report Compared With Vaccination Data From Electronic Health Records, 2018-2020 Influenza Seasons
Having accurate influenza vaccination coverage estimates can guide public health activities. The objectives of this study were to (1) validate the accuracy of electronic health record (EHR)-based influenza vaccination data among pregnant women compared with survey self-report and (2) assess whether survey respondents differed from survey nonrespondents by demographic characteristics and EHR-based vaccination status. This study was conducted in the Vaccine Safety Datalink, a network of 8 large medical care organizations in the United States. Using EHR data, we identified all women pregnant during the 2018-2019 or 2019-2020 influenza seasons. Surveys were conducted among samples of women who did and did not appear vaccinated for influenza according to EHR data. Separate surveys were conducted after each influenza season, and respondents reported their influenza vaccination status. Analyses accounted for the stratified design, sampling probability, and response probability. The survey response rate was 50.5% (630 of 1247) for 2018-2019 and 41.2% (721 of 1748) for 2019-2020. In multivariable analyses combining both survey years, non-Hispanic Black pregnant women had 3.80 (95% CI, 2.13-6.74) times the adjusted odds of survey nonresponse; odds of nonresponse were also higher for Hispanic pregnant women and women who had not received (per EHR data) influenza vaccine during current or prior influenza seasons. The sensitivity, specificity, and positive predictive value of EHR documentation of influenza vaccination compared with self-report were ≥92% for both survey years combined. The negative predictive value of EHR-based influenza vaccine status was 80.5% (95% CI, 76.7%-84.0%). EHR-based influenza vaccination data among pregnant women were generally concordant with self-report. New data sources and novel approaches to mitigating nonresponse bias may be needed to enhance influenza vaccination surveillance efforts.
Authors: Daley, Matthew F; Klein, Nicola P; Singleton, James A; et al.
Public Health Rep. 2022 Jun 08:333549221099932.
Multimorbidity Burden and Incident Heart Failure Among People With and Without HIV: The HIV-HEART Study
To examine the association between multimorbidity burden and incident heart failure (HF) among people with HIV (PWH) and people without HIV (PWoH). The HIV-HEART study is a retrospective cohort study that included adult PWH and PWoH aged 21 years or older at Kaiser Permanente between 2000 and 2016. Multimorbidity burden was defined by the baseline prevalence of 22 chronic conditions and was categorized as 0-1, 2-3, and 4 or more comorbidities on the basis of distribution of the overall population. People with HIV and PWoH were followed for a first HF event, all-cause death, or up to the end of follow-up on December 31, 2016. Using Cox proportional hazard regression, hazard ratios and 95% CIs were calculated to examine the association between multimorbidity burden and incident HF among PWH and PWoH, separately. The prevalences of 0-1, 2-3, and 4 or more comorbidities were 83.3%, 13.0%, and 3.7% in PWH (n=38,868), and 82.2%, 14.3%, and 3.5% in PWoH (n=386,586), respectively. After multivariable adjustment, compared with people with 0-1 comorbidities, the hazard ratios of incident HF associated with 2-3 and 4 or more comorbidities were 1.33 (95% CI, 1.04-1.71) and 2.41 (95% CI, 1.78-3.25) in PWH and 2.10 (95% CI, 1.92-2.29) and 4.09 (95% CI, 3.64-4.61) in PWoH, respectively. Multimorbidity was associated with a higher risk of incident HF among PWH and PWoH, with more prominent associations in PWoH and certain patient subgroups. The identification of specific multimorbidity patterns that contribute to higher HF risk in PWH may lead to future preventative strategies.
Authors: Mefford, Matthew T; Silverberg, Michael J; Leong, Thomas K; Hechter, Rulin C; Towner, William J; Go, Alan S; Horberg, Michael; Hu, Haihong; Harrison, Teresa N; Sung, Sue Hee; Reynolds, Kristi
Mayo Clin Proc Innov Qual Outcomes. 2022 Jun;6(3):218-227. Epub 2022-05-03.
Analysis of Postvaccination Breakthrough COVID-19 Infections Among Adults With HIV in the United States
Recommendations for additional doses of COVID-19 vaccines for people with HIV (PWH) are restricted to those with advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk after vaccination among PWH is essential for informing vaccination guidelines. To estimate the rate and risk of breakthrough infections among fully vaccinated PWH and people without HIV (PWoH) in the United States. This cohort study used the Corona-Infectious-Virus Epidemiology Team (CIVET)-II (of the North American AIDS Cohort Collaboration on Research and Design [NA-ACCORD], which is part of the International Epidemiology Databases to Evaluate AIDS [IeDEA]), collaboration of 4 prospective, electronic health record-based cohorts from integrated health systems and academic health centers. Adult PWH who were fully vaccinated prior to June 30, 2021, were matched with PWoH on date of full vaccination, age, race and ethnicity, and sex and followed up through December 31, 2021. HIV infection. COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after a patient was fully vaccinated. Among 113 994 patients (33 029 PWH and 80 965 PWoH), most were 55 years or older (80 017 [70%]) and male (104 967 [92%]); 47 098 (41%) were non-Hispanic Black, and 43 218 (38%) were non-Hispanic White. The rate of breakthrough infections was higher in PWH vs PWoH (55 [95% CI, 52-58] cases per 1000 person-years vs 43 [95% CI, 42-45] cases per 1000 person-years). Cumulative incidence of breakthroughs 9 months after full vaccination was low (3.8% [95% CI, 3.7%-3.9%]), albeit higher in PWH vs PWoH (4.4% vs 3.5%; log-rank P < .001; risk difference, 0.9% [95% CI, 0.6%-1.2%]) and within each vaccine type. Breakthrough infection risk was 28% higher in PWH vs PWoH (adjusted hazard ratio, 1.28 [95% CI, 1.19-1.37]). Among PWH, younger age (<45 y vs 45-54 y), history of COVID-19, and not receiving an additional dose (aHR, 0.71 [95% CI, 0.58-0.88]) were associated with increased risk of breakthrough infections. There was no association of breakthrough with HIV viral load suppression, but high CD4 count (ie, ≥500 cells/mm3) was associated with fewer breakthroughs among PWH. In this study, COVID-19 vaccination, especially with an additional dose, was effective against infection with SARS-CoV-2 strains circulating through December 31, 2021. PWH had an increased risk of breakthrough infections compared with PWoH. Expansion of recommendations for additional vaccine doses to all PWH should be considered.
Authors: Coburn, Sally B; Silverberg, Michael J; Skarbinski, Jacek; Corona-Infectious-Virus Epidemiology Team (CIVETs) of the NA-ACCORD of IeDEA,; et al.
JAMA Netw Open. 2022 Jun 01;5(6):e2215934. Epub 2022-06-01.
Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study
Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.
Authors: Trickey, Adam; Silverberg, Michael J; Sterne, Jonathan A C; et al.
Lancet HIV. 2022 06;9(6):e404-e413.
Myocarditis or Pericarditis Following mRNA COVID-19 Vaccination
Authors: Weintraub, Eric S; Oster, Matthew E; Klein, Nicola P
JAMA Netw Open. 2022 Jun 01;5(6):e2218512. Epub 2022-06-01.
Effect of Electronic and Mail Outreach From Primary Care Physicians for COVID-19 Vaccination of Black and Latino Older Adults: A Randomized Clinical Trial
COVID-19 morbidity is highest in Black and Latino older adults. These racial and ethnic groups initially had lower vaccination uptake than others, and rates in Black adults continue to lag. To evaluate the effect of outreach via electronic secure messages and mailings from primary care physicians (PCPs) on COVID-19 vaccination uptake among Black and Latino older adults and to compare the effects of culturally tailored and standard PCP messages. This randomized clinical trial was conducted from March 29 to May 20, 2021, with follow-up surveys through July 31, 2021. Latino and Black individuals aged 65 years and older from 4 Kaiser Permanente Northern California (KPNC) service areas were included. Data were analyzed from May 27, 2021, to September 28, 2021. Individuals who had not received COVID-19 vaccination after previous outreach were randomized to electronic secure message and/or mail outreach from their PCP, similar outreach with additional culturally tailored content, or usual care. Outreach groups were sent a secure message or letter in their PCP’s name, followed by a postcard to those still unvaccinated after 4 weeks. The primary outcome was time to receipt of COVID-19 vaccination during the 8 weeks after initial study outreach. KPNC data were supplemented with state data from external sources. Intervention effects were evaluated via proportional hazards regression. Of 8287 included individuals (mean [SD] age, 72.6 [7.0] years; 4665 [56.3%] women), 2434 (29.4%) were Black, 3782 (45.6%) were Latino and preferred English-language communications, and 2071 (25.0%) were Latino and preferred Spanish-language communications; 2847 participants (34.4%) had a neighborhood deprivation index at the 75th percentile or higher. A total of 2767 participants were randomized to culturally tailored PCP outreach, 2747 participants were randomized to standard PCP outreach, and 2773 participants were randomized to usual care. Culturally tailored PCP outreach led to higher COVID-19 vaccination rates during follow-up compared with usual care (664 participants [24.0%] vs 603 participants [21.7%]; adjusted hazard ratio (aHR), 1.22; 95% CI, 1.09-1.37), as did standard PCP outreach (635 participants [23.1%]; aHR, 1.17; 95% CI, 1.04-1.31). Individuals who were Black (aHR, 1.19; 95% CI, 1.06-1.33), had high neighborhood deprivation (aHR, 1.17; 95% CI, 1.03-1.33), and had medium to high comorbidity scores (aHR, 1.19; 95% CI, 1.09-1.31) were more likely to be vaccinated during follow-up. This randomized clinical trial found that PCP outreach using electronic and mailed messages increased COVID-19 vaccination rates among Black and Latino older adults. ClinicalTrials.gov Identifier: NCT05096026.
Authors: Lieu, Tracy A; Klein, Nicola P; Quesenberry, Charles P; Chen, Yi-Fen Irene; et al.
JAMA Netw Open. 2022 Jun 01;5(6):e2217004. Epub 2022-06-01.
Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies
Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation’s largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.
Authors: Figueiredo, Jane C; Kushi, Lawrence H; Corley, Douglas A; Skarbinski, Jacek; et al.
Open Forum Infect Dis. 2022 Jun;9(6):ofac171. Epub 2022-04-27.
Changes in incidence rates of outcomes of interest in vaccine safety studies during the COVID-19 pandemic
The COVID-19 pandemic caused an abrupt drop in in-person health care (inpatient, Emergency Department, outpatient) and an increase in telehealth care, which poses challenges in vaccine safety studies that identify outcomes from in-person encounters. We examined the changes in incidence rates of selected encounter-based outcomes during the COVID-19 pandemic. We assembled a cohort of members from 8 Vaccine Safety Datalink sites from January 1, 2017 through December 31, 2020. Using ICD-10 diagnosis codes or laboratory criteria, we identified 21 incident outcomes in traditional in-person settings and all settings. We defined 4 periods in 2020: January-February (pre-pandemic), April-June (early pandemic), July-September (middle pandemic), and October-December (late pandemic). We defined four corresponding periods in each year during 2017-2019. We calculated incidence rates, conducted difference in difference (DiD) analyses, and reported ratios of incidence rate ratios (RRR) to examine changes in rates from pre-pandemic to early, middle, and late pandemic in 2020, after adjusting for changes across similar periods in 2017-2019. Among > 10 million members, regardless of setting and after adjusting for changes during 2017-2019, we found that incidence rates of acute disseminated encephalomyelitis, encephalitis/myelitis/encephalomyelitis/meningoencephalitis, and thrombotic thrombocytopenic purpura did not significantly change from the pre-pandemic to early, middle or late pandemic periods (p-values ≥ 0.05). Incidence rates decreased from the pre-pandemic to early pandemic period during 2020 for acute myocardial infarction, anaphylaxis, appendicitis, Bell’s palsy, convulsions/seizures, Guillain-Barré syndrome, immune thrombocytopenia (ITP), narcolepsy/cataplexy, hemorrhagic stroke, ischemic stroke, and venous thromboembolism (p-values < 0.05). Incidence rates of Bell's palsy, ITP, and narcolepsy/cataplexy were higher in all settings than in traditional in-person settings during the three pandemic periods (p-values < 0.05). Rates of some clinical outcomes during the pandemic changed and should not be used as historical background rates in vaccine safety studies. Inclusion of telehealth visits should be considered for vaccine studies involving Bell's palsy, ITP, and narcolepsy/cataplexy.
Authors: Xu, Stanley; Zerbo, Ousseny; Qian, Lei; et al.
Vaccine. 2022 05 20;40(23):3150-3158. Epub 2022-04-18.
Safety and Efficacy of a Third Dose of BNT162b2 Covid-19 Vaccine
Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older. In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-μg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose. A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3). A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.).
Authors: Moreira, Edson D; Klein, Nicola P; C4591031 Clinical Trial Group,; et al.
N Engl J Med. 2022 05 19;386(20):1910-1921. Epub 2022-03-23.
Safety of measles and pertussis-containing vaccines in children with autism spectrum disorders
To determine whether children aged 4-7 years with a diagnosis of autism spectrum disorders (ASD) were at increased risk of fever, febrile seizures, or emergency department (ED) visits following measles- or pertussis-containing vaccines compared with children without ASD. The study included children born between 1995-2012, aged 4-7 years at vaccination, and members of six healthcare delivery systems within Vaccine Safety Datalink. We conducted self-controlled risk interval analyses comparing rates of outcomes in risk and control intervals within each group defined by ASD status, and then compared outcome rates between children with and without ASD, in risk and control intervals, by estimating difference-in-differences using logistic regressions. The study included 14,947 children with ASD and 1,650,041 children without ASD. After measles- or pertussis-containing vaccination, there were no differences in association between children with and without ASD for fever (ratio of rate ratio for measles-containing vaccine = 1.07, 95% CI 0.58-1.96; for pertussis-containing vaccine = 1.16, 95% CI 0.63-2.15) or ED visits (ratio of rate ratio for measles-containing vaccine = 1.11, 95% CI 0.80-1.54; for pertussis-containing vaccine = 0.87, 95% CI 0.59-1.28). Febrile seizures were rare. Pertussis-containing vaccines were associated with small increased risk of febrile seizures in children without ASD. Children with ASD were not at increased risk for fever or ED visits compared with children without ASD following measles- or pertussis-containing vaccines. These results may provide further reassurance that these vaccines are safe for all children, including those with ASD.
Authors: Zerbo, Ousseny; Fireman, Bruce; Klein, Nicola P; et al.
Vaccine. 2022 04 20;40(18):2568-2573. Epub 2022-03-18.
Weight gain post-ART in HIV+ Latinos/as differs in the USA, Haiti, and Latin America
An obesity epidemic has been documented among adult Latinos/as in Latin America and the United States (US); however, little is known about obesity among Latinos/as with HIV (PWH). Moreover, Latinos/as PWH in the US may have different weight trajectories than those in Latin America due to the cultural and environmental contexts. We assessed weight and body mass index (BMI) trajectories among PWH initiating antiretroviral therapy (ART) across 5 countries in Latin America and the Caribbean and the US. ART-naÿve PWH ≥18 years old, enrolled in Brazil, Honduras, Mexico, Peru, and Haiti (sites within CCA-SAnet) and the US (NA-ACCORD) starting ART between 2000 and 2017, with at least one weight measured after ART initiation were included. Participants were classified according to site/ethnicity as: Latinos/as in US, non-Latinos/as in US, Haitians, and Latinos/as in Latin America. Generalized least squares models were used to assess trends in weight and BMI. Models estimating probabilities of becoming overweight/obese (BMI ≥25 kg/m2) and of becoming obese (BMI ≥30 kg/m2) post ART initiation for males and females were fit using generalized estimating equations with a logit link and an independence working correlation structure. Among 59,207 PWH, 9% were Latinos/as from Latin America, 9% Latinos/as from the US, 68% non-Latinos/as from the US and 14% were Haitian. At ART initiation, 29% were overweight and 14% were obese. Post-ART weight and BMI increases were steeper for Latinos/as in Latin America compared with other sites/ethnicities; however, BMI at 3-years post ART remained lower compared to Latinos/as and non-Latinos/as in the US. Among females, at 3-years post ART initiation the greatest adjusted probability of obesity was found among non-Latinas in the US (15·2%) and lowest among Latinas in Latin America (8.6%). Among males, while starting with a lower BMI, Latinos in Latin America had the greatest adjusted probability of becoming overweight or obese 3-years post-ART initiation. In the Americas, PWH gain substantial weight after ART initiation. Despite environmental and cultural differences, PWH in Latin America, Haiti and Latinos and non-Latinos in the US share similar BMI trajectories on ART and high probabilities of becoming overweight and obese over time. Multicohort studies are needed to better understand the burden of other metabolic syndrome components in PWH across different countries.
Authors: Coelho, Lara E; Silverberg, Michael J; Rebeiro, Peter F; et al.
Lancet Reg Health Am. 2022 Apr;8. Epub 2022-01-05.
Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink
Postauthorization monitoring of vaccines in a large population may detect rare adverse events not identified in clinical trials such as Guillain-Barré syndrome (GBS), which has a background rate of 1 to 2 per 100 000 person-years. To describe cases and incidence of GBS following COVID-19 vaccination and assess the risk of GBS after vaccination for Ad.26.COV2.S (Janssen) and mRNA vaccines. This cohort study used surveillance data from the Vaccine Safety Datalink at 8 participating integrated health care systems in the United States. There were 10 158 003 participants aged at least 12 years. Data analysis was performed from November 2021 to February 2022. Ad.26.COV2.S, BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccine, including mRNA vaccine doses 1 and 2, December 13, 2020, to November 13, 2021. GBS with symptom onset in the 1 to 84 days after vaccination, confirmed by medical record review and adjudication. Descriptive characteristics of confirmed cases, GBS incidence rates during postvaccination risk intervals after each type of vaccine compared with the background rate, rate ratios (RRs) comparing GBS incidence in the 1 to 21 vs 22 to 42 days postvaccination, and RRs directly comparing risk of GBS after Ad.26.COV2.S vs mRNA vaccination, using Poisson regression adjusted for age, sex, race and ethnicity, site, and calendar day. From December 13, 2020, through November 13, 2021, 15 120 073 doses of COVID-19 vaccines were administered to 7 894 989 individuals (mean [SE] age, 46.5 [0.02] years; 8 138 318 doses received [53.8%] by female individuals; 3 671 199 doses received [24.3%] by Hispanic or Latino individuals, 2 215 064 doses received [14.7%] by Asian individuals, 6 266 424 doses received [41.4%] by White individuals), including 483 053 Ad.26.COV2.S doses, 8 806 595 BNT162b2 doses, and 5 830 425 mRNA-1273 doses. Eleven cases of GBS after Ad.26.COV2.S were confirmed. The unadjusted incidence rate of GBS per 100 000 person-years in the 1 to 21 days after Ad.26.COV2.S was 32.4 (95% CI, 14.8-61.5), significantly higher than the background rate, and the adjusted RR in the 1 to 21 vs 22 to 42 days following Ad.26.COV2.S was 6.03 (95% CI, 0.79-147.79). Thirty-six cases of GBS after mRNA vaccines were confirmed. The unadjusted incidence rate per 100 000 person-years in the 1 to 21 days after mRNA vaccines was 1.3 (95% CI, 0.7-2.4) and the adjusted RR in the 1 to 21 vs 22 to 42 days following mRNA vaccines was 0.56 (95% CI, 0.21-1.48). In a head-to-head comparison of Ad.26.COV2.S vs mRNA vaccines, the adjusted RR was 20.56 (95% CI, 6.94-64.66). In this cohort study of COVID-19 vaccines, the incidence of GBS was elevated after receiving the Ad.26.COV2.S vaccine. Surveillance is ongoing.
Authors: Hanson, Kayla E; Fireman, Bruce; Klein, Nicola P; et al.
JAMA Netw Open. 2022 Apr 01;5(4):e228879. Epub 2022-04-01.
Changes in Cervical Cytology Results and Human Papillomavirus Types Among Persons Screened for Cervical Cancer, 2007 and 2015-2017
Since 2006, the US human papillomavirus (HPV) vaccination program has led to decreases in HPV infections caused by high-risk vaccine-targeted HPV types (HPV 16/18). We assessed differences in high-risk HPV prevalence by cervical cytology result among 20- to 24-year-old persons participating in routine cervical cancer screening in 2015-2017 compared with 2007. Residual routine cervical cancer screening specimens were collected from 20- to 24-year-old members of 2 integrated healthcare delivery systems as part of a cross-sectional study and were tested for 37 HPV types. Cytology results and vaccination status (≥1 dose) were extracted from medical records. Cytology categories were normal, atypical squamous cells of undefined significance, low-grade squamous intraepithelial lesions (SIL), or high-grade SIL/atypical squamous cells cannot exclude high-grade SIL. Prevalences of HPV categories (HPV 16/18, HPV 31/33/45/52/58, HPV 35/39/51/56/59/66/68) were estimated by cytology result for 2007 and 2015-2017. Specimens from 2007 (n = 4046) were from unvaccinated participants; 4574 of 8442 specimens (54.2%) from 2015-2017 were from vaccinated participants. Overall, HPV 16/18 positivity was lower in 2015-2017 compared with 2007 in all groups: high-grade SIL/atypical squamous cells cannot exclude high-grade SIL, 16.0% vs 69.2%; low-grade SIL, 5.4% vs 40.1%; atypical squamous cells of undefined significance, 5.0% vs 25.6%; and normal, 1.3% vs 8.1%. Human papillomavirus 31/33/45/52/58 prevalence was stable for all cytology groups; HPV 35/39/51/56/59/66/68 prevalence increased among low-grade SIL specimens (53.9% to 65.2%) but remained stable in other groups. Prevalence of vaccine-targeted high-risk HPV types 16/18 was dramatically lower in 2015-2017 than 2007 across all cytology result groups while prevalence of other high-risk HPV types was mainly stable, supporting vaccine impact with no evidence of type replacement.
Authors: Lewis, Rayleen M; Klein, Nicola P; Markowitz, Lauri E; et al.
J Low Genit Tract Dis. 2022 Apr 01;26(2):135-139.
Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S (Janssen [Johnson & Johnson]) Vaccine Dose Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults – VISION Network, 10 States, December 2021-March 2022
CDC recommends that all persons aged ≥18 years receive a single COVID-19 vaccine booster dose ≥2 months after receipt of an Ad.26.COV2.S (Janssen [Johnson & Johnson]) adenovirus vector-based primary series vaccine; a heterologous COVID-19 mRNA vaccine is preferred over a homologous (matching) Janssen vaccine for booster vaccination. This recommendation was made in light of the risks for rare but serious adverse events following receipt of a Janssen vaccine, including thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome† (1), and clinical trial data indicating similar or higher neutralizing antibody response following heterologous boosting compared with homologous boosting (2). Data on real-world vaccine effectiveness (VE) of different booster strategies following a primary Janssen vaccine dose are limited, particularly during the period of Omicron variant predominance. The VISION Network§ determined real-world VE of 1 Janssen vaccine dose and 2 alternative booster dose strategies: 1) a homologous booster (i.e., 2 Janssen doses) and 2) a heterologous mRNA booster (i.e., 1 Janssen dose/1 mRNA dose). In addition, VE of these booster strategies was compared with VE of a homologous booster following mRNA primary series vaccination (i.e., 3 mRNA doses). The study examined 80,287 emergency department/urgent care (ED/UC) visits¶ and 25,244 hospitalizations across 10 states during December 16, 2021-March 7, 2022, when Omicron was the predominant circulating variant.** VE against laboratory-confirmed COVID-19-associated ED/UC encounters was 24% after 1 Janssen dose, 54% after 2 Janssen doses, 79% after 1 Janssen/1 mRNA dose, and 83% after 3 mRNA doses. VE for the same vaccination strategies against laboratory-confirmed COVID-19-associated hospitalizations were 31%, 67%, 78%, and 90%, respectively. All booster strategies provided higher protection than a single Janssen dose against ED/UC visits and hospitalizations during Omicron variant predominance. Vaccination with 1 Janssen/1 mRNA dose provided higher protection than did 2 Janssen doses against COVID-19-associated ED/UC visits and was comparable to protection provided by 3 mRNA doses during the first 120 days after a booster dose. However, 3 mRNA doses provided higher protection against COVID-19-associated hospitalizations than did other booster strategies during the same time interval since booster dose. All adults who have received mRNA vaccines for their COVID-19 primary series vaccination should receive an mRNA booster dose when eligible. Adults who received a primary Janssen vaccine dose should preferentially receive a heterologous mRNA vaccine booster dose ≥2 months later, or a homologous Janssen vaccine booster dose if mRNA vaccine is contraindicated or unavailable. Further investigation of the durability of protection afforded by different booster strategies is warranted.
Authors: Natarajan, Karthik; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Dixon, Brian E; et al.
MMWR Morb Mortal Wkly Rep. 2022 Apr 01;71(13):495-502. Epub 2022-04-01.
Development and Validation of a Model for Prediction of End-Stage Liver Disease in People With HIV
End-stage liver disease (ESLD) is a leading cause of non-AIDS-related death among people with HIV (PWH). Factors that increase the progression of liver disease include comorbidities and HIV-specific factors, but we currently lack a tool to apply this evidence into clinical practice. We developed and validated a risk prediction model for ESLD among PWH who received care in 12 cohorts of the North American AIDS Cohort Collaboration on Research and Design between 2000 and 2016 and had fibrosis-4 index > 1.45. The first occurrence of ascites, variceal bleed, spontaneous bacterial peritonitis, or hepatic encephalopathy was verified by standardized medical record review. The Bayesian model averaging was used to select predictors among biomarkers and diagnoses and the Harrell C statistic to assess model discrimination. Among 13,787 PWH in the training set, 82% were men and 54% were Black with a mean age of 48 years. Three hundred ninety ESLD events occurred over a mean 5.4 years. Among the ESLD cases, 52% had hepatitis C virus, 15% hepatitis B virus, and 31% alcohol use disorder. Twelve factors together predicted ESLD risk moderately well (C statistic 0.79, 95% confidence interval: 0.76 to 0.81): age, sex, race/ethnicity, chronic hepatitis B or C, and routinely collected laboratory values reflecting hepatic impairment (serum albumin, aspartate aminotransferase, total bilirubin, and platelets) and lipid metabolism (triglycerides, high-density lipoprotein, and total cholesterol). Our model performed well in the test set (C statistic 0.81, 95% confidence interval: 0.76 to 0.86). This model of readily accessible clinical parameters predicted ESLD in a large diverse population of PWH.
Authors: Kim, H Nina; Silverberg, Michael J; Kitahata, Mari M; et al.
J Acquir Immune Defic Syndr. 2022 04 01;89(4):396-404.
Added Benefit of Covid-19 Vaccination after Previous Infection
Authors: Klein, Nicola P
N Engl J Med. 2022 03 31;386(13):1278-1279.
Is There a Link Between Hormone Use and Diabetes Incidence in Transgender People? Data from the STRONG Cohort
Risk of type 2 diabetes mellitus (T2DM) in transgender and gender diverse (TGD) persons, especially those receiving gender-affirming hormone therapy (GAHT) is an area of clinical and research importance. We used data from an electronic health record-based cohort study of persons 18 years and older enrolled in 3 integrated health care systems. The cohort included 2869 transfeminine members matched to 28 300 cisgender women and 28 258 cisgender men on age, race/ethnicity, calendar year, and site, and 2133 transmasculine members similarly matched to 20 997 cisgender women and 20 964 cisgender men. Cohort ascertainment spanned 9 years from 2006 through 2014 and follow-up extended through 2016. Data on T2DM incidence and prevalence were analyzed using Cox proportional hazards and logistic regression models, respectively. All analyses controlled for body mass index. Both prevalent and incident T2DM was more common in the transfeminine cohort relative to cisgender female referents with odds ratio and hazard ratio (95% CI) estimates of 1.3 (1.1-1.5) and 1.4 (1.1-1.8), respectively. No significant differences in prevalence or incidence of T2DM were observed across the remaining comparison groups, both overall and in TGD persons with evidence of GAHT receipt. Although transfeminine people may be at higher risk for T2DM compared with cisgender females, the corresponding difference relative to cisgender males is not discernable. Moreover, there is little evidence that T2DM occurrence in either transfeminine or transmasculine persons is attributable to GAHT use.
Authors: Islam, Noreen; Silverberg, Michael J; Goodman, Michael; et al.
J Clin Endocrinol Metab. 2022 03 24;107(4):e1549-e1557.
Comparative Outcomes for Mature T and NK/T-cell Lymphomas in People with and without HIV and to AIDS-Defining Lymphomas
There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt’s lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin’s lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt’s (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade.
Authors: Koh, Min Jung; Silverberg, Michael J; Jain, Salvia; et al.
Blood Adv. 2022 03 08;6(5):1420-1431.
Effectiveness of COVID-19 Pfizer-BioNTech BNT162b2 mRNA Vaccination in Preventing COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Nonimmunocompromised Children and Adolescents Aged 5-17 Years – VISION Network, 10 States, April 2021-January 2022
The efficacy of the BNT162b2 (Pfizer-BioNTech) vaccine against laboratory-confirmed COVID-19 exceeded 90% in clinical trials that included children and adolescents aged 5-11, 12-15, and 16-17 years (1-3). Limited real-world data on 2-dose mRNA vaccine effectiveness (VE) in persons aged 12-17 years (referred to as adolescents in this report) have also indicated high levels of protection against SARS-CoV-2 (the virus that causes COVID-19) infection and COVID-19-associated hospitalization (4-6); however, data on VE against the SARS-CoV-2 B.1.1.529 (Omicron) variant and duration of protection are limited. Pfizer-BioNTech VE data are not available for children aged 5-11 years. In partnership with CDC, the VISION Network* examined 39,217 emergency department (ED) and urgent care (UC) encounters and 1,699 hospitalizations† among persons aged 5-17 years with COVID-19-like illness across 10 states during April 9, 2021-January 29, 2022,§ to estimate VE using a case-control test-negative design. Among children aged 5-11 years, VE against laboratory-confirmed COVID-19-associated ED and UC encounters 14-67 days after dose 2 (the longest interval after dose 2 in this age group) was 46%. Among adolescents aged 12-15 and 16-17 years, VE 14-149 days after dose 2 was 83% and 76%, respectively; VE ≥150 days after dose 2 was 38% and 46%, respectively. Among adolescents aged 16-17 years, VE increased to 86% ≥7 days after dose 3 (booster dose). VE against COVID-19-associated ED and UC encounters was substantially lower during the Omicron predominant period than the B.1.617.2 (Delta) predominant period among adolescents aged 12-17 years, with no significant protection ≥150 days after dose 2 during Omicron predominance. However, in adolescents aged 16-17 years, VE during the Omicron predominant period increased to 81% ≥7 days after a third booster dose. During the full study period, including pre-Delta, Delta, and Omicron predominant periods, VE against laboratory-confirmed COVID-19-associated hospitalization among children aged 5-11 years was 74% 14-67 days after dose 2, with wide CIs that included zero. Among adolescents aged 12-15 and 16-17 years, VE 14-149 days after dose 2 was 92% and 94%, respectively; VE ≥150 days after dose 2 was 73% and 88%, respectively. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations, including a booster dose for those aged 12-17 years.
Authors: Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Verani, Jennifer R; et al.
MMWR Morb Mortal Wkly Rep. 2022 Mar 04;71(9):352-358. Epub 2022-03-04.
Comparison of dementia incidence and prevalence between individuals with and without HIV infection in primary care from 2000 to 2016
To compare dementia incidence and prevalence after age 50 years by HIV status. Observational cohort, 2000-2016. People with HIV (PWH) on antiretroviral therapy (ART) and demographically similar people without HIV (PWoH), all aged 50 years and older, were identified from Kaiser Permanente healthcare systems in Northern California, Southern California, and Mid-Atlantic States (Maryland, Virginia, Washington DC). Dementia diagnoses were obtained from electronic health records. Incidence and prevalence of dementia, overall and by time period (i.e. 2000-2002, 2003-2004, …, 2015-2016), were calculated using Poisson regression. Trends were examined using Joinpoint regression. Rate ratios were used to compare dementia by HIV status with adjustment for sociodemographics, substance use, and clinical factors. The study included 13 296 PWH and 155 354 PWoH (at baseline: for both, mean age = 54 years, 89% men; for PWH, 80% with HIV RNA <200 copies/ml). From 2000 to 2016, overall incidence of dementia was higher among PWH [adjusted incidence rate ratio (aIRR) = 1.80, 95% confidence interval (CI) = 1.60-2.04]. Dementia incidence decreased among both PWH and PWoH (-8.0 and -3.1% per period, respectively) but remained higher among PWH in the most recent time period, 2015-2016 (aIRR = 1.58, 95% CI = 1.18-2.12). The overall prevalence of dementia from 2000 to 2016 was higher among PWH [adjusted prevalence ratio (aPR) = 1.86, 95% CI = 1.70-2.04] and was also higher among PWH in 2015-2016 (aPR = 1.75, 95% CI = 1.56-1.97). Reductions in dementia incidence are encouraging and may reflect ART improvement, but PWH are still more likely to have dementia than PWoH. Monitoring the burden of dementia among PWH is important as this population ages.
Authors: Lam, Jennifer O; Lee, Catherine; Gilsanz, Paola; Hou, Craig E; Leyden, Wendy A; Satre, Derek D; Flamm, Jason A; Towner, William J; Horberg, Michael A; Silverberg, Michael J
AIDS. 2022 03 01;36(3):437-445.
Observed CD4 counts at entry into HIV care and at antiretroviral therapy prescription by age in the USA, 2004-18: a cohort study
Adults aged 50 years or older comprise a majority of people with HIV in the USA. Our objective was to describe observed differences by age in CD4 count at entry into HIV care, timing of antiretroviral therapy (ART) prescription, and CD4 count at time of ART prescription before (2004-11) and during (2012-18) the current era of universal treatment. For this descriptive study, we calculated median (IQR) CD4 count at entry into care, days from entry into care to ART prescription, and CD4 count at time of ART prescription among patients enrolled in US-based clinical cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD; see appendix). We excluded participants with no CD4 count recorded at entry into care, medical records that suggested previous ART use, or previous AIDS diagnosis. All calculations were stratified by age (≥50 and 18-50 years) and calendar year. Of 35 293 ART-naive adult participants entering care between Jan 1, 2004 and Dec 31, 2018, 5794 (16%) were women and 29 499 (84%) were men; 15817 (45%) were Black, 11566 (33%) were White, 5538 (16%) were Hispanic (any race), 737 (2%) were Asian or Pacific Islander, 152 (0.4%) were Indigenous, and 98 (0.3%) were multiracial. Median age at entry into care was 39 years (IQR 29-49); 8004 (23%) were aged 50 years or older. Of 29 141 participants initially prescribed ART, 7274 (25%) were aged 50 years or older. From 2004 to 2018, median CD4 count at entry into care increased from 228 cells per µL (IQR 80-422) to 295 cells per µL (134-489) among adults aged 50 years and older, and from 297 cells per µL (119-480) to 378 cells per µL (202-564) among adults younger than 50 years. Median days from entry into care to ART prescription declined from 56 (IQR 17-658) to 6 (0-15) among adults older than 50 years, and from 61 (17-509) to 6 (0-16) among adults younger than 50 years. Median CD4 count at time of ART prescription increased from 139 cells per µL (IQR 59-257) to 311 cells per µL (137-504) among adults aged 50 years or older, and from 166 cells per µL (49-287) to 377 cells per µL (198-564) among adults younger than 50 years. Before the release of universal treatment guidelines by the US Department of Health and Human Services in 2012, median time to ART prescription was already falling, leading to increases in median CD4 count at ART prescription for both age groups; both measures continued to improve in the treat-all era. However, median CD4 counts, both at entry into care and at ART prescription, among adults aged 50 years and older were lower than those of adults younger than 50 years throughout the study period. Furthermore, even into the treat-all era, over half of adults aged 50 years and older entered care with CD4 counts of less than 350 cells per µL, potentially because of factors including immunosenescence, delayed HIV diagnosis, and late presentation to care. Given that age-related immunological changes might not be fully avoidable, targeted strategies for increasing HIV risk awareness, routine testing, and immediate linkage to HIV care at diagnosis are particularly essential for this population. US National Institutes of Health grant U01AI069918.
Authors: Lee, Jennifer S; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD),; et al.
Lancet HIV. 2022 03;9 Suppl 1:S2.
Incidence and Estimated Vaccine Effectiveness Against Hospitalizations for All-Cause Pneumonia Among Older US Adults Who Were Vaccinated and Not Vaccinated With 13-Valent Pneumococcal Conjugate Vaccine
Following routine use of 13-valent pneumococcal conjugate vaccine (PCV13) in children in 2010, invasive pneumococcal disease rates have decreased substantially in children and adults. In 2014, the Advisory Committee for Immunization Practices recommended routine use of PCV13 among adults aged 65 years or older; previously only 23-valent pneumococcal polysaccharide vaccine (PPV23) was recommended. To estimate the association between the incidence of hospitalized all-cause pneumonia and lower respiratory tract infections (LRTI) and PCV13 vaccination among older adults at Kaiser Permanente Northern California (KPNC). This retrospective cohort study included adults at KPNC aged 65 years or older between July 1, 2015, and June 30, 2018, born after 1936 with no known history of PPV23 or PCV13 receipt before age 65. The study took place at an integrated health care system with an annual membership more than 4 million individuals, approximately 15% of whom are 65 years or older and broadly representative of the region. Data analysis took place from July 2018 to December 2021, and data collection took place from November 2016 to June 2018. PCV13 vaccination status was ascertained from the electronic medical record (EMR). Individuals were considered vaccinated 14 days following immunization. First hospitalized all-cause pneumonia was identified in the EMR using primary/secondary discharge diagnosis International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. First hospitalized LRTI was identified using pneumonia codes and acute bronchitis codes. Relative risk (RR) of first pneumonia or LRTI hospitalization of individuals who were PCV13 vaccinated vs PCV13 unvaccinated was estimated using Poisson regressions adjusted for sex, race, ethnicity, age, influenza vaccine receipt, PPV23 receipt since age 65, pneumonia risk factors, health care use, and season. Vaccine effectiveness (VE) was estimated as (1-RR) × 100%. Of 192 061 adults, 107 957 (56%) were female and 139 024 (72%) were White individuals. PCV13 coverage increased from 0 in 2014 to 135 608 (76.9%) by 2018. There were 3488 individuals with 3766 pneumonia hospitalizations and 3846 individuals with 4173 LRTI hospitalizations. PCV13 was associated with an adjusted VE of 10.0% (95% CI, 2.4-17.0; P = .01) against hospitalized pneumonia and 9.4% (95% CI, 2.1-16.1; P = .01) against hospitalized LRTI. In the context of a robust pediatric PCV13 immunization program, PCV13 vaccination of adults aged 65 years or older was associated with significant reductions in hospitalizations for all-cause pneumonia and LRTI. Vaccinating older adults with PCVs may provide broader public health benefit against pneumonia hospitalizations.
Authors: Hsiao, Amber; Hansen, John; Timbol, Julius; Lewis, Ned; Isturiz, Raul; Alexander-Parrish, Ronika; McLaughlin, John M; Gessner, Bradford D; Klein, Nicola P
JAMA Netw Open. 2022 03 01;5(3):e221111. Epub 2022-03-01.
Human Immunodeficiency Virus Infection and Variation in Heart Failure Risk by Age, Sex, and Ethnicity: The HIV HEART Study
To evaluate the risk of heart failure (HF) linked to human immunodeficiency virus (HIV) infection, how risk varies by demographic characteristics, and whether it is explained by atherosclerotic disease or risk factor treatment. We performed a retrospective cohort study of persons with HIV (PWHs) from January 1, 2000, through December 31, 2016, frequency-matched 1:10 to persons without HIV on year of entry, age, sex, race/ethnicity, and treating facility. We evaluated the risk of incident HF associated with HIV infection, overall and by left ventricular systolic function, and whether HF risk varied by demographic characteristics. Among 38,868 PWHs and 386,586 matched persons without HIV, mean ± SD age was 41.4±10.8 years, with 12.3% female, 21.1% Black, 20.5% Hispanic, and 3.9% Asian/Pacific Islander. During median follow-up of 3.8 years (interquartile range, 1.4-9.0 years), the rate (per 100 person-years) of incident HF was 0.23 in PWHs vs 0.15 in those without HIV (P<.001). The PWHs had a higher adjusted HF rate (adjusted hazard ratio [aHR], 1.73; 95% confidence interval [CI], 1.57 to 1.91), which was only modestly attenuated after accounting for interim acute coronary syndrome events. Results were similar by systolic function category. The adjusted risk of HF in PWHs was more prominent for those 40 years and younger (aHR, 2.45; 95% CI, 1.92 to 3.03), women (aHR, 2.48; 95% CI, 1.90 to 3.26), and Asian/Pacific Islanders (aHR, 2.46; 95% CI, 1.27 to 4.74). HIV infection increases the risk of HF, which varied by demographic characteristics and was not primarily mediated through atherosclerotic disease pathways or differential use of cardiopreventive medications.
Authors: Go, Alan S; Lee, Keane K; Silverberg, Michael J; et al.
Mayo Clin Proc. 2022 03;97(3):465-479. Epub 2021-12-13.
The shifting age distribution of people with HIV using antiretroviral therapy in the United States, 2020 to 2030
To project the future age distribution of people with HIV using antiretroviral therapy (ART) in the United States, under expected trends in HIV diagnosis and survival (baseline scenario) and achieving the ending the HIV epidemic (EHE) goals of a 75% reduction in HIV diagnoses from 2020 to 2025 and sustaining levels to 2030 (EHE75% scenario). An agent-based simulation model with mathematical functions estimated from North American AIDS Cohort Collaboration on Research and Design data and parameters from the US Centers for Disease Control and Prevention’s annual HIV surveillance reports. The PEARL (ProjEcting Age, MultimoRbidity, and PoLypharmacy in adults with HIV) model simulated individuals in 15 subgroups of sex-and-HIV acquisition risk and race/ethnicity. Simulation outcomes from the baseline scenario are compared with outcomes from the EHE75% scenario. Under the baseline scenario, PEARL projects a substantial increase in number of ART-users over time, reaching a population of 909 638 [95% uncertainty range (UR): 878 449-946 513] by 2030. The overall median age increased from 50 years in 2020 to 52 years in 2030, with 23% of ART-users age ≥65 years in 2030. Under the EHE75% scenario, the projected number of ART-users was 718 348 [703 044-737 817] (median age = 56 years) in 2030, with a 70% relative reduction in ART-users <30 years and a 4% relative reduction in ART-users age ≥65 years compared to baseline, and persistent heterogeneities in projected numbers by sex-and-HIV acquisition risk group and race/ethnicity. It is critical to prepare healthcare systems to meet the impending demand of the US population aging with HIV.
Authors: Althoff, Keri N; Silverberg, Michael J; Kasaie, Parastu; et al.
AIDS. 2022 03 01;36(3):459-471.
The HIV preexposure prophylaxis (PrEP) continuum of care among transgender individuals in an integrated healthcare system
Authors: Hojilla, J Carlo; Hurley, Leo B; Marcus, Julia L; Satre, Derek D; Silverberg, Michael J; Zaritsky, Eve F; Getahun, Darios; Goodman, Michael; Volk, Jonathan E
J Acquir Immune Defic Syndr. 2022 03 01;89(3):e30.
Antibiotic prescribing across age groups in the Kaiser Permanente Northern California population in association with different diagnoses, and with influenza incidence, 2010-2018
There is limited information on the volume of antibiotic prescribing that is influenza-associated, resulting from influenza infections and their complications (such as streptococcal pharyngitis and otitis media). Here, we estimated age/diagnosis-specific proportions of antibiotic prescriptions (fills) for the Kaiser Permanente Northern California population during 2010-2018 that were influenza-associated. The proportion of influenza-associated antibiotic prescribing among all antibiotic prescribing was higher in children aged 5-17 years compared to children aged under 5 years, ranging from 1.4% [95% CI (0.7-2.1)] in aged <1 year to 2.7% (1.9-3.4) in aged 15-17 years. For adults aged over 20 years, the proportion of influenza-associated antibiotic prescribing among all antibiotic prescribing was lower, ranging from 0.7% (0.5-1) for aged 25-29 years to 1.6% (1.2-1.9) for aged 60-64 years. Most of the influenza-associated antibiotic prescribing in children aged under 10 years was for ear infections, while for age groups over 25 years, 45-84% of influenza-associated antibiotic prescribing was for respiratory diagnoses without a bacterial indication. This suggests a modest benefit of increasing influenza vaccination coverage for reducing antibiotic prescribing, as well as the potential benefit of other measures to reduce unnecessary antibiotic prescribing for respiratory diagnoses with no bacterial indication in persons aged over 25 years, both of which may further contribute to the mitigation of antimicrobial resistance.
Authors: Goldstein, Edward; Fireman, Bruce H; Klein, Nicola P; Lipsitch, Marc; Ray, G Thomas
Epidemiol Infect. 2022 Feb 24;150:e85. Epub 2022-02-24.
A decade of data: Adolescent vaccination in the vaccine safety datalink, 2007 through 2016
Between May 2005 and March 2007, three vaccines were recommended by the Advisory Committee on Immunization Practices for routine use in adolescents in the United States: quadrivalent meningococcal conjugate vaccine (MenACWY), tetanus, diphtheria and acellular pertussis vaccine (Tdap), and human papillomavirus vaccine (HPV). Understanding historical adolescent vaccination patterns may inform future vaccination coverage efforts for these and emerging adolescent vaccines, including COVID-19 vaccines. This was a descriptive, retrospective cohort study. All vaccines administered to adolescents aged 11 through 18 years in the Vaccine Safety Datalink population between January 1, 2007 and December 31, 2016 were examined. Vaccination coverage was assessed by study year for ≥1 dose Tdap or Td, ≥1 dose Tdap, ≥1 dose MenACWY, ≥1 dose HPV, and ≥3 dose HPV. The proportion of vaccine visits with concurrent vaccination (≥2 vaccines administered at the same visit) was calculated by sex and study year. The most common vaccine combinations administered in the study population were described by sex for two time periods: 2007-2010 and 2011-2016. The number of 11-18-year-olds in the study population averaged 522,565 males and 503,112 females per study year. Between January 2007 and December 2016 there were 4,884,553 vaccine visits in this population (45% among males). The overall proportion of concurrent vaccine visits among males was 43% (33-61% by study year). Among females, 39% of all vaccine visits included concurrent vaccination (32-48% by study year). Vaccine coverage for Tdap, MenACWY, and 1- and 3-dose HPV increased across the study period. A wide variety of vaccine combinations were administered among both sexes and in both time periods. The high vaccine uptake and multitude of vaccine combinations administered concurrently in the adolescent population of the Vaccine Safety Datalink provide historical patterns with which to compare future adolescent vaccination campaigns.
Authors: Irving, Stephanie A; Klein, Nicola P; Stokley, Shannon; et al.
Vaccine. 2022 02 23;40(9):1246-1252. Epub 2022-02-04.
Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance – VISION Network, 10 States, August 2021-January 2022
CDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance† (1-5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates).¶ Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021-January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination. During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4-5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose. For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19-associated hospitalizations and ED/UC visits.
Authors: Ferdinands, Jill M; Klein, Nicola P; Zerbo, Ousseny; Fireman, Bruce; et al.
MMWR Morb Mortal Wkly Rep. 2022 Feb 18;71(7):255-263. Epub 2022-02-18.
Patient and provider perspectives on self-administered electronic substance use and mental health screening in HIV primary care
Substance use disorders, depression and anxiety disproportionately affect people with HIV (PWH) and lead to increased morbidity and mortality. Routine screening can help address these problems but is underutilized. This study sought to describe patient and provider perspectives on the acceptability and usefulness of systematic electronic, self-administered screening for tobacco, alcohol, other substance use, and mental health symptoms among patients in HIV primary care. Screening used validated instruments delivered pre-appointment by both secure messaging and clinic-based tablets, with results integrated into the electronic health record (EHR). Qualitative analysis of semi-structured interviews with 9 HIV primary care providers and 12 patients in the 3 largest HIV primary care clinics in the Kaiser Permanente Northern California health system who participated in a clinical trial evaluating computerized screening and behavioral interventions was conducted. Interviews were audio-recorded and transcribed. A thematic approach was utilized for coding and analysis of interview data using a combination of deductive and inductive methods. Four key themes were identified: (1) perceived clinical benefit of systematic, electronic screening and EHR integration for providers and patients; (2) usefulness of having multiple methods of questionnaire completion; (3) importance of the patient-provider relationship to facilitate completion and accurate reporting; and (4) barriers, include privacy and confidentiality concerns about reporting sensitive information, particularly about substance use, and potential burden from repeated screenings. Findings suggest that electronic, self-administered substance use and mental health screening is acceptable to patients and may have clinical utility to providers. While offering different methods of screening completion can capture a wider range of patients, a strong patient-provider relationship is a key factor in overcoming barriers and ensuring accurate patient responses. Further investigation into facilitators, barriers, and utility of electronic screening for PWH and other high-priority patient populations is indicated. Trial registration ClinicalTrials.gov, NCT03217058. Registered 13 July 2017, https://clinicaltrials.gov/ct2/show/NCT03217058.
Authors: Lea, Alexandra N; Altschuler, Andrea; Leibowitz, Amy S; Levine-Hall, Tory; McNeely, Jennifer; Silverberg, Michael J; Satre, Derek D
Addict Sci Clin Pract. 2022 02 09;17(1):10. Epub 2022-02-09.
Evaluation of Trends in Homeschooling Rates After Elimination of Nonmedical Exemptions to Childhood Immunizations in California, 2012-2020
In 2015, California passed Senate Bill No. 277 (SB 277) and became the first state in more than 30 years to eliminate nonmedical exemptions to mandatory childhood immunizations for school entry. One concern that emerged was that the law created an incentive for parents to remove children from brick-and-mortar schools to bypass the immunization requirements. To assess the trends in homeschooling rates after the elimination of nonmedical exemptions to the requirement of childhood immunizations for school entry. This preintervention-postintervention cross-sectional study calculated homeschooling rates as the number of students in kindergarten through grade 8 (K-8) enrolled through each of California’s 3 homeschooling mechanisms (independent study program, private school affidavit, and private school satellite program) divided by all K-8 students enrolled in the same academic year. Data on homeschooling rates were obtained from the California Department of Education. Interrupted time series analyses were conducted using a linear regression model in which the outcome variable was the percentage of students enrolled in a homeschool program before and after SB 277. Data were collected and analyzed from October 3, 2012, to October 2, 2019. Passage of SB 277, which eliminated nonmedical exemptions to childhood immunizations for school entry. Homeschooling rates for K-8 students. Among the students included in the analysis, the homeschooling enrollment for K-8 students in California increased from 35 122 students (0.8%) during the 2012-2013 school year to 86 574 students (1.9%) during the 2019-2020 school year; however, the implementation of SB 277 was not associated with an increase in the percentage of students enrolled in homeschooling programs in California beyond the secular trend. The increase in homeschooling was greatest for the lower grade levels: kindergarten homeschooling enrollment increased from 2068 students (0.4%) in the 2012-2013 school year to 10 553 students (1.9%) in the 2019-2020 school year, whereas the grade 8 homeschool enrollment rate increased from 5146 students (1.0%) in the 2012-2013 school year to 10 485 students (2.0%) in the 2019-2020 school year. Independent study programs accounted for 20 149 students (45.3%) of homeschooling enrollment, private school affidavits accounted for 19 333 students (43.5%), and private school satellite programs accounted for 4935 students (11.1%) during the 2015-2016 school year. The findings of this study suggest that legislative action to limit nonmedical exemptions for compulsory vaccination for school entry is not associated with removal of students from classroom-based instruction in brick-and-mortar institutions.
Authors: Patel, Kavin M; McFadden, SarahAnn M; Mohanty, Salini; Joyce, Caroline M; Delamater, Paul L; Klein, Nicola P; Salmon, Daniel A; Omer, Saad B; Buttenheim, Alison M
JAMA Netw Open. 2022 02 01;5(2):e2146467. Epub 2022-02-01.
Virologic outcomes among adults with HIV using integrase inhibitor-based antiretroviral therapy
Integrase strand transfer inhibitor (InSTI)-based regimens have been recommended as first-line antiretroviral therapy (ART) for adults with HIV. But data on long-term effects of InSTI-based regimens on virologic outcomes remain limited. Here we examined whether InSTI improved long-term virologic outcomes compared with efavirenz (EFV). We included adults from the North American AIDS Cohort Collaboration on Research and Design who initiated their first ART regimen containing either InSTI or EFV between 2009 and 2016. We estimated differences in the proportion virologically suppressed up to 7 years of follow-up in observational intention-to-treat and per-protocol analyses. Of 15 318 participants, 5519 (36%) initiated an InSTI-based regimen and 9799 (64%) initiated the EFV-based regimen. In observational intention-to-treat analysis, 81.3% of patients in the InSTI group and 67.3% in the EFV group experienced virologic suppression at 3 months after ART initiation, corresponding to a difference of 14.0% (95% CI 12.4-15.6). At 1 year after ART initiation, the proportion virologically suppressed was 89.5% in the InSTI group and 90.2% in the EFV group, corresponding to a difference of -0.7% (95% CI -2.1 to 0.8). At 7 years, the proportion virologically suppressed was 94.5% in the InSTI group and 92.5% in the EFV group, corresponding to a difference of 2.0% (95% CI -7.3 to 11.3). The observational per-protocol results were similar to intention-to-treat analyses. Although InSTI-based initial ART regimens had more rapid virologic response than EFV-based regimens, the long-term virologic effect was similar. Our findings may inform guidelines regarding preferred initial regimens for HIV treatment.
Authors: Lu, Haidong; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research, Design of the International Epidemiologic Databases to Evaluate AIDS,; et al.
AIDS. 2022 02 01;36(2):277-286.
Do contemporary antiretrovirals increase the risk of end-stage liver disease? Signals from patients starting therapy in the North American AIDS Cohort Collaboration on Research and Design
Despite effective antiretroviral therapy, rates of end-stage liver disease (ESLD) remain high. It is not clear whether contemporary antiretrovirals contribute to the risk of ESLD. We included patients from cohorts with validated ESLD data in the North American AIDS Cohort Collaboration on Research and Design. Patients had to initiate antiretroviral therapy after 1 January 2004 with a nucleos(t)ide backbone of either abacavir/lamivudine or tenofovir/emtricitabine and a contemporary third (anchor) drug. Patients were followed until a first ESLD event, death, end of a cohort’s ESLD validation period, loss to follow-up or 31 December 2015. We estimated associations between cumulative exposure to each drug and ESLD using a hierarchical Bayesian survival model with weakly informative prior distributions. Among 10 564 patients included from 12 cohorts, 62 had an ESLD event. Of the nine anchor drugs, boosted protease inhibitors atazanavir and darunavir had the strongest signals for ESLD, with increasing hazard ratios (HR) and narrowing credible intervals (CrI), from a prior HR of 1.5 (95% CrI 0.32-7.1) per 5 year’s exposure to posterior HRs respectively of 1.8 (95% CrI 0.82-3.9) and 2.0 (95% CrI 0.86-4.7). Both backbones and efavirenz showed no signal. Hepatitis C coinfection was the most important covariate risk factor (HR 4.4, 95% CrI 2.6-7.0). While contemporary antiretrovirals pose less risk for ESLD than hepatitis coinfection, atazanavir and darunavir had a toxicity signal. We show how hierarchical Bayesian modelling can be used to detect toxicity signals in cohort event monitoring data even with complex treatments and few events.
Authors: Young, Jim; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA,; et al.
Pharmacoepidemiol Drug Saf. 2022 02;31(2):214-224. Epub 2021-11-23.
Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study
Recombinant influenza vaccine (RIV) has been in use in US adults since 2013. This study evaluated the safety of quadrivalent recombinant influenza vaccine (RIV4, Flublok® Quadrivalent, Sanofi Pasteur) compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) in self-identified Chinese adults at Kaiser Permanente Northern California (KPNC). This study evaluated adults aged 18-64 years within KPNC during the 2018-2019 influenza season who self-identified as Chinese (NCT03694392). We compared the rates of prespecified diagnoses of interest in the emergency department and inpatient settings as done in prior influenza studies, for three risk intervals: 0-2 days, 0-13 days, and 0-41 days following influenza vaccination, as well as number of deaths within 0-180 days after vaccination. We estimated the odds ratios (ORs) and 95% confidence intervals using logistic regression adjusted for sex, age group, presence of comorbidities, and same-day concomitant vaccination. Comparing 15,574 adults who received RIV4 with 27,110 who received SD-IIV4, there was no statistically significant difference in the prespecified diagnoses of interest and deaths between the 2 groups. There were 35 deaths total, none of which were considered to be related to influenza vaccination. This study did not identify any safety concerns regarding RIV4 use among 18-64-year-olds who self-identified as Chinese. This study supports the safety of RIV4 vaccine in this population.
Authors: Hsiao, Amber; Hansen, John; Nunley, Karen Valdez; Lewis, Ned; Selmani, Alex; Inamdar, Ajinkya; Mallett-Moore, Tamala; Izikson, Ruvim; Rudin, Deborah; Klein, Nicola P
Vaccine. 2022 01 31;40(5):774-779. Epub 2022-01-06.
Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance – VISION Network, 10 States, August 2021-January 2022
Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose.† A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5-7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network§ examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021¶ to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.
Authors: Thompson, Mark G; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Ong, Toan C; et al.
MMWR Morb Mortal Wkly Rep. 2022 Jan 21;71(4):139-145. Epub 2022-01-21.
Differences in COVID-19 testing and adverse outcomes by race, ethnicity, sex, and health system setting in a large diverse US cohort
Racial/ethnic disparities during the first six months of the COVID-19 pandemic led to differences in COVID-19 testing and adverse outcomes. We examine differences in testing and adverse outcomes by race/ethnicity and sex across a geographically diverse and system-based COVID-19 cohort collaboration. Observational study among adults (≥18 years) within six US cohorts from March 1, 2020 to August 31, 2020 using data from electronic health record and patient reporting. Race/ethnicity and sex as risk factors were primary exposures, with health system type (integrated health system, academic health system, or interval cohort) as secondary. Proportions measured SARS-CoV-2 testing and positivity; attributed hospitalization and death related to COVID-19. Relative risk ratios (RR) with 95% confidence intervals quantified associations between exposures and main outcomes. 5,958,908 patients were included. Hispanic patients had the highest proportions of SARS-CoV-2 testing (16%) and positivity (18%), while Asian/Pacific Islander patients had the lowest portions tested (11%) and White patients had the lowest positivity rates (5%). Men had a lower likelihood of testing (RR = 0.90 [0.89-0.90]) and a higher positivity risk (RR = 1.16 [1.14-1.18]) compared to women. Black patients were more likely to have COVID-19-related hospitalizations (RR = 1.36 [1.28-1.44]) and death (RR = 1.17 [1.03-1.32]) compared with White patients. Men were more likely to be hospitalized (RR = 1.30 [1.16-1.22]) or die (RR = 1.70 [1.53-1.89]) compared to women. These racial/ethnic and sex differences were reflected in both health system types. This study supports evidence of disparities by race/ethnicity and sex during the COVID-19 pandemic that persisted even in healthcare settings with reduced barriers to accessing care. Further research is needed to understand and prevent the drivers that resulted in higher burdens of morbidity among certain Black patients and men.
Authors: Jefferson, Celeena; Silverberg, Michael J; Skarbinski, Jacek; NA-ACCORD Corona-Infectious-Virus Epidemiology Team (CIVET),; et al.
PLoS One. 2022;17(11):e0276742. Epub 2022-11-23.
Development and validation of a prediction algorithm to identify birth in countries with high tuberculosis incidence in two large California health systems
Though targeted testing for latent tuberculosis infection (“LTBI”) for persons born in countries with high tuberculosis incidence (“HTBIC”) is recommended in health care settings, this information is not routinely recorded in the electronic health record (“EHR”). We develop and validate a prediction model for birth in a HTBIC using EHR data. In a cohort of patients within Kaiser Permanente Southern California (“KPSC”) and Kaiser Permanent Northern California (“KPNC”) between January 1, 2008 and December 31, 2019, KPSC was used as the development dataset and KPNC was used for external validation using logistic regression. Model performance was evaluated using area under the receiver operator curve (“AUCROC”) and area under the precision and recall curve (“AUPRC”). We explored various cut-points to improve screening for LTBI. KPSC had 73% and KPNC had 54% of patients missing country-of-birth information in the EHR, leaving 2,036,400 and 2,880,570 patients with EHR-documented country-of-birth at KPSC and KPNC, respectively. The final model had an AUCROC of 0.85 and 0.87 on internal and external validation datasets, respectively. It had an AUPRC of 0.69 and 0.64 (compared to a baseline HTBIC-birth prevalence of 0.24 at KPSC and 0.19 at KPNC) on internal and external validation datasets, respectively. The cut-points explored resulted in a number needed to screen from 7.1-8.5 persons/positive LTBI diagnosis, compared to 4.2 and 16.8 persons/positive LTBI diagnosis from EHR-documented birth in a HTBIC and current screening criteria, respectively. Using logistic regression with EHR data, we developed a simple yet useful model to predict birth in a HTBIC which decreased the number needed to screen compared to current LTBI screening criteria. Our model improves the ability to screen for LTBI in health care settings based on birth in a HTBIC.
Authors: Fischer, Heidi; Skarbinski, Jacek; Tartof, Sara Y; et al.
PLoS One. 2022;17(8):e0273363. Epub 2022-08-25.
Associations of COVID-19-Related Health, Healthcare and Economic Factors With Prenatal Depression and Anxiety
Objective: This study evaluated whether COVID-19 pandemic-related health, healthcare and economic factors during pregnancy are associated with prenatal depression and anxiety. Methods: We conducted a cross-sectional study of 6,628 pregnant members of Kaiser Permanente Northern California who responded to a survey between 22 June and 30 September 2020. The survey included questions about depression (Patient Health Questionnaire) and anxiety (Generalized Anxiety Disorder) symptoms and COVID-19-related health and healthcare (e.g., had COVID-19) and economic (e.g., food insecurity) factors. Results: Over one third of individuals reported depression (25% mild, 8% moderate, 3% severe) or anxiety (22% mild, 8% moderate, 5% severe) symptoms. In multivariable analyses, COVID-19 during pregnancy, employment with greater risk of COVID-19, distress over changes in prenatal care, job loss, changes in childcare and food insecurity were associated with greater odds of prenatal depression or anxiety. Conclusion: Findings suggest the COVID-19 pandemic may have severe mental health repercussions for pregnant individuals. Support services for pregnant individuals experiencing these COVID-19-related factors and monitoring of those who had moderate/severe prenatal depression and anxiety symptoms during the COVID-19 pandemic is warranted.
Authors: Avalos, Lyndsay A; Nance, Nerissa; Badon, Sylvia E; Young-Wolff, Kelly; Ames, Jennifer; Zhu, Yeyi; Hedderson, Monique M; Ferrara, Assiamira; Zerbo, Ousseny; Greenberg, Mara; Croen, Lisa A
Int J Public Health. 2022;67:1604433. Epub 2022-05-04.
Contributions of COVID-19 Pandemic-Related Stressors to Racial and Ethnic Disparities in Mental Health During Pregnancy
This study aimed to identify racial and ethnic disparities in prenatal mental health and identify COVID-19 pandemic-related health/healthcare and economic contributors to these disparities, using an established framework for disparity investigation. This cross-sectional study includes 10,930 pregnant people at Kaiser Permanente Northern California who completed an online survey between June 22, 2020 and April 28, 2021 on COVID-19 pandemic-related health/healthcare and economic stressors, depression, and anxiety. Self-reported race and ethnicity were extracted from electronic health records. Weighted analyses were used to evaluate the association between racial and ethnic category and prenatal depression and anxiety; the prevalence of each stressor by race and ethnicity; and the relationship between each stressor and prenatal depression and anxiety in each racial and ethnic category. The sample was 22% Asian, 3% Black, 20% Hispanic, 5% Other/Multiracial/Unknown, and 49% White. Compared to White people, Black and Hispanic people had a higher prevalence of prenatal depression (aPR: 1.85, 95% CI: 1.45, 2.35 and aPR: 1.17, 95% CI: 1.00, 1.37, respectively) and anxiety (aPR: 1.71, 95% CI: 1.34, 2.18 and aPR: 1.10, 95% CI: 0.94, 1.29, respectively). Compared to White people, Black and Hispanic people had a higher prevalence of moderate/severe distress due to changes in prenatal care (24 vs. 34 and 31%), and food insecurity (9 vs. 31 and 24%). Among Black and Hispanic people, distress due to changes in prenatal care was associated with a greater prevalence of prenatal depression (aPR: 2.27, 95% CI: 1.41, 3.64 and aPR: 2.76, 95% CI: 2.12, 3.58, respectively) and prenatal anxiety (aPR: 3.00, 95% CI: 1.85, 4.84 and aPR: 2.82, 95% CI: 2.15, 3.71, respectively). Additionally, among Hispanic people, high-risk employment and food insecurity were associated with a greater prevalence of prenatal depression and anxiety. This study identified racial and ethnic disparities in mental health for pregnant Black and Hispanic people. Distress due to prenatal care changes contributed to the observed disparities in prenatal depression and anxiety for Black and Hispanic people and food insecurity additionally contributed to the observed disparities for Hispanic people. Addressing distress due to changes to prenatal care and food insecurity specifically in Black and Hispanic people may help reduce the high burden of poor mental health and reduce observed disparities in these communities.
Authors: Avalos, Lyndsay A; Nance, Nerissa; Zhu, Yeyi; Croen, Lisa A; Young-Wolff, Kelly C; Zerbo, Ousseny; Hedderson, Monique M; Ferrara, Assiamira; Ames, Jennifer L; Badon, Sylvia E
Front Psychiatry. 2022;13:837659. Epub 2022-03-14.
Association of the VACS Index With Hospitalization Among People With HIV in the NA-ACCORD
People with HIV (PWH) have a higher hospitalization rate than the general population. The Veterans Aging Cohort Study (VACS) Index at study entry well predicts hospitalization in PWH, but it is unknown if the time-updated parameter improves hospitalization prediction. We assessed the association of parameterizations of the VACS Index 2.0 with the 5-year risk of hospitalization. PWH ≥30 years old with at least 12 months of antiretroviral therapy (ART) use and contributing hospitalization data from 2000 to 2016 in North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Three parameterizations of the VACS Index 2.0 were assessed and categorized by quartile: (1) “baseline” measurement at study entry; (2) time-updated measurements; and (3) cumulative scores calculated using the trapezoidal rule. Discrete-time proportional hazard models estimated the crude and adjusted associations (and 95% confidence intervals [CIs]) of the VACS Index parameterizations and all-cause hospitalizations. The Akaike information criterion (AIC) assessed the model fit with each of the VACS Index parameters. Among 7289 patients, 1537 were hospitalized. Time-updated VACS Index fitted hospitalization best with a more distinct dose-response relationship [score <43: reference; score 43-55: aHR = 1.93 (95% CI: 1.66 to 2.23); score 55-68: aHR = 3.63 (95% CI: 3.12 to 4.23); score ≥68: aHR = 9.98 (95% CI: 8.52 to 11.69)] than study entry and cumulative VACS Index after adjusting for known risk factors. Time-updated VACS Index 2.0 had the strongest association with hospitalization and best fit to the data. Health care providers should consider using it when assessing hospitalization risk among PWH.
Authors: Qian, Yuhang; Silverberg, Michael J; Althoff, Keri N; et al.
J Acquir Immune Defic Syndr. 2022 01 01;89(1):9-18.
Effectiveness of two-dose vaccination with mRNA COVID-19 vaccines against COVID-19-associated hospitalizations among immunocompromised adults-Nine States, January-September 2021
Authors: Embi, Peter J; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; DeSilva, Malini B; et al.
Am J Transplant. 2022 01;22(1):306-314.
Association of the COVID-19 Pandemic With Routine Childhood Vaccination Rates and Proportion Up to Date With Vaccinations Across 8 US Health Systems in the Vaccine Safety Datalink
The COVID-19 pandemic has affected routine vaccine delivery in the US and globally. The magnitude of these disruptions and their association with childhood vaccination coverage are unclear. To compare trends in pediatric vaccination before and during the pandemic and to evaluate the proportion of children up to date (UTD) with vaccinations by age, race, and ethnicity. This surveillance study used a prepandemic-postpandemic control design with data from 8 health systems in California, Oregon, Washington, Colorado, Minnesota, and Wisconsin in the Vaccine Safety Datalink. Children from age groups younger than 24 months and 4 to 6, 11 to 13, and 16 to 18 years were included if they had at least 1 week of health system enrollment from January 5, 2020, through October 3, 2020, over periods before the US COVID-19 pandemic (January 5, 2020, through March 14, 2020), during age-limited preventive care (March 15, 2020, through May 16, 2020), and during expanded primary care (May 17, 2020, through October 3, 2020). These individuals were compared with those enrolled during analogous weeks in 2019. This study evaluated UTD status among children reaching specific ages in February, May, and September 2020, compared with those reaching these ages in 2019. Weekly vaccination rates for routine age-specific vaccines and the proportion of children UTD for all age-specific recommended vaccines. Of 1 399 708 children in 2019 and 1 402 227 in 2020, 1 371 718 were female (49.0%) and 1 429 979 were male (51.0%); 334 216 Asian individuals (11.9%), 900 226 were Hispanic individuals (32.1%), and 201 619 non-Hispanic Black individuals (7.2%). Compared with the prepandemic period and 2019, the age-limited preventive care period was associated with lower weekly vaccination rates, with ratios of rate ratios of 0.82 (95% CI, 0.80-0.85) among those younger than 24 months, 0.18 (95% CI, 0.16-0.20) among those aged 4 to 6 years, 0.16 (95% CI, 0.14-0.17) among those aged 11 to 13 years, and 0.10 (95% CI, 0.08-0.13) among those aged 16 to 18 years. Vaccination rates during expanded primary care remained lower for most ages (ratios of rate ratios: <24 months, 0.96 [95% CI, 0.93-0.98]; 11-13 years, 0.81 [95% CI, 0.76-0.86]; 16-18 years, 0.57 [95% CI, 0.51-0.63]). In September 2020, 74% (95% CI, 73%-76%) of infants aged 7 months and 57% (95% CI, 56%-58%) of infants aged 18 months were UTD vs 81% (95% CI, 80%-82%) and 61% (95% CI, 60%-62%), respectively, in September 2019. The proportion UTD was lowest in non-Hispanic Black children across most age groups, both during and prior to the COVID-19 pandemic (eg, in May 2019, 70% [95% CI, 64%-75%] of non-Hispanic Black infants aged 7 months were UTD vs 82% [95% CI, 81%-83%] in all infants aged 7 months combined). As of September 2020, childhood vaccination rates and the proportion who were UTD remained lower than 2019 levels. Interventions are needed to promote catch-up vaccination, particularly in populations at risk for underimmunization.
Authors: DeSilva, Malini B; Klein, Nicola P; Kharbanda, Elyse O; et al.
JAMA Pediatr. 2022 01 01;176(1):68-77.
Projecting the age-distribution of men who have sex with men receiving HIV treatment in the United States
The age-distribution of men who have sex with men (MSM) continues to change in the ‘Treat-All’ era as effective test-and-treat programs target key-populations. However, the nature of these changes and potential racial heterogeneities remain uncertain. The PEARL model is an agent-based simulation of MSM in HIV care in the US, calibrated to data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). PEARL projects a gradual decrease in median age of MSM at ART initiation from 36 to 31 years during 2010-2030, accompanied by changes in mortality among Black, White, and Hispanic MSM on ART by -8.4%, 42.4% and -19.6%. The median age of all MSM on ART is projected to increase from 45 to 47 years from 2010-2030, with the proportion of ART-users age ≥60y increasing from 6.7% to 28.0%. Almost half (49.7%) of White MSM ART-users are projected to age ≥60y by 2030, compared to 19.5% of Black and 17.2% of Hispanic MSM. The overall age of US MSM in HIV care is expected to increase over the next decade, and differentially by race/ethnicity. As this population age, HIV programs should expand care for age-related causes of morbidity and mortality.
Authors: Kasaie, Parastu; Silverberg, Michael J; Althoff, Keri N; et al.
Ann Epidemiol. 2022 01;65:46-55. Epub 2021-10-07.
Population-based assessment of risks for severe COVID-19 disease outcomes
Among approximately 4.6 million members of Kaiser Permanente Northern California, we examined associations of severe COVID-19 with demographic factors and comorbidities. As of July 23, 2021, 16 182 had been hospitalized, 2416 admitted to an ICU, and 1525 died due to COVID-19. Age was strongly associated with hospitalization, ICU admission, and death. Black persons and Hispanic ethnicity had higher risk of death compared with Whites. Among the comorbidities examined, Alzheimer’s disease was associated with the highest risk for hospitalization (aHR 3.19, CI: 2.88-3.52) and death (aHR 4.04, CI: 3.32-4.91). Parkinson’s disease had the second highest risk of death (aHR = 2.07, CI: 1.50-2.87).
Authors: Zerbo, Ousseny; Lewis, Ned; Fireman, Bruce; Goddard, Kristin; Skarbinski, Jacek; Sejvar, James J; Azziz-Baumgartner, Eduardo; Klein, Nicola P
Influenza Other Respir Viruses. 2022 01;16(1):159-165. Epub 2021-08-25.
A multi-country investigation of influenza vaccine coverage in pregnant individuals, 2010-2016
Many countries recommend influenza vaccination during pregnancy. Despite this recommendation, influenza vaccine among pregnant individuals remains under-utilized and uptake varies by country. Factors associated with influenza vaccine uptake during pregnancy may also vary across countries. As members of the Pregnancy Influenza Vaccine Effectiveness Network (PREVENT), five sites from four countries (Australia, Canada, Israel, and the United States) retrospectively identified cohorts of individuals aged 18-50 years who were pregnant during pre-defined influenza seasons. Influenza vaccine coverage estimates were calculated for the 2010-11 through 2015-16 northern hemisphere and the 2012 through 2015 southern hemisphere influenza seasons, by site. Sites used electronic health records, administrative data, and immunization registries to collect information on pregnancy, health history, demographics, and vaccination status. Each season, vaccination coverage was calculated as the percentage of individuals who received influenza vaccine among the individuals in the cohort that season. Characteristics were compared between those vaccinated and unvaccinated, by site. More than two million pregnancies were identified over the study period. Influenza vaccination coverage ranged from 5% to 58% across sites and seasons. Coverage increased consistently over the study period at three of the five sites (Western Australia, Alberta, and Israel), and was highest in all seasons at the United States study site (39-58%). Associations with vaccination varied by country and across seasons; where available, parity >0, presence of a high-risk medical condition, and urban residence were consistently associated with increased likelihood of vaccination. Though increasing, uptake of influenza vaccine among pregnant individuals remains lower than recommended. Coverage varied substantially by country, suggesting an ongoing need for targeted strategies to improve influenza vaccine uptake in this population.
Authors: Irving, Stephanie A; Klein, Nicola P; PREVENT study team,; et al.
Vaccine. 2021 12 20;39(52):7598-7605. Epub 2021-11-19.
COVID-19 infections post-vaccination by HIV status in the United States
Recommendations for additional doses of COVID vaccine are restricted to people with HIV who have advanced disease or unsuppressed HIV viral load. Understanding SARS-CoV-2 infection risk post-vaccination among PWH is essential for informing vaccination guidelines. Estimate the risk of breakthrough infections among fully vaccinated people with (PWH) and without (PWoH) HIV in the US. The Corona-Infectious-Virus Epidemiology Team (CIVET)-II cohort collaboration consists of 4 longitudinal cohorts from integrated health systems and academic health centers. Each cohort identified individuals ≥18 years old, in-care, and fully vaccinated for COVID-19 through 30 June 2021. PWH were matched to PWoH on date fully vaccinated, age group, race/ethnicity, and sex at birth. Incidence rates per 1,000 person-years and cumulative incidence of breakthrough infections with 95% confidence intervals ([,]) were estimated by HIV status. Cox proportional hazards models estimated adjusted hazard ratios (aHR) of breakthrough infections by HIV status adjusting for demographic factors, prior COVID-19 illness, vaccine type (BNT162b2, [Pfizer], mRNA-1273 [Moderna], Jansen Ad26.COV2.S [J&J]), calendar time, and cohort. Risk factors for breakthroughs among PWH, were also investigated. HIV infection. COVID-19 breakthrough infections, defined as laboratory evidence of SARS-CoV-2 infection or COVID-19 diagnosis after an individual was fully vaccinated. Among 109,599 individuals (31,840 PWH and 77,759 PWoH), the rate of breakthrough infections was higher in PWH versus PWoH: 44 [41, 48] vs. 31 [29, 33] per 1,000 person-years. Cumulative incidence at 210 days after date fully vaccinated was low, albeit higher in PWH versus PWoH overall (2.8% versus 2.1%, log-rank p<0.001, risk difference=0.7% [0.4%, 1.0%]) and within each vaccine type. Breakthrough infection risk was 41% higher in PWH versus PWoH (aHR=1.41 [1.28, 1.56]). Among PWH, younger age (18-24 versus 45-54), history of COVID-19 prior to fully vaccinated date, and J&J vaccination (versus Pfizer) were associated with increased risk of breakthroughs. There was no association of breakthrough with HIV viral load suppression or CD4 count among PWH. COVID-19 vaccination is effective against infection with SARS-CoV-2 strains circulating through 30 Sept 2021. PWH have an increased risk of breakthrough infections compared to PWoH. Recommendations for additional vaccine doses should be expanded to all PWH.
Authors: Coburn, Sally B; Silverberg, Michael; Skarbinski, Jacek; Corona-Infectious-Virus Epidemiology Team (CIVETs) of the NA-ACCORD of IeDEA,; et al.
medRxiv. 2021 Dec 05.
The Childhood Vaccination Schedule and the Lack of Association With Type 1 Diabetes
Safety studies assessing the association between the entire recommended childhood immunization schedule and autoimmune diseases, such as type 1 diabetes mellitus (T1DM), are lacking. To examine the association between the recommended immunization schedule and T1DM, we conducted a retrospective cohort study of children born between 2004 and 2014 in 8 US health care organizations that participate in the Vaccine Safety Datalink. Three measures of the immunization schedule were assessed: average days undervaccinated (ADU), cumulative antigen exposure, and cumulative aluminum exposure. T1DM incidence was identified by International Classification of Disease codes. Cox proportional hazards models were used to analyze associations between the 3 exposure measures and T1DM incidence. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated. Models were adjusted for sex, race and ethnicity, birth year, mother’s age, birth weight, gestational age, number of well-child visits, and study site. In a cohort of 584 171 children, the mean ADU was 38 days, the mean cumulative antigen exposure was 263 antigens (SD = 54), and the mean cumulative aluminum exposure was 4.11 mg (SD = 0.73). There were 1132 incident cases of T1DM. ADU (aHR = 1.01; 95% CI, 0.99-1.02) and cumulative antigen exposure (aHR = 0.98; 95% CI, 0.97-1.00) were not associated with T1DM. Cumulative aluminum exposure >3.00 mg was inversely associated with T1DM (aHR = 0.77; 95% CI, 0.60-0.99). The recommended schedule is not positively associated with the incidence of T1DM in children. These results support the safety of the recommended childhood immunization schedule.
Authors: Glanz, Jason M; Klein, Nicola P; DeStefano, Frank; et al.
Pediatrics. 2021 12 01;148(6).
Treatment for alcohol use disorder among persons with and without HIV in a clinical care setting in the United States
Alcohol use disorders (AUD) can lead to poor health outcomes. Little is known about AUD treatment among persons with HIV (PWH). In an integrated health system in Northern California, 2014-2017, we compared AUD treatment rates between PWH with AUD and persons without HIV (PWoH) with AUD. Using Poisson regression with GEE, we estimated prevalence ratios (PRs) comparing the annual probability of receiving AUD treatment (behavioral intervention or dispensed medication), adjusted for sociodemographics, psychiatric comorbidities, insurance type, and calendar year. Among PWH, we examined independent AUD treatment predictors using PRs adjusted for calendar year only. PWH with AUD (N = 633; 93% men, median age 49) were likelier than PWoH with AUD (N = 7006; 95% men, median age 52) to have depression (38% vs. 21%) and a non-alcohol substance use disorder (SUD, 48% vs. 25%) (both P < 0.01). Annual probabilities of receiving AUD treatment were 45.4% for PWH and 34.4% for PWoH. After adjusting, there was no difference by HIV status (PR 1.02 [95% CI 0.94-1.11]; P = 0.61). Of treated PWH, 59% received only a behavioral intervention, 5% only a medication, and 36% both, vs. 67%, 4%, 30% for treated PWoH, respectively. Irrespective of HIV status, the most common medication was gabapentin. Among PWH, receiving AUD treatment was associated with having depression (PR 1.78 [1.51-2.10]; P < 0.01) and another SUD (PR 2.68 [2.20-3.27]; P < 0.01). PWH with AUD had higher AUD treatment rates than PWoH with AUD in unadjusted but not adjusted analyses, which may be explained by higher psychiatric comorbidity burden among PWH.
Authors: Davy-Mendez, Thibaut; Sarovar, Varada; Levine-Hall, Tory; Lea, Alexandra N; Sterling, Stacy A; Chi, Felicia W; Palzes, Vanessa A; Bryant, Kendall J; Weisner, Constance M; Silverberg, Michael J; Satre, Derek D
Drug Alcohol Depend. 2021 12 01;229(Pt A):109110. Epub 2021-09-28.
Cancer in people with and without hepatitis C virus infection: comparison of risk before and after introduction of direct-acting antivirals
Chronic hepatitis C virus (HCV) infection is a leading cause of liver cancer. The association of HCV infection with extrahepatic cancers, and the impact of direct-acting antiviral (DAA) treatment on these cancers, is less well known. We conducted a cohort study in a healthcare delivery system. Using electronic health record data from 2007 to 2017, we determined cancer incidence, overall and by type, in people with HCV infection and by DAA treatment status. All analyses included comparisons with a reference population of people without HCV infection. Covariate-adjusted Poisson models were used to estimate incidence rate ratios. 2,451 people with HCV and 173,548 people without HCV were diagnosed with at least one type of cancer. Compared with people without HCV, those with HCV were at higher risk for liver cancer [adjusted incidence rate ratio (aIRR) = 31.4, 95% confidence interval (CI) = 28.9-34.0], hematologic cancer (aIRR = 1.3, 95% CI = 1.1-1.5), lung cancer (aIRR = 1.3, 95% CI = 1.2-1.5), pancreatic cancer (aIRR = 2.0, 95% CI = 1.6-2.5), oral/oropharynx cancer (aIRR = 1.4, 95% CI = 1.1-1.8), and anal cancer (aIRR = 1.6, 95% CI = 1.1-2.4). Compared with people without HCV, the aIRR for liver cancer was 31.9 (95% CI = 27.9-36.4) among DAA-untreated and 21.2 (95% CI = 16.8-26.6) among DAA-treated, and the aIRR for hematologic cancer was 1.5 (95% CI = 1.1-2.0) among DAA-untreated and 0.6 (95% CI = 0.3-1.2) among DAA-treated. People with HCV infection were at increased risk of liver cancer, hematologic cancer, and some other extrahepatic cancers. DAA treatment was associated with reduced risk of liver cancers and hematologic cancers. DAA treatment is important for reducing cancer incidence among people with HCV infection.
Authors: Lam, Jennifer O; Champsi, Jamila H; Silverberg, Michael J; et al.
Cancer Epidemiol Biomarkers Prev. 2021 12;30(12):2188-2196. Epub 2021-09-28.
Hypotonic-hyporesponsive Episodes After Diphtheria, Tetanus and Acellular Pertussis Vaccination
Hypotonic-hyporesponsive episode (HHE) after whole cell pertussis vaccination is a known adverse event. Less is known about the risk of HHE after administration of acellular pertussis vaccines. Using parental interviews, this study actively surveyed for HHE among infants after doses 1 and 2 of acellular pertussis vaccine. We interviewed the parents of 52,531 infants. HHE was reported at a rate of 22.8 per 100,000 doses (95% CI: 11.8-39.9) of acellular pertussis vaccine, approximately 45 episodes per 100,000 children. These rates are lower than HHE rates reported after whole cell pertussis vaccines and within the range of HHE rates reported in other studies of acellular pertussis vaccines.
Authors: Hansen, John; Decker, Michael D; Lewis, Edwin; Fireman, Bruce; Pool, Vitali; Greenberg, David P; Johnson, David R; Black, Steven; Klein, Nicola P
Pediatr Infect Dis J. 2021 12 01;40(12):1122-1126.
Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19-Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity – Nine States, January-September 2021
Previous infection with SARS-CoV-2 (the virus that causes COVID-19) or COVID-19 vaccination can provide immunity and protection from subsequent SARS-CoV-2 infection and illness. CDC used data from the VISION Network* to examine hospitalizations in adults with COVID-19-like illness and compared the odds of receiving a positive SARS-CoV-2 test result, and thus having laboratory-confirmed COVID-19, between unvaccinated patients with a previous SARS-CoV-2 infection occurring 90-179 days before COVID-19-like illness hospitalization, and patients who were fully vaccinated with an mRNA COVID-19 vaccine 90-179 days before hospitalization with no previous documented SARS-CoV-2 infection. Hospitalized adults aged ≥18 years with COVID-19-like illness were included if they had received testing at least twice: once associated with a COVID-19-like illness hospitalization during January-September 2021 and at least once earlier (since February 1, 2020, and ≥14 days before that hospitalization). Among COVID-19-like illness hospitalizations in persons whose previous infection or vaccination occurred 90-179 days earlier, the odds of laboratory-confirmed COVID-19 (adjusted for sociodemographic and health characteristics) among unvaccinated, previously infected adults were higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine with no previous documented infection (adjusted odds ratio [aOR] = 5.49; 95% confidence interval [CI] = 2.75-10.99). These findings suggest that among hospitalized adults with COVID-19-like illness whose previous infection or vaccination occurred 90-179 days earlier, vaccine-induced immunity was more protective than infection-induced immunity against laboratory-confirmed COVID-19. All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2.
Authors: Bozio, Catherine H; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Stenehjem, Edward; et al.
MMWR Morb Mortal Wkly Rep. 2021 Nov 05;70(44):1539-1544. Epub 2021-11-05.
Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults – Nine States, January-September 2021
Immunocompromised persons, defined as those with suppressed humoral or cellular immunity resulting from health conditions or medications, account for approximately 3% of the U.S. adult population (1). Immunocompromised adults are at increased risk for severe COVID-19 outcomes (2) and might not acquire the same level of protection from COVID-19 mRNA vaccines as do immunocompetent adults (3,4). To evaluate vaccine effectiveness (VE) among immunocompromised adults, data from the VISION Network* on hospitalizations among persons aged ≥18 years with COVID-19-like illness from 187 hospitals in nine states during January 17-September 5, 2021 were analyzed. Using selected discharge diagnoses,† VE against COVID-19-associated hospitalization conferred by completing a 2-dose series of an mRNA COVID-19 vaccine ≥14 days before the index hospitalization date§ (i.e., being fully vaccinated) was evaluated using a test-negative design comparing 20,101 immunocompromised adults (10,564 [53%] of whom were fully vaccinated) and 69,116 immunocompetent adults (29,456 [43%] of whom were fully vaccinated). VE of 2 doses of mRNA COVID-19 vaccine against COVID-19-associated hospitalization was lower among immunocompromised patients (77%; 95% confidence interval [CI] = 74%-80%) than among immunocompetent patients (90%; 95% CI = 89%-91%). This difference persisted irrespective of mRNA vaccine product, age group, and timing of hospitalization relative to SARS-CoV-2 (the virus that causes COVID-19) B.1.617.2 (Delta) variant predominance in the state of hospitalization. VE varied across immunocompromising condition subgroups, ranging from 59% (organ or stem cell transplant recipients) to 81% (persons with a rheumatologic or inflammatory disorder). Immunocompromised persons benefit from mRNA COVID-19 vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons, and VE varies among immunocompromised subgroups. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive 3 doses and a booster, consistent with CDC recommendations (5), practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes.
Authors: Embi, Peter J; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; DeSilva, Malini B; et al.
MMWR Morb Mortal Wkly Rep. 2021 Nov 05;70(44):1553-1559. Epub 2021-11-05.
Human immunodeficiency virus infection and risks of morbidity and death in adults with incident heart failure
Human immunodeficiency virus (HIV) increases the risk of heart failure (HF), but whether it influences subsequent morbidity and mortality remains unclear. We investigated the risks of hospitalization for HF, HF-related emergency department (ED) visits, and all-cause death in an observational cohort of incident HF patients with and without HIV using data from three large US integrated healthcare delivery systems. We estimated incidence rates and adjusted hazard ratios (aHRs) by HIV status at the time of HF diagnosis for subsequent outcomes. We identified 448 persons living with HIV (PLWH) and 3429 without HIV who developed HF from a frequency-matched source cohort of 38 868 PLWH and 386 586 without HIV. Mean age was 59.5 ± 11.3 years with 9.8% women and 31.8% Black, 13.1% Hispanic, and 2.2% Asian/Pacific Islander. Compared with persons without HIV, PLWH had similar adjusted rates of HF hospitalization [aHR 1.01, 95% confidence interval (CI): 0.81-1.26] and of HF-related ED visits [aHR 1.22 (95% CI: 0.99-1.50)], but higher adjusted rates of all-cause death [aHR 1.31 (95% CI: 1.08-1.58)]. Adjusted rates of HF-related morbidity and all-cause death were directionally consistent across a wide range of CD4 counts but most pronounced in the subset with a baseline CD4 count <200 or 200-499 cells/μL. In a large, diverse cohort of adults with incident HF receiving care within integrated healthcare delivery systems, PLWH were at an independently higher risk of all-cause death but not HF hospitalizations or HF-related ED visits. Future studies investigating modifiable HIV-specific risk factors may facilitate more personalized care to optimize outcomes for PLWH and HF.
Authors: Avula, Harshith R; Ambrosy, Andrew P; Silverberg, Michael J; Lee, Keane K; Go, Alan S; et al.
Eur Heart J Open. 2021 Nov;1(3):oeab040. Epub 2021-12-01.
Improved gonorrhea and chlamydia testing among men who have sex with men living with HIV through implementation of self-collected tests
We implemented self-collected gonorrhea/chlamydia testing in 17 medical centers in California serving men who have sex with men living with HIV. From 2012 to 2018, gonorrhea/chlamydia testing increased from 45.2% to 63.4%. Among those tested, rectal testing increased from 42.0% to 77.3%; pharyngeal testing increased from 31.0% to 79.9% (all, Ptrend < 0.0001).
Authors: Park, Ina U; Reminick, Dominique; Schapiro, Jeffrey M; Hurley, Leo B; Hare, Charles Brad; Slome, Sally; Flamm, Jason A; Anderson, Alexandra; Silverberg, Michael J; Allerton, Michael W
Sex Transm Dis. 2021 11 01;48(11):e165-e167.
COVID-19 Vaccination and Non-COVID-19 Mortality Risk – Seven Integrated Health Care Organizations, United States, December 14, 2020-July 31, 2021
By September 21, 2021, an estimated 182 million persons in the United States were fully vaccinated against COVID-19.* Clinical trials indicate that Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Janssen (Johnson & Johnson; Ad.26.COV2.S) vaccines are effective and generally well tolerated (1-3). However, daily vaccination rates have declined approximately 78% since April 13, 2021†; vaccine safety concerns have contributed to vaccine hesitancy (4). A cohort study of 19,625 nursing home residents found that those who received an mRNA vaccine (Pfizer-BioNTech or Moderna) had lower all-cause mortality than did unvaccinated residents (5), but no studies comparing mortality rates within the general population of vaccinated and unvaccinated persons have been conducted. To assess mortality not associated with COVID-19 (non-COVID-19 mortality) after COVID-19 vaccination in a general population setting, a cohort study was conducted during December 2020-July 2021 among approximately 11 million persons enrolled in seven Vaccine Safety Datalink (VSD) sites.§ After standardizing mortality rates by age and sex, this study found that COVID-19 vaccine recipients had lower non-COVID-19 mortality than did unvaccinated persons. After adjusting for demographic characteristics and VSD site, this study found that adjusted relative risk (aRR) of non-COVID-19 mortality for the Pfizer-BioNTech vaccine was 0.41 (95% confidence interval [CI] = 0.38-0.44) after dose 1 and 0.34 (95% CI = 0.33-0.36) after dose 2. The aRRs of non-COVID-19 mortality for the Moderna vaccine were 0.34 (95% CI = 0.32-0.37) after dose 1 and 0.31 (95% CI = 0.30-0.33) after dose 2. The aRR after receipt of the Janssen vaccine was 0.54 (95% CI = 0.49-0.59). There is no increased risk for mortality among COVID-19 vaccine recipients. This finding reinforces the safety profile of currently approved COVID-19 vaccines in the United States.
Authors: Xu, Stanley; Klein, Nicola P; Qian, Lei; et al.
MMWR Morb Mortal Wkly Rep. 2021 Oct 29;70(43):1520-1524. Epub 2021-10-29.
The Adjuvanted Recombinant Zoster Vaccine in Adults Aged ≥65 Years Previously Vaccinated With a Live-Attenuated Herpes Zoster Vaccine
Efficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients. Adults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)-specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed. Through 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed. RZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected. NCT02581410.
Authors: Dagnew AF; Klein NP; Hervé C; Kalema G; Di Paolo E; Peterson J; Salaun B; Schuind A
J Infect Dis. 2021 10 13;224(7):1139-1146.
Surveillance for Adverse Events After COVID-19 mRNA Vaccination
Safety surveillance of vaccines against COVID-19 is critical to ensure safety, maintain trust, and inform policy. To monitor 23 serious outcomes weekly, using comprehensive health records on a diverse population. This study represents an interim analysis of safety surveillance data from Vaccine Safety Datalink. The 10 162 227 vaccine-eligible members of 8 participating US health plans were monitored with administrative data updated weekly and supplemented with medical record review for selected outcomes from December 14, 2020, through June 26, 2021. Receipt of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccination, with a risk interval of 21 days for individuals after vaccine dose 1 or 2 compared with an interval of 22 to 42 days for similar individuals after vaccine dose 1 or 2. Incidence of serious outcomes, including acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome. Incidence of events that occurred among vaccine recipients 1 to 21 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. For a signal, a 1-sided P < .0048 was required to keep type I error below .05 during 2 years of weekly analyses. For 4 additional outcomes, including anaphylaxis, only descriptive analyses were conducted. A total of 11 845 128 doses of mRNA vaccines (57% BNT162b2; 6 175 813 first doses and 5 669 315 second doses) were administered to 6.2 million individuals (mean age, 49 years; 54% female individuals). The incidence of events per 1 000 000 person-years during the risk vs comparison intervals for ischemic stroke was 1612 vs 1781 (RR, 0.97; 95% CI, 0.87-1.08); for appendicitis, 1179 vs 1345 (RR, 0.82; 95% CI, 0.73-0.93); and for acute myocardial infarction, 935 vs 1030 (RR, 1.02; 95% CI, 0.89-1.18). No vaccine-outcome association met the prespecified requirement for a signal. Incidence of confirmed anaphylaxis was 4.8 (95% CI, 3.2-6.9) per million doses of BNT162b2 and 5.1 (95% CI, 3.3-7.6) per million doses of mRNA-1273. In interim analyses of surveillance of mRNA COVID-19 vaccines, incidence of selected serious outcomes was not significantly higher 1 to 21 days postvaccination compared with 22 to 42 days postvaccination. While CIs were wide for many outcomes, surveillance is ongoing.
Authors: Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Weintraub, Eric S; et al.
JAMA. 2021 10 12;326(14):1390-1399.
City-wide school-located influenza vaccination: A retrospective cohort study
We measured the effectiveness of a city-wide school-located influenza vaccination (SLIV) program implemented in over 102 elementary schools in Oakland, California. We conducted a retrospective cohort study among Kaiser Permanente Northern California (KPNC) members of all ages residing in either the intervention or a multivariate-matched comparison site from September 2011 – August 2017. Outcomes included medically attended acute respiratory illness (MAARI), influenza hospitalization, and Oseltamivir prescriptions. We estimated difference-in-differences (DIDs) in 2014-15, 2015-16, and 2016-17 using generalized linear models and adjusted for race, ethnicity, age, sex, health plan, and language. Pre-intervention member characteristics were similar between sites. The proportion of KPNC members vaccinated for influenza by KPNC or the SLIV program was 8-11% higher in the intervention site than the comparison site during the intervention period. Among school-aged children, SLIV was associated with lower Oseltamivir prescriptions per 1,000 (DIDs: -3.5 (95% CI -5.5, -1.5) in 2015-16; -4.0 (95% CI -6.5, -1.6) in 2016-17) but not with other outcomes. SLIV was associated with lower MAARI per 1,000 in adults 65 + years (2014-15: -13.2, 95% CI -23.2, -3.2; 2015-16: -21.5, 95% CI -31.1, -11.9; 2016-17: -13.0, 95% CI -23.2, -2.9). There were few significant associations with other outcomes among adults. A city-wide SLIV intervention was associated with higher influenza vaccination coverage, lower Oseltamivir prescriptions in school-aged children, and lower MAARI among people over 65 years, suggesting possible indirect effects of SLIV among older adults.
Authors: Benjamin-Chung, Jade; Klein, Nicola P; Colford, John M; et al.
Vaccine. 2021 10 08;39(42):6302-6307. Epub 2021-09-14.
Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings
There are limited data on the effectiveness of the vaccines against symptomatic coronavirus disease 2019 (Covid-19) currently authorized in the United States with respect to hospitalization, admission to an intensive care unit (ICU), or ambulatory care in an emergency department or urgent care clinic. We conducted a study involving adults (≥50 years of age) with Covid-19-like illness who underwent molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We assessed 41,552 admissions to 187 hospitals and 21,522 visits to 221 emergency departments or urgent care clinics during the period from January 1 through June 22, 2021, in multiple states. The patients’ vaccination status was documented in electronic health records and immunization registries. We used a test-negative design to estimate vaccine effectiveness by comparing the odds of a positive test for SARS-CoV-2 infection among vaccinated patients with those among unvaccinated patients. Vaccine effectiveness was adjusted with weights based on propensity-for-vaccination scores and according to age, geographic region, calendar time (days from January 1, 2021, to the index date for each medical visit), and local virus circulation. The effectiveness of full messenger RNA (mRNA) vaccination (≥14 days after the second dose) was 89% (95% confidence interval [CI], 87 to 91) against laboratory-confirmed SARS-CoV-2 infection leading to hospitalization, 90% (95% CI, 86 to 93) against infection leading to an ICU admission, and 91% (95% CI, 89 to 93) against infection leading to an emergency department or urgent care clinic visit. The effectiveness of full vaccination with respect to a Covid-19-associated hospitalization or emergency department or urgent care clinic visit was similar with the BNT162b2 and mRNA-1273 vaccines and ranged from 81% to 95% among adults 85 years of age or older, persons with chronic medical conditions, and Black or Hispanic adults. The effectiveness of the Ad26.COV2.S vaccine was 68% (95% CI, 50 to 79) against laboratory-confirmed SARS-CoV-2 infection leading to hospitalization and 73% (95% CI, 59 to 82) against infection leading to an emergency department or urgent care clinic visit. Covid-19 vaccines in the United States were highly effective against SARS-CoV-2 infection requiring hospitalization, ICU admission, or an emergency department or urgent care clinic visit. This vaccine effectiveness extended to populations that are disproportionately affected by SARS-CoV-2 infection. (Funded by the Centers for Disease Control and Prevention.).
Authors: Thompson, Mark G; Fireman, Bruce; Zerbo, Ousseny; Klein, Nicola P; et al.
N Engl J Med. 2021 10 07;385(15):1355-1371. Epub 2021-09-08.
CD4 count at entry into HIV care and at antiretroviral therapy prescription in the US, 2005-2018
From 2005 to 2018, among 32013 adults with human immunodeficiency virus entering care, median time to antiretroviral therapy (ART) prescription declined from 69 to 6 days, CD4 count at entry into care increased from 300 to 362 cells/μL, and CD4 count at ART prescription increased from 160 to 364 cells/μL.
Authors: Lee, Jennifer S; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD),; et al.
Clin Infect Dis. 2021 10 05;73(7):e2334-e2337.
Clinical effectiveness of integrase strand transfer inhibitor-based antiretroviral regimens among adults with human immunodeficiency virus: a collaboration of cohort studies in the United States and Canada
Integrase strand transfer inhibitor (InSTI)-based regimens are now recommended as first-line antiretroviral therapy (ART) for adults with human immunodeficiency virus, but evidence on long-term clinical effectiveness of InSTI-based regimens remains limited. We examined whether InSTI-based regimens improved longer-term clinical outcomes. We included participants from clinical cohorts in the North American AIDS Cohort Collaboration on Research and Design who initiated their first ART regimen, containing either InSTI (ie, raltegravir, dolutegravir, and elvitegravir-cobicistat) or efavirenz (EFV) as an active comparator, between 2009 and 2016. We estimated observational analogs of 6-year intention-to-treat and per-protocol risks, risk differences (RDs), and hazard ratios (HRs) for the composite outcome of AIDS, acute myocardial infarction, stroke, end-stage renal disease, end-stage liver disease, or death. Of 15 993 participants, 5824 (36%) initiated an InSTI-based and 10 169 (64%) initiated an EFV-based regimen. During the 6-year follow-up, 440 in the InSTI group and 1097 in the EFV group incurred the composite outcome. The estimated 6-year intention-to-treat risks were 14.6% and 14.3% for the InSTI and EFV groups, respectively, corresponding to a RD of 0.3% (95% confidence interval, -2.7% to 3.3%) and a HR of 1.08 (.97-1.19); the estimated 6-year per-protocol risks were 12.2% for the InSTI group and 11.9% for the EFV group, corresponding to a RD of 0.3% (-3.0% to 3.7%) and a HR of 1.09 (.96-1.25). InSTI- and EFV-based initial ART regimens had similar 6-year composite clinical outcomes. The risk of adverse clinical outcomes remains substantial even when initiating modern ART.
Authors: Lu, Haidong; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS,; et al.
Clin Infect Dis. 2021 10 05;73(7):e1408-e1414.
Safety and Immunogenicity of a 20-valent Pneumococcal Conjugate Vaccine in Healthy Infants in the United States
The development and widespread use of pneumococcal conjugate vaccines (PCVs) substantially reduced the global burden of pneumococcal disease. Expanding the serotypes covered by PCVs may further reduce disease burden. A 20-valent PCV (PCV20) has been developed to add coverage for 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F and 33F) to those in the existing 13-valent PCV (PCV13). This phase 2 study evaluated the safety, tolerability and immunogenicity of PCV20 in healthy US infants. In this randomized, active-controlled, double-blind study, 460 infants were randomized 1:1 to receive a 4-dose series of either PCV20 or PCV13 at 2, 4, 6 and 12 months of age. Solicited local reactions and systemic events, adverse events (AEs) and serious AEs were recorded. Immunogenicity was assessed by measuring serotype-specific IgG concentrations and opsonophagocytic activity titers at 1 month after Dose 3, before Dose 4 and 1 month after Dose 4. Of 460 infants, 82.8% completed the 1-month visit after Dose 4. Local reactions and systemic events were mostly mild to moderate in severity and similar between the PCV20 and PCV13 groups. Treatment-related AEs were uncommon, with no related serious AEs or deaths reported. IgG and opsonophagocytic activity responses elicited by PCV20 were robust and demonstrated a booster response after Dose 4. Administration of PCV20 in US infants was well tolerated, with a safety profile similar to PCV13, and induced robust serotype-specific immune responses. These findings support continued development of PCV20 in the pediatric population.
Authors: Senders, Shelly; Lamberth, Erik; Watson, Wendy; et al.
Pediatr Infect Dis J. 2021 10 01;40(10):944-951.
Survey of Dermatologic Procedures in Transgender Adults
Dermatologists have the opportunity to provide medically necessary procedures, including laser hair removal, to transgender patients for gender affirmation. Further research is required to better assess the unique dermatologic needs of this population. To examine the prevalence of dermatologic procedures among transgender people in the context of gender-affirming treatment. This cross-sectional study examined survey responses from 696 transgender persons enrolled in the Study of Transition, Outcomes, and Gender cohort. Prevalence of self-reported dermatologic procedures was examined and compared across participant subgroups. Electrolysis was the most commonly reported procedure (32.9%). Transfeminine patients were more likely to use dermatologic procedures compared with transmasculine patients. Only 19 participants (2.8%) reported the use of dermal filler injections. Differences in utilization of dermatologic procedures were noted in transgender populations. Motivations, barriers, and optimal timing for gender-affirming dermatologic procedures among transgender persons should be examined in future studies.
Authors: Ragmanauskaite, Laura; Zhang, Qi; Kim, Jin; Getahun, Darios; Silverberg, Michael J; Goodman, Michael; Yeung, Howa
Dermatol Surg. 2021 10 01;47(10):1379-1383.
Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19-Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B.1.617.2 (Delta) Variant Predominance – Nine States, June-August 2021
Data on COVID-19 vaccine effectiveness (VE) since the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, became the predominant circulating strain in the United States are limited (1-3). CDC used the VISION Network* to examine medical encounters (32,867) from 187 hospitals and 221 emergency departments (EDs) and urgent care (UC) clinics across nine states during June-August 2021, beginning on the date the Delta variant accounted for >50% of sequenced isolates in each medical facility’s state. VISION Network methods have been published (4).
Authors: Grannis, Shaun J; Rowley, Elizabeth A; Ong, Toan C; Stenehjem, Edward; Klein, Nicola P; DeSilva, Malini B; Naleway, Allison L; Natarajan, Karthik; Thompson, Mark G; VISION Network,
MMWR Morb Mortal Wkly Rep. 2021 Sep 17;70(37):1291-1293. Epub 2021-09-17.
A phase 3, randomized, double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age
Introduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20. This phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18-49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28-42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated. Equivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups. Three different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).
Authors: Klein, Nicola P; Peyrani, Paula; Yacisin, Kari; Caldwell, Nicole; Xu, Xia; Scully, Ingrid L; Scott, Daniel A; Jansen, Kathrin U; Gruber, William C; Watson, Wendy
Vaccine. 2021 09 07;39(38):5428-5435. Epub 2021-07-24.
Longitudinal Changes in Liver Enzyme Levels Among Transgender People Receiving Gender Affirming Hormone Therapy
The effect of gender affirming hormone therapy (GAHT) on clinical laboratory parameters, including levels of liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST), is an area of uncertainty in transgender health. We sought to estimate the distribution parameters of liver enzyme levels among transmasculine (TM) and transfeminine (TF) persons receiving GAHT relative to the corresponding measures in cisgender reference groups, and to evaluate longitudinal changes in these laboratory measures following GAHT initiation. The data for this longitudinal study included 624 TF and 438 transmasculine (TM) people as well as 4,090 cisgender males and 4,797 cisgender females enrolled in 3 integrated health systems. Time under observation was divided into 2 intervals: from the first blood test to the date of the first filled GAHT prescription and from GAHT initiation to the most recent ALT or AST measurement. Linear mixed models were used to compare changes in log-transformed ALT and AST values among transgender cohort members before and after GAHT initiation, and relative to the reference groups. The results were expressed as relative differences (in %) and the ratios of these differences (ratios-of-ratios) along with the 95% confidence intervals (CIs). Changes in ALT and AST levels among transgender people over time and relative to the corresponding changes in cisgender referents. Among TM study participants, the post GAHT ratios-of-ratios for AST were 1.61 (95% CI: 1.13, 2.31) and 1.57 (95% CI: 1.06, 2.31) relative to cisgender males and females respectively. For ALT, the corresponding comparisons yielded the ratios-of-ratios (95% CIs) of 2.06 (1.67, 2.54) and 1.90 (1.50, 2.40). No statistically significant changes were observed among TF participants. Other factors associated with higher liver enzyme levels included alcohol use/abuse and obesity. TM persons may experience modest increases in ALT and AST concentrations following testosterone initiation; however, clinical significance of the observed association remains unclear and requires further investigation. By contrast, feminizing GAHT is unlikely to induce appreciable changes in liver enzyme levels. The strengths of this study are the longitudinal design and the ability to assemble an unselected cohort nested within large health systems. The main limitations include the lack of information on hormone levels and the inability to take into account GAHT doses and routes of administration. The influence of long-term GAHT on ALT and AST levels appears modest and not likely to reflect clinically meaningful changes in liver function. Hashemi L, Zhang Q, Getahun D, et al. Longitudinal Changes in Liver Enzyme Levels Among Transgender People Receiving Gender Affirming Hormone Therapy. J Sex Med 2021;18:1662-1675.
Authors: Hashemi, Leila; Zhang, Qi; Getahun, Darios; Jasuja, Guneet K; McCracken, Courtney; Pisegna, Joseph; Roblin, Douglas; Silverberg, Michael J; Tangpricha, Vin; Vupputuri, Suma; Goodman, Michael
J Sex Med. 2021 09;18(9):1662-1675. Epub 2021-08-05.
Mortality Among Persons Entering HIV Care Compared With the General U.S. Population : An Observational Study
Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population. To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time. Observational cohort study. Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design. 82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics. Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function. Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017. Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors. Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. National Institutes of Health.
Authors: Edwards, Jessie K; Silverberg, Michael J; Eron, Joseph J; et al.
Ann Intern Med. 2021 09;174(9):1197-1206. Epub 2021-07-06.
Risk of Hepatocellular Carcinoma with Hepatitis B Viremia among HIV/Hepatitis B Virus-Coinfected Persons in North America
Chronic HBV is the predominant cause of HCC worldwide. Although HBV coinfection is common in HIV, the determinants of HCC in HIV/HBV coinfection are poorly characterized. We examined the predictors of HCC in a multicohort study of individuals coinfected with HIV/HBV. We included persons coinfected with HIV/HBV within 22 cohorts of the North American AIDS Cohort Collaboration on Research and Design (1995-2016). First occurrence of HCC was verified by medical record review and/or cancer registry. We used multivariable Cox regression to determine adjusted HRs (aHRs [95% CIs]) of factors assessed at cohort entry (age, sex, race, body mass index), ever during observation (heavy alcohol use, HCV), or time-updated (HIV RNA, CD4+ percentage, diabetes mellitus, HBV DNA). Among 8,354 individuals coinfected with HIV/HBV (median age, 43 years; 93% male; 52.4% non-White), 115 HCC cases were diagnosed over 65,392 person-years (incidence rate, 1.8 [95% CI, 1.5-2.1] events/1,000 person-years). Risk factors for HCC included age 40-49 years (aHR, 1.97 [1.22-3.17]), age ≥50 years (aHR, 2.55 [1.49-4.35]), HCV coinfection (aHR, 1.61 [1.07-2.40]), and heavy alcohol use (aHR, 1.52 [1.04-2.23]), while time-updated HIV RNA >500 copies/mL (aHR, 0.90 [0.56-1.43]) and time-updated CD4+ percentage <14% (aHR, 1.03 [0.56-1.90]) were not. The risk of HCC was increased with time-updated HBV DNA >200 IU/mL (aHR, 2.22 [1.42-3.47]) and was higher with each 1.0 log10 IU/mL increase in time-updated HBV DNA (aHR, 1.18 [1.05-1.34]). HBV suppression with HBV-active antiretroviral therapy (ART) for ≥1 year significantly reduced HCC risk (aHR, 0.42 [0.24-0.73]). Individuals coinfected with HIV/HBV on ART with detectable HBV viremia remain at risk for HCC. To gain maximal benefit from ART for HCC prevention, sustained HBV suppression is necessary.
Authors: Kim, H Nina; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research, Design of IeDEA,; et al.
Hepatology. 2021 09;74(3):1190-1202. Epub 2021-06-22.
Current and Past Immunodeficiency Are Associated With Higher Hospitalization Rates Among Persons on Virologically Suppressive Antiretroviral Therapy for up to 11 Years
Persons with human immunodeficiency virus (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk. In 6 US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005-2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by early (years 2-5) and long-term (years 6-11) suppression and lowest presuppression CD4 count <200 and ≥200 cells/µL, Poisson regression models estimated hospitalization incidence rate ratios (aIRRs) comparing patients by time-updated CD4 count category, adjusted for cohort, age, gender, calendar year, suppression duration, and lowest presuppression CD4 count. The 6997 included patients (19 980 person-years) were 81% cisgender men and 40% white. Among patients with lowest presuppression CD4 count <200 cells/μL (44%), patients with current CD4 count 200-350 vs >500 cells/μL had aIRRs of 1.44 during early suppression (95% confidence interval [CI], 1.01-2.06), and 1.67 (95% CI, 1.03-2.72) during long-term suppression. Among patients with lowest presuppression CD4 count ≥200 (56%), patients with current CD4 351-500 vs >500 cells/μL had an aIRR of 1.22 (95% CI, .93-1.60) during early suppression and 2.09 (95% CI, 1.18-3.70) during long-term suppression. Virologically suppressed patients with lower CD4 counts experienced higher hospitalization rates and could potentially benefit from targeted clinical management strategies.
Authors: Davy-Mendez, Thibaut; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA); et al.
J Infect Dis. 2021 08 16;224(4):657-666. Epub 2020-12-26.
Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices – United States, July 2021
In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for Pfizer-BioNTech and Moderna COVID-19 vaccines, and in February 2021, FDA issued an EUA for the Janssen (Johnson & Johnson) COVID-19 vaccine. After each EUA, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for vaccine use; currently Pfizer-BioNTech is authorized and recommended for persons aged ≥12 years and Moderna and Janssen for persons aged ≥18 years (1-3). Both Pfizer-BioNTech and Moderna vaccines, administered as 2-dose series, are mRNA-based COVID-19 vaccines, whereas the Janssen COVID-19 vaccine, administered as a single dose, is a recombinant replication-incompetent adenovirus-vector vaccine. As of July 22, 2021, 187 million persons in the United States had received at least 1 dose of COVID-19 vaccine (4); close monitoring of safety surveillance has demonstrated that serious adverse events after COVID-19 vaccination are rare (5,6). Three medical conditions have been reported in temporal association with receipt of COVID-19 vaccines. Two of these (thrombosis with thrombocytopenia syndrome [TTS], a rare syndrome characterized by venous or arterial thrombosis and thrombocytopenia, and Guillain-Barré syndrome [GBS], a rare autoimmune neurologic disorder characterized by ascending weakness and paralysis) have been reported after Janssen COVID-19 vaccination. One (myocarditis, cardiac inflammation) has been reported after Pfizer-BioNTech COVID-19 vaccination or Moderna COVID-19 vaccination, particularly after the second dose; these were reviewed together and will hereafter be referred to as mRNA COVID-19 vaccination. ACIP has met three times to review the data associated with these reports of serious adverse events and has comprehensively assessed the benefits and risks associated with receipt of these vaccines. During the most recent meeting in July 2021, ACIP determined that, overall, the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and mortality outweigh the risks for these rare serious adverse events in adults aged ≥18 years; this balance of benefits and risks varied by age and sex. ACIP continues to recommend COVID-19 vaccination in all persons aged ≥12 years. CDC and FDA continue to closely monitor reports of serious adverse events and will present any additional data to ACIP for consideration. Information regarding risks and how they vary by age and sex and type of vaccine should be disseminated to providers, vaccine recipients, and the public.
Authors: Rosenblum, Hannah G; Klein, Nicola P; Oliver, Sara E; et al.
MMWR Morb Mortal Wkly Rep. 2021 Aug 13;70(32):1094-1099. Epub 2021-08-13.
Characterization of HIV Preexposure Prophylaxis Use Behaviors and HIV Incidence Among US Adults in an Integrated Health Care System
Long-term follow-up is needed to evaluate gaps in HIV preexposure prophylaxis (PrEP) care delivery and to identify individuals at risk for falling out of care. To characterize the PrEP continuum of care, including prescription, initiation, discontinuation, and reinitiation, and evaluate incident HIV infections. This retrospective cohort study used data from the electronic health records (EHR) at Kaiser Permanente Northern California to identify individuals aged 18 years and older who received PrEP care between July 2012 and March 2019. Individuals were followed up from date of linkage (defined as a PrEP referral or PrEP-coded encounter) until March 2019, HIV diagnosis, discontinuation of health plan membership, or death. Data were analyzed from December 2019 to January 2021. Sociodemographic factors included age, sex, race and ethnicity, and neighborhood deprivation index, and clinical characteristics were extracted from the EHR. The primary outcomes were attrition at each step of the PrEP continuum of care and incident HIV infections. Among 13 906 individuals linked to PrEP care, the median (interquartile range [IQR]) age was 33 (27-43) years, 6771 individuals (48.7%) were White, and 13 227 (95.1%) were men. Total follow-up was 26 210 person-years (median [IQR], 1.6 [0.7-2.8] years). Of individuals linked to PrEP care, 88.1% (95% CI, 86.1%-89.9%) were prescribed PrEP and of these, 98.2% (95% CI, 97.2%-98.8%) initiated PrEP. After PrEP initiation, 52.2% (95% CI, 48.9%-55.7%) discontinued PrEP at least once during the study period, and 60.2% (95% CI, 52.2%-68.3%) of these individuals subsequently reinitiated. Compared with individuals aged 18 to 25 years, older individuals were more likely to receive a PrEP prescription (eg, age >45 years: hazard ratio [HR], 1.21 [95% CI, 1.14-1.29]) and initiate PrEP (eg, age >45 years: HR, 1.09 [95% CI, 1.02-1.16]) and less likely to discontinue (eg, age >45 years: HR, 0.46 [95% CI, 0.42-0.52]). Compared with White patients, African American and Latinx individuals were less likely to receive a PrEP prescription (African American: HR, 0.74 [95% CI, 0.69-0.81]; Latinx: HR, 0.88 [95% CI, 0.84-0.93]) and initiate PrEP (African American: HR, 0.87 [95% CI, 0.80-0.95]; Latinx: HR, 0.90 [95% CI, 0.86-0.95]) and more likely to discontinue (African American: HR, 1.36 [95% CI, 1.17-1.57]; Latinx: 1.33 [95% CI, 1.22-1.46]). Similarly, women, individuals with lower neighborhood-level socioeconomic status (SES), and persons with a substance use disorder (SUD) were less likely to be prescribed (women: HR, 0.56 [95% CI, 0.50-0.62]; lowest SES: HR, 0.72 [95% CI, 0.68-0.76]; SUD: HR, 0.88 [95% CI, 0.82-0.94]) and initiate PrEP (women: HR, 0.71 [95% CI, 0.64-0.80]; lower SES: HR, 0.93 [95% CI, 0.87-.0.99]; SUD: HR, 0.88 [95% CI, 0.81-0.95]) and more likely to discontinue (women: HR, 1.99 [95% CI, 1.67-2.38]); lower SES: HR, 1.40 [95% CI, 1.26-1.57]; SUD: HR, 1.23 [95% CI, 1.09-1.39]). HIV incidence was highest among individuals who discontinued PrEP and did not reinitiate PrEP (1.28 [95% CI, 0.93-1.76] infections per 100 person-years). These findings suggest that gaps in the PrEP care continuum were concentrated in populations disproportionately impacted by HIV, including African American individuals, Latinx individuals, young adults (aged 18-25 years), and individuals with SUD. Comprehensive strategies to improve PrEP continuum outcomes are needed to maximize PrEP impact and equity.
Authors: Hojilla, J Carlo; Hurley, Leo B; Marcus, Julia L; Silverberg, Michael J; Skarbinski, Jacek; Satre, Derek D; Volk, Jonathan E
JAMA Netw Open. 2021 08 02;4(8):e2122692. Epub 2021-08-02.
COVID-19 Vaccination Coverage Among Insured Persons Aged ≥16 Years, by Race/Ethnicity and Other Selected Characteristics – Eight Integrated Health Care Organizations, United States, December 14, 2020-May 15, 2021
COVID-19 vaccination is critical to ending the COVID-19 pandemic. Members of minority racial and ethnic groups have experienced disproportionate COVID-19-associated morbidity and mortality (1); however, COVID-19 vaccination coverage is lower in these groups (2). CDC used data from CDC’s Vaccine Safety Datalink (VSD)* to assess disparities in vaccination coverage among persons aged ≥16 years by race and ethnicity during December 14, 2020-May 15, 2021. Measures of coverage included receipt of ≥1 COVID-19 vaccine dose (i.e., receipt of the first dose of the Pfizer-BioNTech or Moderna COVID-19 vaccines or 1 dose of the Janssen COVID-19 vaccine [Johnson & Johnson]) and full vaccination (receipt of 2 doses of the Pfizer-BioNTech or Moderna COVID-19 vaccines or 1 dose of Janssen COVID-19 vaccine). Among 9.6 million persons aged ≥16 years enrolled in VSD during December 14, 2020-May 15, 2021, ≥1-dose coverage was 48.3%, and 38.3% were fully vaccinated. As of May 15, 2021, coverage with ≥1 dose was lower among non-Hispanic Black (Black) and Hispanic persons (40.7% and 41.1%, respectively) than it was among non-Hispanic White (White) persons (54.6%). Coverage was highest among non-Hispanic Asian (Asian) persons (57.4%). Coverage with ≥1 dose was higher among persons with certain medical conditions that place them at higher risk for severe COVID-19 (high-risk conditions) (63.8%) than it was among persons without such conditions (41.5%) and was higher among persons who had not had COVID-19 (48.8%) than it was among those who had (42.4%). Persons aged 18-24 years had the lowest ≥1-dose coverage (28.7%) among all age groups. Continued monitoring of vaccination coverage and efforts to improve equity in coverage are critical, especially among populations disproportionately affected by COVID-19.
Authors: Pingali, Cassandra; Klein, Nicola P; Fireman, Bruce; Zerbo, Ousseny; Patel, Suchita A; et al.
MMWR Morb Mortal Wkly Rep. 2021 Jul 16;70(28):985-990. Epub 2021-07-16.
Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents
Until very recently, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had not been authorized for emergency use in persons younger than 16 years of age. Safe, effective vaccines are needed to protect this population, facilitate in-person learning and socialization, and contribute to herd immunity. In this ongoing multinational, placebo-controlled, observer-blinded trial, we randomly assigned participants in a 1:1 ratio to receive two injections, 21 days apart, of 30 μg of BNT162b2 or placebo. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was an immunogenicity objective. Safety (reactogenicity and adverse events) and efficacy against confirmed coronavirus disease 2019 (Covid-19; onset, ≥7 days after dose 2) in the 12-to-15-year-old cohort were assessed. Overall, 2260 adolescents 12 to 15 years of age received injections; 1131 received BNT162b2, and 1129 received placebo. As has been found in other age groups, BNT162b2 had a favorable safety and side-effect profile, with mainly transient mild-to-moderate reactogenicity (predominantly injection-site pain [in 79 to 86% of participants], fatigue [in 60 to 66%], and headache [in 55 to 65%]); there were no vaccine-related serious adverse events and few overall severe adverse events. The geometric mean ratio of SARS-CoV-2 50% neutralizing titers after dose 2 in 12-to-15-year-old participants relative to 16-to-25-year-old participants was 1.76 (95% confidence interval [CI], 1.47 to 2.10), which met the noninferiority criterion of a lower boundary of the two-sided 95% confidence interval greater than 0.67 and indicated a greater response in the 12-to-15-year-old cohort. Among participants without evidence of previous SARS-CoV-2 infection, no Covid-19 cases with an onset of 7 or more days after dose 2 were noted among BNT162b2 recipients, and 16 cases occurred among placebo recipients. The observed vaccine efficacy was 100% (95% CI, 75.3 to 100). The BNT162b2 vaccine in 12-to-15-year-old recipients had a favorable safety profile, produced a greater immune response than in young adults, and was highly effective against Covid-19. (Funded by BioNTech and Pfizer; C4591001 ClinicalTrials.gov number, NCT04368728.).
Authors: Frenck, Robert W; Klein, Nicola P; C4591001 Clinical Trial Group,; et al.
N Engl J Med. 2021 07 15;385(3):239-250. Epub 2021-05-27.
School-level perceptions and enforcement of the elimination of nonmedical exemptions to vaccination in California
In 2015, California passed Senate Bill 277 eliminating all nonmedical exemptions to school vaccinations. We aimed to explore school-level modes of SB277 enforcement, characterize vaccination knowledge, attitudes, and beliefs of school officials, and identify whether school vaccination policies are associated with medical exemptions being granted. Surveys were mailed to a stratified random sample of 1,450 schools in California. School personnel (n = 752) reported their medical training, vaccination beliefs, enforcement of vaccination policies, and school rates of medical exemptions. Multiple logistic regression was used to assess whether school policies are associated with the likelihood of medical exemption requests being granted. Nurses were more likely than non-nurses to hold beliefs recognizing the importance of vaccination. A school where the survey respondent was a nurse was more likely to have granted a medical exemption request compared to a school where the respondent was not a nurse (OR 2.11, 95% CI 1.34-3.36). The training of school officials and school-level practices may impact the enforcement of medical exemptions. Equipping school officials as competent sources of vaccine information for concerned parents will be valuable in improving parental vaccine uptake.
Authors: Holroyd, Taylor A; Howa, Amanda C; Proveaux, Tina M; Delamater, Paul L; Klein, Nicola P; Buttenheim, Alison M; Limaye, Rupali J; Omer, Saad B; Salmon, Daniel A
Hum Vaccin Immunother. 2021 07 03;17(7):1986-1993. Epub 2021-01-25.
Factors Associated With Symptoms of Depression and Anxiety Among Women Experiencing Homelessness and Unstable Housing During the COVID-19 Pandemic
Authors: Riley, Elise D; Dilworth, Samantha E; Satre, Derek D; Silverberg, Michael J; Neilands, Torsten B; Mangurian, Christina; Weiser, Sheri D
JAMA Netw Open. 2021 07 01;4(7):e2117035. Epub 2021-07-01.
Temporal Trends in Undervaccination: A Population-Based Cohort Study
Monitoring the trends in undervaccination, including that because of parental vaccine refusal or delay, can inform public health responses directed at improving vaccine confidence and vaccination coverage. A retrospective cohort study was conducted in the Vaccine Safety Datalink. The cohort included all children born in 2004-2017 with ≥3 well-child visits between ages 2 and 23 months. Using electronic health record-based vaccination data, the average days undervaccinated was calculated for each child. Undervaccination patterns were assessed through age 23 months. Temporal trends were inspected for inflection points and were analyzed using linear regression. Nested within the cohort study, a survey was conducted to compare parent reports of vaccine refusal or delay with observed vaccination patterns. Data were analyzed in 2020. The study cohort consisted of 808,170 children. The percentage of children with average days undervaccinated=0 (fully vaccinated, no delays) rose from a nadir of 47.1% for the birth year 2008 to 68.4% for the birth year 2017 (ptrend<0.001). The percentage with no vaccines rose from 0.35% for the birth year 2004 to 1.28% for the birth year 2017 (ptrend<0.001). Consistent vaccine limiting was observed in 2.04% for the birth year 2017. Omission of measles, mumps, and rubella vaccine peaked at 4.76% in the birth year 2007 and declined thereafter (ptrend<0.001). On the parent survey (response rate 60.2%), a high proportion of parents of the most undervaccinated children reported refusing or delaying vaccines. In a 14-year cohort study, vaccination timeliness has improved. However, the small but increasing number of children who received no vaccines by age 23 months warrants additional attention.
Authors: Daley, Matthew F; Klein, Nicola P; Glanz, Jason M; et al.
Am J Prev Med. 2021 07;61(1):64-72. Epub 2021-04-30.
Progression of Gender Dysphoria in Children and Adolescents: A Longitudinal Study
The progression of gender-expansive behavior to gender dysphoria and to gender-affirming hormonal treatment (GAHT) in children and adolescents is poorly understood. A cohort of 958 gender-diverse (GD) children and adolescents who did not have a gender dysphoria-related diagnosis (GDRD) or GAHT at index were identified. Rates of first GDRD and first GAHT prescription were compared across demographic groups. Overall, 29% of participants received a GDRD and 25% were prescribed GAHT during the average follow-up of 3.5 years (maximum 9 years). Compared with youth assigned male sex at birth, those assigned female sex at birth were more likely to receive a diagnosis and initiate GAHT with hazard ratio (95% confidence interval) estimates of 1.3 (1.0-1.7), and 2.5 (1.8-3.3), respectively. A progression to diagnosis was more common among those aged ≥15 years at initial presentation compared with those aged 10 to 14 years and those aged 3 to 9 years (37% vs 28% vs 16%, respectively). By using the youngest group as a reference, the adjusted hazard ratios (95% confidence interval) for a GDRD were 2.0 (1.3-3.0) for age 10 to 14 years and 2.7 (1.8-3.9) for age ≥15 years. Racial and ethnic minorities were less likely to receive a diagnosis or be prescribed GAHT. This study characterized the progression of GD behavior in children and adolescents. Less than one-third of GD youth receive an eventual GDRD, and approximately one-quarter receive GAHT. Female sex at birth, older age of initial GD presentation to medical care, and non-Hispanic white race and ethnicity increased the likelihood of receiving diagnosis and treatment.
Authors: Wagner, Stephanie; Panagiotakopoulos, Leonidas; Nash, Rebecca; Bradlyn, Andrew; Getahun, Darios; Lash, Timothy L; Roblin, Douglas; Silverberg, Michael J; Tangpricha, Vin; Vupputuri, Suma; Goodman, Michael
Pediatrics. 2021 07;148(1). Epub 2021-06-07.
Racial, ethnic, and gender disparities in hospitalizations among persons with HIV in the United States and Canada, 2005-2015
To examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the United States and Canada. HIV clinical cohort consortium. We followed PWH at least 18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classifications Software to categorize hospital discharge diagnoses. Incidence rate ratios (IRR) were estimated using Poisson regression with robust variances to compare racial and ethnic groups, stratified by gender, adjusted for cohort, calendar year, injection drug use history, and annually updated age, CD4+, and HIV viral load. Among 27 085 patients (122 566 person-years), 80% were cisgender men, 1% transgender, 43% White, 33% Black, 17% Hispanic of any race, and 1% Indigenous. Unadjusted all-cause hospitalization rates were higher for Black [IRR 1.46, 95% confidence interval (CI) 1.32-1.61] and Indigenous (1.99, 1.44-2.74) versus White cisgender men, and for Indigenous versus White cisgender women (2.55, 1.68-3.89). Unadjusted AIDS-related hospitalization rates were also higher for Black, Hispanic, and Indigenous versus White cisgender men (all P < 0.05). Transgender patients had 1.50 times (1.05-2.14) and cisgender women 1.37 times (1.26-1.48) the unadjusted hospitalization rate of cisgender men. In adjusted analyses, among both cisgender men and women, Black patients had higher rates of cardiovascular and renal/genitourinary hospitalizations compared to Whites (all P < 0.05). Black, Hispanic, Indigenous, women, and transgender PWH in the United States and Canada experienced substantially higher hospitalization rates than White patients and cisgender men, respectively. Disparities likely have several causes, including differences in virologic suppression and chronic conditions such as diabetes and renal disease.
Authors: Davy-Mendez, Thibaut; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA,; et al.
AIDS. 2021 07 01;35(8):1229-1239.
COVID-19 Vaccination Coverage Among Pregnant Women During Pregnancy – Eight Integrated Health Care Organizations, United States, December 14, 2020-May 8, 2021
COVID-19 vaccines are critical for ending the COVID-19 pandemic; however, current data about vaccination coverage and safety in pregnant women are limited. Pregnant women are at increased risk for severe illness and death from COVID-19 compared with nonpregnant women of reproductive age, and are at risk for adverse pregnancy outcomes, such as preterm birth (1-4). Pregnant women are eligible for and can receive any of the three COVID-19 vaccines available in the United States via Emergency Use Authorization.* Data from Vaccine Safety Datalink (VSD), a collaboration between CDC and multiple integrated health systems, were analyzed to assess receipt of ≥1 dose (first or second dose of the Pfizer-BioNTech or Moderna vaccines or a single dose of the Janssen [Johnson & Johnson] vaccine) of any COVID-19 vaccine during pregnancy, receipt of first dose of a 2-dose COVID-19 vaccine (initiation), or completion of a 1- or 2-dose COVID-19 vaccination series. During December 14, 2020-May 8, 2021, a total of 135,968 pregnant women were identified, 22,197 (16.3%) of whom had received ≥1 dose of a vaccine during pregnancy. Among these 135,968 women, 7,154 (5.3%) had initiated and 15,043 (11.1%) had completed vaccination during pregnancy. Receipt of ≥1 dose of COVID-19 vaccine during pregnancy was highest among women aged 35-49 years (22.7%) and lowest among those aged 18-24 years (5.5%), and higher among non-Hispanic Asian (Asian) (24.7%) and non-Hispanic White (White) women (19.7%) than among Hispanic (11.9%) and non-Hispanic Black (Black) women (6.0%). Vaccination coverage increased among all racial and ethnic groups over the analytic period, likely because of increased eligibility for vaccination† and increased availability of vaccine over time. These findings indicate the need for improved outreach to and engagement with pregnant women, especially those from racial and ethnic minority groups who might be at higher risk for severe health outcomes because of COVID-19 (4). In addition, providing accurate and timely information about COVID-19 vaccination to health care providers, pregnant women, and women of reproductive age can improve vaccine confidence and coverage by ensuring optimal shared clinical decision-making.
Authors: Razzaghi, Hilda; Zerbo, Ousseny; Patel, Suchita A; et al.
MMWR Morb Mortal Wkly Rep. 2021 Jun 18;70(24):895-899. Epub 2021-06-18.
Incidence of pediatric inflammatory bowel disease within the Vaccine Safety Datalink network and evaluation of association with rotavirus vaccination
Recent studies have reported an increase in Inflammatory bowel disease (IBD) incidence in young children, highlighting the need to better understand risk factors for the development of IBD. Licensed for use in infants in 2006, the oral, live-attenuated rotavirus vaccine has biologic plausibility for instigating inflammation of the gut mucosa as a pathway to immune dysregulation. Over a ten-year period, we evaluated incidence of IBD within a cohort of children under the age of ten, enrolled in seven integrated healthcare delivery systems. We conducted a nested case-control study to evaluate the association between rotavirus vaccination and IBD using conditional logistic regression. Cases were confirmed via medical record review and matched to non-IBD controls on date of birth, sex, and study site. Among 2.4 million children under the age of 10 years, 333 cases of IBD were identified with onset between 2007 and 2016. The crude incidence of IBD increased slightly over the study period (p-value for trend = 0.046). Of the 333 cases, 227 (68%) were born prior to 2007. Forty-two cases born in 2007 or later, with continuous enrollment since birth were included in the case-control study and matched to 210 controls. The adjusted odds ratio for any rotavirus vaccination in IBD cases, compared to matched controls, was 0.72 (95% confidence interval 0.19-2.65). Data from this large pediatric cohort demonstrate a small overall increase in IBD incidence in young children over a ten-year period. The data suggest that rotavirus vaccination is not associated with development of IBD.
Authors: Liles, Elizabeth; Klein, Nicola P; Naleway, Allison L; et al.
Vaccine. 2021 06 16;39(27):3614-3620. Epub 2021-05-26.
Hospitalization Rates and Causes among Persons with HIV in the US and Canada, 2005-2015
To assess the possible impact of antiretroviral therapy improvements, aging, and comorbidities, we examined trends in all-cause and cause-specific hospitalization rates among persons with HIV (PWH) from 2005 to 2015. In 6 clinical cohorts, we followed PWH in care (≥1 outpatient CD4 count or HIV load [VL] every 12 months) and categorized ICD codes of primary discharge diagnoses using modified Clinical Classifications Software. Poisson regression estimated hospitalization rate ratios for calendar time trends, adjusted for demographics, HIV risk factor, and annually updated age, CD4, and VL. Among 28 057 patients (125 724 person-years), from 2005 to 2015, the median CD4 increased from 389 to 580 cells/µL and virologic suppression from 55% to 85% of patients. Unadjusted all-cause hospitalization rates decreased from 22.3 per 100 person-years in 2005 (95% confidence interval [CI], 20.6-24.1) to 13.0 in 2015 (95% CI, 12.2-14.0). Unadjusted rates decreased for almost all diagnostic categories. Adjusted rates decreased for all-cause, cardiovascular, and AIDS-defining conditions, increased for non-AIDS-defining infection, and were stable for most other categories. Among PWH with increasing CD4 counts and viral suppression, unadjusted hospitalization rates decreased for all-cause and most cause-specific hospitalizations, despite the potential effects of aging, comorbidities, and cumulative exposure to HIV and antiretrovirals.
Authors: Davy-Mendez, Thibaut; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design of IeDEA,; et al.
J Infect Dis. 2021 06 15;223(12):2113-2123.
Genetic associations with a fever after measles-containing vaccines
Children have elevated fever risk 1 to 2 weeks after the first dose of a measles-containing vaccine (MCV), which is likely affected by genetic, immunologic, and clinical factors. Fever after MCV is associated with febrile seizures, though may also be associated with higher measles antibody titers. This exploratory study investigated genetic and immunologic associations with a fever after MCV. Concurrent with a randomized Phase 3 clinical trial of 12-15-month-olds who received their first measles-mumps-rubella (MMR) vaccine in which parents recorded post-vaccination temperatures daily, we consented a subset to collect additional blood and performed human leukocyte antigens (HLA) typing. Association between fever 5-12 days after MMR (“MMR-associated”) and HLA type was assessed using logistic regression. We compared 42-day post-vaccination geometric mean titers (GMT) to measles between children who did and did not have fever using a t-test. We enrolled 86 children and performed HLA typing on 82; 13 (15.1%) had MMR-associated fever. Logistic regressions identified associations between MMR-associated fever and HLA Class I loci A-29:02 (P = .036), B-57:01 (P = .018), C-06:02 (P = .006), C-14:02 (P = .022), and Class II loci DRB1-15 (P = .045). However, Bonferroni’s adjustment for multiple comparisons suggests that these associations could have been due to chance. Ninety-eight percent of children had protective antibody titers to measles; however, GMT was higher among those with fever compared with children without fever (P = .006). Fever after the measles vaccine correlated with genetic factors and higher immune response. This study suggests a possible genetic susceptibility to MMR-associated fever.
Authors: Klein, Nicola P; Zerbo, Ousseny; Goddard, Kristin; Wang, Weiqi; Fohner, Alison E; Wiesner, Amy; Shokoohi, Vida; Coller, John; Bok, Karin; Gans, Hayley A
Hum Vaccin Immunother. 2021 06 03;17(6):1763-1769. Epub 2020-12-22.
Parental vaccine attitudes, beliefs, and practices: initial evidence in California after a vaccine policy change
Senate Bill 277 (SB277) eliminated nonmedical exemptions for school-entry vaccines in California, but the impact of parental vaccine knowledge, attitudes, and beliefs on vaccine decision-making has not been extensively examined within the post-SB277 context. This study generates preliminary understanding and discussion of the vaccination knowledge, attitudes, and beliefs among a pilot population of parents of kindergarten students in California after the implementation of SB277. School officials administered a cross-sectional survey to parents of kindergarten children in California from April to July 2019. Parents reported their perceptions of diseases and vaccines, key immunization beliefs, and confidence in different sources of vaccine information. Most parents (92%) had fully vaccinated their children post-SB277 and generally perceived vaccines to be safe and effective, but about 44% reported they were hesitant about childhood vaccines. The majority of parents (87%) rated vaccine information from their doctor as highly credible. This pilot group of kindergarten parents was generally supportive of vaccination and had fully vaccinated their children, but most parents still harbored concerns and misconceptions about vaccines and about public health authorities. This indicates a disconnect between parental vaccine compliance and confidence, and suggests that educational interventions could impact parental vaccine behavior and decision-making.
Authors: Holroyd, Taylor A; Howa, Amanda C; Delamater, Paul L; Klein, Nicola P; Buttenheim, Alison M; Limaye, Rupali J; Proveaux, Tina M; Omer, Saad B; Salmon, Daniel A
Hum Vaccin Immunother. 2021 06 03;17(6):1675-1680. Epub 2020-11-24.
Timing of Antiretroviral Therapy Initiation and Risk of Cancer among Persons Living with HIV
Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART). We evaluated AIDS-free, ART-naive PLWH during 1996-2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350-500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject’s age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses. Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37-.86), AIDS-defining cancers (HR 0.23; 95% CI, .11-.49), any virus-related cancer (HR 0.30; 95% CI, .16-.54), Kaposi sarcoma (HR 0.25; 95% CI, .10-.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06-.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference -1.6; 95% CI, -2.8, -.5). Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology.
Authors: Silverberg, Michael J; Neugebauer, Romain S; et al.
Clin Infect Dis. 2021 06 01;72(11):1900-1909.
Multisystem inflammatory syndrome in children and adults (MIS-C/A): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data
This is a Brighton Collaboration Case Definition of the term “Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A)” to be utilized in the evaluation of adverse events following immunization. The case definition was developed by topic experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2. The format of the Brighton Collaboration was followed, including an exhaustive review of the literature, to develop a consensus definition and defined levels of certainty. The document underwent peer review by the Brighton Collaboration Network and by selected expert external reviewers prior to submission. The comments of the reviewers were taken into consideration and edits incorporated into this final manuscript.
Authors: Vogel, Tiphanie P; Klein, Nicola P; Munoz, Flor M; et al.
Vaccine. 2021 05 21;39(22):3037-3049. Epub 2021-02-25.
Changes in Size and Demographic Composition of Transgender and Gender Non-Binary Population Receiving Care at Integrated Health Systems
To examine temporal changes in the number and demographic composition of transgender/gender non-binary (TGNB) population using data from integrated health care systems. Electronic health records from Kaiser Permanente health plans in Georgia and Northern and Southern California were used to identify TGNB individuals, who sought care from January 2006 to December 2014, and the data were analyzed by year, site, age, and sex assigned at birth. In 2006, the number of TGNB people (and corresponding 95% CI) per 100 000 population were 3.5 (1.9, 6.3) in Georgia, 5.5 (4.8, 6.4) in Southern California, and 17 (16, 19) in Northern California. In 2014, these frequencies increased to 38 (32, 45), 44 (42, 46), and 75 (72, 78) per 100 000 population, respectively. When analyzed by age, the most rapid increase was observed among persons 18 to 25 years old, and this increase accelerated after 2010. The ratio of transmasculine to transfeminine persons also changed from 1:1.7 in 2006 to 1:1 in 2014 overall and from 1:1 in 2006 to 1.8:1 in 2014 among persons <18 years of age. This analysis confirms previous observations that the proportion of TGNB people is growing, especially among young adults. The composition of the TGNB population is also changing from predominantly transfeminine to roughly 1:1 overall and to predominantly transmasculine in children and adolescents.
Authors: Zhang, Qi; Silverberg, Michael J; Goodman, Michael; et al.
Endocr Pract. 2021 May;27(5):390-395. Epub 2020-12-15.
Secular Trends in Breast Cancer Risk among Women with HIV Initiating ART in North America
Studies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased. Women with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016. We estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity. We observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods. These findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.
Authors: Coburn, Sally B; Silverberg, Michael J; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiology Databases to Evaluate AIDS,; et al.
J Acquir Immune Defic Syndr. 2021 05 01;87(1):663-670.
Rationale and Design of the Pragmatic Randomized Trial of Icosapent Ethyl for High Cardiovascular Risk Adults (MITIGATE)
The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California – a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.
Authors: Ambrosy, Andrew P; Solomon, Matthew D; Skarbinski, Jacek; Go, Alan S; et al.
Am Heart J. 2021 05;235:54-64. Epub 2021-01-28.
Comparison of dementia risk after age 50 between individuals with and without HIV infection
To compare risk of dementia after age 50 by HIV status among individuals in a primary care setting. Observational cohort study; participants were identified from 2013 to 2017 and followed through 2019. Participants were people with HIV (PWH) on antiretroviral therapy (ART) and demographically similar people without HIV (PWOH), all at least 50 years old and with no prior diagnosis of dementia. The study setting was Kaiser Permanente Northern California, an integrated healthcare delivery system in the United States. Incident dementia diagnoses and baseline data on sociodemographics, smoking, alcohol use, other substance use, and clinical factors were gathered from the electronic health record. Cumulative proportion of incident dementia by HIV status was assessed using Kaplan–Meier curves. Unadjusted and adjusted hazard ratios for incident dementia by HIV status were generated using Cox proportional hazards models with age as the time scale. The study included 5381 PWH and 119 022 PWOH (average age at baseline: 57 and 58 years, respectively). Incident dementia was diagnosed in 117 PWH and 2427 PWOH. By age 80, 25.8% of PWH and 13.8% of PWOH had been diagnosed with dementia, corresponding with an unadjusted hazard ratio of 1.98 (95% CI 1.64-2.39). After adjustment for sociodemographic, substance use, and clinical factors, including frequency of outpatient visits, the risk of dementia among PWH remained elevated (vs. PWOH, adjusted hazard ratio = 1.58, 95% CI 1.31-1.92). Compared with PWOH, PWH were at 58% higher risk for dementia despite HIV treatment with ART. Research is needed to investigate the potential benefits of targeted risk factor management or earlier cognitive screening in this population.
Authors: Lam, Jennifer O; Hou, Craig E; Hojilla, J Carlo; Anderson, Alexandra N; Gilsanz, Paola; Alexeeff, Stacey E; Levine-Hall, Tory; Hood, Nicole; Lee, Catherine; Satre, Derek D; Silverberg, Michael J
AIDS. 2021 04 01;35(5):821-828.
Association of Inadvertent 9-Valent Human Papillomavirus Vaccine in Pregnancy With Spontaneous Abortion and Adverse Birth Outcomes
The 9-valent human papillomavirus (9vHPV) vaccine is recommended for individuals through age 26 years and may be administered to women up to age 45 years. Data on 9vHPV vaccine exposures during pregnancy are limited. To evaluate the associations between 9vHPV vaccine exposures during pregnancy or peripregnancy and selected pregnancy and birth outcomes (spontaneous abortion [SAB], preterm birth, small-for-gestational age [SGA] birth, and major structural birth defect). This cohort study analyzed data from 7 participating health systems in the Vaccine Safety Datalink. The cohort comprised pregnancies among girls and women aged 12 to 28 years that ended between October 26, 2015, and November 15, 2018. Singleton pregnancies that ended in a live birth, stillbirth, or SAB were included. Vaccine exposure windows were distal (9vHPV or 4vHPV vaccine administered from 22 to 16 weeks before last menstrual period [LMP]), peripregnancy (9vHPV vaccine administered from 42 days before LMP until LMP), and during pregnancy (9vHPV vaccine administered from LMP to 19 completed weeks’ gestation). Primary comparisons were (1) girls and women with 9vHPV vaccine exposures during pregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, (2) girls and women with vaccine exposures peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, and (3) girls and women with 9vHPV vaccine exposures during pregnancy or peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposure. Spontaneous abortions were confirmed based on medical record review and adjudication. Preterm and SGA births were identified from electronic health record and birth data. Major structural birth defects were based on diagnostic codes using a validated algorithm. Inverse probability weighting was used to balance the covariates. Time-dependent covariate Cox proportional hazards regression models and Poisson regression were used to estimate the associations between 9vHPV vaccine exposures and pregnancy and birth outcomes. The final cohort included 1493 pregnancies among girls and women with a mean (SD) maternal age of 23.9 (2.9) years. Of these pregnancies, 445 (29.8%) had exposures to the 9vHPV vaccine during pregnancy, 496 (33.2%) had exposures to the 9vHPV vaccine peripregnancy, and 552 (37.0%) had 4vHPV or 9vHPV distal vaccine exposures. The 9vHPV vaccine administered during pregnancy was not associated with increased risk for SAB (hazard ratio, 1.12; 95% CI, 0.66-1.93) compared with distal vaccine exposures. Findings were similar for 9vHPV vaccine exposures peripregnancy (relative risk [RR], 0.72; 95% CI, 0.42-1.24). Among live births (n = 1409), 9vHPV vaccine exposures during pregnancy were not associated with increased risks for preterm birth (RR, 0.73; 95% CI, 0.44-1.20) or SGA birth (RR, 1.31; 95% CI, 0.78-2.20). Results were similar regarding the association between 9vHPV vaccine exposures peripregnancy and preterm birth (RR, 0.72; 95% CI, 0.45-1.17) and SGA birth (RR, 1.10; 95% CI, 0.65-1.88). Birth defects were rare in all exposure groups, occurring in about 1% of live births with available infant data. This study found that 9vHPV vaccine exposures during or around the time of pregnancy were uncommon and not associated with SABs or selected adverse birth outcomes. These findings can inform counseling for inadvertent 9vHPV vaccine exposures.
Authors: Kharbanda, Elyse O; Klein, Nicola P; Lipkind, Heather S; et al.
JAMA Netw Open. 2021 04 01;4(4):e214340. Epub 2021-04-01.
Studying attitudes towards vaccine hesitance and California law SB 277 in online discourse: A dataset and methodology
This article presents data that are further analyzed and interpreted in “Shouting at Each Other into the Void: A Semantic Network Analysis of Vaccine Hesitance and Support in Online Discourse Regarding California Law SB277” [1]. This research modified snowball sampling, a technique usually used to generate chains of informants that illuminate the structure of social networks, to collect digital documents following a chain of web links and recommendations, thus illuminating the underlying social, technical, and linguistic structure of online discourse. The resulting documents were manually coded according to the attitude towards vaccines they represented and/or the position they took with regard to California Senate Bill 277, a vaccine mandate policy that banned all nonmedical exemptions from school immunization requirements. Each attitude category, as well as the dataset as a whole, was subjected to quantitative linguistic analysis to identify key words and phrases in the data according to the frequency with which they appeared. A combination of that technique and semantic network analysis were used to generate clusters of related words that could be used for qualitative and narrative analysis, as detailed in the companion paper. The data collection and analysis processes described here will be of use to researchers conducting mixed-method analysis of online discourse who want their data to reflect the potential information and digital resources available to individuals who attempt to inform themselves about a particular topic using Internet searches. The data presented here could be useful for anyone seeking deeper insight into the linguistic and narrative patterns surrounding online debates about vaccination, controversial government policies, or both.
Authors: DeDominicis, Kali; Buttenheim, Alison M; Howa, Amanda C; Delamater, Paul L; Salmon, Daniel; Klein, Nicola P; Omer, Saad B
Data Brief. 2021 Apr;35:106841. Epub 2021-02-24.
Concomitant administration of a liquid formulation of human rotavirus vaccine (porcine circovirus-free) with routine childhood vaccines in infants in the United States: Results from a phase 3, randomized trial
In response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV. This was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6-12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines. Of 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups. Routine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.
Authors: Abu-Elyazeed, Remon; Klein, Nicola P; Moerman, Leentje; Povey, Michael; Pruitt, Anthony; Senders, Shelly; Silas, Peter; Bi, Dan; Rota-090 Study Group,
Vaccine. 2021 03 05;39(10):1534-1543. Epub 2020-10-17.
An automated algorithm using free-text clinical notes to improve identification of transgender people
Accurate identification of transgender persons is a critical first step in conducting transgender health studies. To develop an automated algorithm for identifying transgender individuals from electronic medical records (EMR) using free-text clinical notes. The development and validation of the algorithm was based on data from an integrated healthcare system that served as a participating site in the multicenter Study of Transition Outcomes and Gender. The training and test datasets each contained a total of 300 individuals identified between 2006 and 2014. Both datasets underwent a full medical record review by experienced research abstractors. The validated algorithm was then implemented to identify transgender individuals in the EMR using all clinical notes of patients that received care between January 1, 2015 and June 30, 2018. Validation of the algorithm against the full chart review demonstrated a high degree of accuracy with 97% sensitivity, 95% specificity, 94% positive predictive value, and 97% negative predictive value. The algorithm classified 7,409 individuals (3.5%) as “Definitely transgender” and 679 individuals (0.3%) as “Probably transgender” out of 212,138 candidates with a total of 378,641 clinical notes. The computerized NLP algorithm can support essential efforts to improve the health of transgender people.
Authors: Xie, Fagen; Silverberg, Michael J; Goodman, Michael; et al.
Inform Health Soc Care. 2021 Mar 02;46(1):18-28. Epub 2020-11-17.
A Risk Score to Predict Clostridioides difficile Infection
Clostridioides difficile infection (CDI) is a major cause of severe diarrhea. In this retrospective study, we identified CDI risk factors by comparing demographic and clinical characteristics for Kaiser Permanente Northern California members ≥18 years old with and without laboratory-confirmed incident CDI. We included these risk factors in logistic regression models to develop 2 risk scores that predict future CDI after an Index Date for Risk Score Assessment (IDRSA), marking the beginning of a period for which we estimated CDI risk. During May 2011 to July 2014, we included 9986 CDI cases and 2 230 354 members without CDI. The CDI cases tended to be older, female, white race, and have more hospitalizations, emergency department and office visits, skilled nursing facility stays, antibiotic and proton pump inhibitor use, and specific comorbidities. Using hospital discharge as the IDRSA, our risk score model yielded excellent performance in predicting the likelihood of developing CDI in the subsequent 31-365 days (C-statistic of 0.848). Using a random date as the IDRSA, our model also predicted CDI risk in the subsequent 31-365 days reasonably well (C-statistic 0.722). These results can be used to identify high-risk populations for enrollment in C difficile vaccine trials and facilitate study feasibility regarding sample size and time to completion.
Authors: Aukes, Laurie; Fireman, Bruce; Lewis, Edwin; Timbol, Julius; Hansen, John; Yu, Holly; Cai, Bing; Gonzalez, Elisa; Lawrence, Jody; Klein, Nicola P
Open Forum Infect Dis. 2021 Mar;8(3):ofab052. Epub 2021-02-04.
Moderate-to-Severe Acne and Mental Health Symptoms in Transmasculine Persons Who Have Received Testosterone
Authors: Braun, Hayley; Zhang, Qi; Getahun, Darios; Silverberg, Michael J; Tangpricha, Vin; Goodman, Michael; Yeung, Howa
JAMA Dermatol. 2021 03 01;157(3):344-346.
The relationship of smoking and unhealthy alcohol use to the HIV care continuum among people with HIV in an integrated health care system
Smoking tobacco and unhealthy alcohol use may negatively influence HIV care continuum outcomes but have not been examined in combination. Participants were people with HIV (PWH) in Kaiser Permanente Northern California. Predictors included smoking status and unhealthy alcohol use (exceeding daily and/or weekly limits) reported by patients during primary care screening (index date). Outcomes were based on not achieving the following steps in the care continuum: linkage to HIV care (≥1 visit within 90 days of newly identified HIV diagnosis), retention (2+ in-person visits, 60+ days apart) and HIV RNA control (<75 copies/mL). Adjusted odds ratios (ORs) were obtained from separate logistic regression models for each outcome associated with smoking and unhealthy alcohol use independently and combined. The overall sample (N = 8958) had a mean age of 48.0 years; was 91.3 % male; 54.0 % white, 17.6 % Latino, 15.1 % black, and 9.6 % other race/ethnicity. Smoking was associated with higher odds of not being linked to HIV care (OR = 1.60 [95 % CI 1.03-2.48]), not retained (OR = 1.30 [95 % CI 1.13-1.50]), and HIV RNA not in control (OR = 1.91 [95 % CI 1.60-2.27]). Alcohol measures were not independently associated with outcomes. The combination of unhealthy alcohol use and smoking (versus neither) was associated with higher odds of not being linked to care (OR = 2.83 [95 % CI 1.40-5.71]), although the interaction did not reach significance (p = 0.18). In this large sample of PWH in an integrated health care system, smoking, both independently and in combination with unhealthy alcohol use, was associated with worse HIV care continuum outcomes.
Authors: Satre, Derek D; Sterling, Stacy A; Young-Wolff, Kelly C; Lam, Jennifer O; Alexeeff, Stacey; Weisner, Constance; Silverberg, Michael J; et al.
Drug Alcohol Depend. 2021 02 01;219:108481. Epub 2021-01-08.
Developing Algorithms for Identifying Major Structural Birth Defects Using Automated Electronic Health Data
Given the 2015 transition to International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic coding, updates to our previously published algorithms for major structural birth defects (BDs) were necessary. Aims of this study were to update, validate, and refine algorithms for identifying selected BDs, and then to use these algorithms to describe BD prevalence in the vaccine safety datalink (VSD) population. We converted our ICD-9-CM list of selected BDs to ICD-10-CM using available crosswalks with manual review of codes. We identified, chart reviewed, and adjudicated a sample of infants in the VSD with ≥2 ICD-10-CM diagnoses for one of seven common BDs. Positive predictive values (PPVs) were calculated; for BDs with suboptimal PPV, algorithms were refined. Final automated algorithms were applied to a cohort of live births delivered 10/1/2015-9/30/2017 at eight VSD sites to estimate BD prevalence. This research was approved by the HealthPartners Institutional Review Board, by all participating VSD sites, and by the CDC, with a waiver of informed consent. Of 573 infants with ≥2 diagnoses for a targeted BD, on adjudication, we classified 399 (69.6%) as probable cases, 31 (5.4%) as possible cases and 143 (25.0%) as not having the targeted BD. PPVs for the final BD algorithms ranged from 0.76 (hypospadias) to 1.0 (gastroschisis). Among 212 857 births over 2 years following transition to ICD-10-CM coding, prevalence for the full list of selected defects in the VSD was 1.8%. Algorithms can identify infants with selected BDs using automated healthcare data with reasonable accuracy. Our updated algorithms can be used in observational studies of maternal vaccine safety and may be adapted for use in other surveillance systems.
Authors: Kharbanda, Elyse O; Klein, Nicola P; Romitti, Paul A; et al.
Pharmacoepidemiol Drug Saf. 2021 02;30(2):266-274. Epub 2020-12-03.
COVID-19 prevalence, symptoms, and sociodemographic disparities in infection among insured pregnant women in Northern California
Research on COVID-19 during pregnancy has mainly focused on women hospitalized for COVID-19 or other reasons during their pregnancy. Little is known about COVID-19 in the general population of pregnant women. To describe the prevalence of COVID-19, symptoms, consequent healthcare use, and possible sources of COVID-19 exposure among a population-based sample of pregnant women residing in Northern California. We analyzed data from 19,458 members of Kaiser Permanente Northern California who were pregnant between January 2020 and April 2021 and responded to an online survey about COVID-19 testing, diagnosis, symptoms, and their experiences during the COVID-19 pandemic. Medical diagnosis of COVID-19 during pregnancy was defined separately by self-report and by documentation in electronic health records (EHR). We examined relationships of COVID-19 with sociodemographic factors, underlying comorbidities, and survey measures of COVID-19-like symptoms, consequent healthcare utilization, and possible COVID-19 exposures. Among 19,458 respondents, the crude prevalence of COVID-19 was 2.5% (n = 494) according to self-report and 1.4% (n = 276) according to EHR. After adjustment, the prevalence of self-reported COVID-19 was higher among women aged <25 years compared with women aged ≥35 years (prevalence ratio [PR], 1.75, 95% CI: 1.23, 2.49) and among Hispanic women compared with White women (PR, 1.91, 95% CI: 1.53, 2.37). Prevalence of self-reported COVID-19 was higher among women affected by personal or partner job loss during the pandemic (PR, 1.23, 95% CI: 1.02, 1.47) and among women living in areas of high vs. low neighborhood deprivation (PR, 1.74, 95% CI: 1.33, 2.27). We did not observe differences in self-reported COVID-19 between women with and without underlying comorbidities. Results were similar for EHR-documented COVID-19. Loss of smell or taste was a unique and common symptom reported among women with COVID-19 (42.3% in self-reported; 54.0% in EHR-documented). Among women with symptomatic COVID-19, approximately 2% were hospitalized, 71% had a telehealth visit, and 75% quarantined at home. Over a third of women with COVID-19 reported no known exposure to someone with COVID-19. Observed COVID-19 prevalence differences by sociodemographic and socioeconomic factors underscore social and health inequities among reproductive-aged women. Women with COVID-19 reported unique symptoms and low frequency of hospitalization. Many were not aware of an exposure to someone with COVID-19.
Authors: Ames, Jennifer L; Ferrara, Assiamira; Avalos, Lyndsay A; Badon, Sylvia E; Greenberg, Mara B; Hedderson, Monique M; Kuzniewicz, Michael W; Young-Wolff, Kelly C; Zerbo, Ousseny; Zhu, Yeyi; Croen, Lisa A; et al.
PLoS One. 2021;16(9):e0256891. Epub 2021-09-03.
Vaccine Safety Datalink infrastructure enhancements for evaluating the safety of maternal vaccination
Identifying pregnancy episodes and accurately estimating their beginning and end dates are imperative for observational maternal vaccine safety studies using electronic health record (EHR) data. We modified the Vaccine Safety Datalink (VSD) Pregnancy Episode Algorithm (PEA) to include both the International Classification of Disease, ninth revision (ICD-9 system) and ICD-10 diagnosis codes, incorporated additional gestational age data, and validated this enhanced algorithm with manual medical record review. We also developed the new Dynamic Pregnancy Algorithm (DPA) to identify pregnancy episodes in real time. Around 75% of the pregnancy episodes identified by the enhanced VSD PEA were live births, 12% were spontaneous abortions (SABs), 10% were induced abortions (IABs), and 0.4% were stillbirths (SBs). Gestational age was identified for 99% of live births, 89% of SBs, 69% of SABs, and 42% of IABs. Agreement between the PEA-assigned and abstractor-identified pregnancy outcome and outcome date was 100% for live births, but was lower for pregnancy losses. When gestational age was available in the medical record, the agreement was higher for live births (97%), but lower for pregnancy losses (75%). The DPA demonstrated strong concordance with the PEA and identified pregnancy episodes ⩾6 months prior to the outcome date for 89% of live births. The enhanced VSD PEA is a useful tool for identifying pregnancy episodes in EHR databases. The DPA improves the timeliness of pregnancy identification and can be used for near real-time maternal vaccine safety studies. Improving identification of pregnancies in the Vaccine Safety Datalink electronic medical record databases to allow for better and faster monitoring of vaccination safety during pregnancy Introduction: It is important to monitor of the safety of vaccines after they have been approved and licensed by the Food and Drug Administration, especially among women vaccinated during pregnancy. The Vaccine Safety Datalink (VSD) monitors vaccine safety through observational studies within large databases of electronic medical records. Since 2012, VSD researchers have used an algorithm called the Pregnancy Episode Algorithm (PEA) to identify the medical records of women who have been pregnant. Researchers then use these medical records to study whether receiving a particular vaccine is linked to any negative outcomes for the woman or her child.Methods: The goal of this study was to update and enhance the PEA to include the full set of medical record diagnostic codes [both from the older International Classification of Disease, ninth revision (ICD-9 system) and the newer ICD-10 system] and to incorporate additional sources of data about gestational age. To ensure the validity of the PEA following these enhancements, we manually reviewed medical records and compared the results with the algorithm. We also developed a new algorithm, the Dynamic Pregnancy Algorithm (DPA), to identify women earlier in pregnancy, allowing us to conduct more timely vaccine safety assessments.Results: The new version of the PEA identified 2,485,410 pregnancies in the VSD database. The enhanced algorithm more precisely estimated the beginning of pregnancies, especially those that did not result in live births, due to the new sources of gestational age data.Conclusion: Our new algorithm, the DPA, was successful at identifying pregnancies earlier in gestation than the PEA. The enhanced PEA and the new DPA will allow us to better evaluate the safety of current and future vaccinations administered during or around the time of pregnancy.
Authors: Naleway, Allison L; Klein, Nicola P; Zerbo, Ousseny; Kharbanda, Elyse O; et al.
Ther Adv Drug Saf. 2021;12:20420986211021233. Epub 2021-06-14.
HIV Stigma and Its Associations with Longitudinal Health Outcomes Among Persons Living with HIV with a History of Unhealthy Alcohol Use
This study examined the demographic and clinical correlates of HIV stigma and evaluated how HIV stigma was associated with physical and mental health outcomes one year later in a primary-care based cohort of persons living with HIV (PLHIV; N = 584). HIV stigma was measured using a modified Berger HIV stigma scale, which includes four subscales: (1) personalized stigma; (2) disclosure concerns; (3) negative self-image; and (4) concerns around public attitudes towards PLHIV. Physical and mental health were assessed using the 12-item short form survey (SF-12). Compared to whites, African Americans were more likely to have higher personalized stigma scores (adjusted prevalence ratio [aPR] 1.54 [95% confidence interval 1.10-2.15]), disclosure concerns (aPR 1.40 [1.03-1.92]), and concerns with public attitudes about PLHIV (aPR 1.61 [1.11-2.34]). Hispanic/Latinx participants were more likely to have concerns around public attitudes towards PLHIV (aPR 1.50 [1.11-2.02]) than whites. Compared to men, women were more likely to have higher negative self-image scores (aPR 1.50 [1.08-2.08]). Higher stigma scores were associated with poorer subsequent self-reported physical and mental health functional status. Our findings highlight the substantial need for addressing HIV stigma, particularly among minority subgroups. El objetivo de este estudio era examinar la correlación del estigma del VIH con aspectos demográficos y clínicos. Se buscaba evaluar la asociación del estigma del VIH con los efectos de la salud física y mental luego de un año en un cohorte de personas viviendo con VIH (PVV; N = 584) provenientes de una clínica de servicios primarios. El estigma del VIH se midió utilizando la escala modificada de estigma del VIH de Berger que incluye cuatro sub-escalas: (1) estigma personalizado; (2) preocupaciones por revelación de diagnóstico; (3) auto-imagen negativa; y (4) preocupaciones acerca de actitudes hacia PVV. La salud física y mental fue evaluada utilizando una encuesta corta de 12 ítems. En comparación con las personas blancas, entre las personas Afroamericanas había más probabilidad de obtener una mayor puntuación en las escalas de estigma personalizado (razón de prevalencia ajustada [aRP] 1.54 [95% intervalo de confianza 1.10–2.15]), preocupaciones por revelación de diagnóstico (aRP 1.40 [1.03–1.92]), y preocupacionespor actitudes negativas hacia PVV (aRP 1.61 [1.11–2.34]). Participantes Hispanos/Latinos tenían más probabilidad de tener preocupaciones por las actitudes negativas hacia PVV (aRP 1.50 [1.11–2.02]) en comparación con personas blancas. En comparación con los hombres, las mujeres tenían mayor probabilidad de tener un resultado más alto en la escala de auto-imagen negativa (aRP 1.50 [1.08–2.08]). Resultados mayores estuvieron asociados a estatus más pobres de funcionalidad de salud física y mental. Nuestros resultados destacan la necesidad substancial de atender asuntos de estigma por el VIH, particularmente en grupos minoritarios.
Authors: Hojilla JC; Santiago-Rodriguez EI; Sterling S; Williams EC; Leyden W; Hare CB; Silverberg MJ; Satre DD
AIDS Behav. 2021 Jan;25(1):215-224.
Current and Past Immunodeficiency are Associated with Higher Hospitalization Rates among Persons on Virologically Suppressive Antiretroviral Therapy for up to Eleven Years
Persons with HIV (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk. In six US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005-2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by early (Years 2-5) and long-term (Years 6-11) suppression and lowest pre-suppression CD4 count <200 and ≥200 cells/µL, Poisson regression models estimated hospitalization incidence rate ratios (aIRR) comparing patients by time-updated CD4 count category, adjusted for cohort, age, gender, calendar year, suppression duration, and lowest pre-suppression CD4 count. The 6997 included patients (19 980 person-years) were 81% cisgender men and 40% White. Among patients with lowest pre-suppression CD4 <200 cells/μL (44%), patients with current CD4 200-350 versus >500 cells/μL had an aIRR of 1.44 during early suppression (95% CI 1.01-2.06), and 1.67 (1.03-2.72) during long-term suppression. Among patients with lowest pre-suppression CD4 ≥200 (56%), patients with current CD4 351-500 versus >500 cells/μL had an aIRR of 1.22 (0.93-1.60) during early suppression and 2.09 (1.18-3.70) during long-term suppression. Virologically suppressed patients with lower CD4 counts experienced higher hospitalization rates, and could potentially benefit from targeted clinical management strategies.
Authors: Davy-Mendez T; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA; et al.
J Infect Dis. 2020 Dec 26.
Effect of Body Weight and Other Metabolic Factors on Risk of Non-Small Cell Lung Cancer among Veterans with HIV and a History of Smoking
Among people living with HIV (PWH), there has been an increasing incidence of non-small cell lung cancer (NSCLC) and metabolic abnormalities, including dyslipidemia, which can modulate NSCLC risk. In this article, we evaluate which metabolic risk factors are associated with incident risk among PWH who smoke. This is done through a retrospective cohort study, using data of HIV+ veterans who smoke from the nationwide Veterans Affairs (VA) healthcare system. Data on diagnostic codes, medication, and laboratory values of 33,351 veterans were obtained using the VA’s Corporate Data Warehouse and Central Cancer Registry. We calculated NSCLC incidence and utilized Cox regression to determine metabolic factors associated with NSCLC risk. HIV+ cohort was 97.4% male; median age = 47 years and 20,050 (60.1%) well-controlled (≥80% follow-up time undetectable viral load). Crude incidence rates were lower in well-controlled PWH (1.46 vs. 2.06/1000 PY). Metabolic factors associated with incident NSCLC risk included lower BMI at HIV diagnosis and cachexia history in both groups, while HDL and triglycerides were significant in non-well-controlled smokers only. Our findings that lower BMI at HIV diagnosis, history of cachexia among individuals with well-controlled HIV, and cachexia presence at diagnosis are associated with increased risk of developing NSCLC in PWH with a history of smoking have important implications.
Authors: Garcia, Jose M; Kramer, Jennifer R; Richardson, Peter A; Ahmed, Sarah; Royse, Kathryn E; White, Donna L; Raychaudhury, Suchismita; Chang, Elaine; Hartman, Christine M; Silverberg, Michael J; Chiao, Elizabeth Y
Cancers (Basel). 2020 Dec 17;12(12). Epub 2020-12-17.
Early Adopters of Event-driven Human Immunodeficiency Virus Pre-exposure Prophylaxis in a Large Healthcare System in San Francisco
Among 279 patients within a large healthcare system in San Francisco, event-driven HIV pre-exposure prophylaxis using a 2-1-1 regimen was a desirable alternative to daily dosing. Problems with adherence, planning sex in advance, or side effects were infrequent (13.9%). We found no new HIV infections over 136 person-years of follow-up.
Authors: Hojilla JC; Marcus JL; Silverberg MJ; Hare CB; Herbers R; Hurley L; Satre DD; Volk JE
Clin Infect Dis. 2020 12 17;71(10):2710-2712.
Self-reported tattoo prevalence and motivations in transgender adults: a cross-sectional survey
To assess the prevalence and motivations for obtaining tattoos among transgender persons. A survey of 696 transgender persons recruited from the Study of Transition, Outcomes, and Gender (STRONG) cohort evaluated the prevalence of tattoos and motivations for acquiring tattoos. Transmasculine persons were more likely than transfeminine persons to have tattoos (66.5% versus 24.0%, P<0.05). Most commonly reported motivators were personal preference, aesthetics, and/or symbolism (61.8%). Scar coverage and replacement of anatomic features accounted for 10.2% of responses. Future studies should look into the relationship between tattoos and health status in the transgender population.
Authors: Ragmanauskaite, Laura; Kim, Jin; Zhang, Qi; Luk, Kevin M; Getahun, Darios; Silverberg, Michael J; Goodman, Michael; Yeung, Howa
Dermatol Online J. 2020 Dec 15;26(12). Epub 2020-12-15.
Evaluating the Association of Stillbirths After Maternal Vaccination in the Vaccine Safety Datalink
To evaluate whether the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccinations in pregnancy are associated with increased risk of stillbirth. We performed a case-control study in the Vaccine Safety Datalink that was matched 1:4 on site, month, and year of last menstrual period, comparing the odds of vaccination in pregnancies that ended in stillbirth (defined as fetal loss at or after 20 weeks of gestation) compared with those that ended in live birth from January 1, 2012, to September 30, 2015. We included patients with singleton pregnancies that ended in stillbirth or live birth who had at least one prenatal care visit, pregnancy dating information, and continuous health plan enrollment for the duration of pregnancy. Medical records for all stillbirths were reviewed. We were statistically powered to detect an odds ratio (OR) of 1.37 when evaluating the association between influenza or Tdap vaccination and stillbirth. We also examined stillbirth rates in pregnant patients aged 14-49 years in the Vaccine Safety Datalink between 2007 and 2015. In our matched analysis of 795 confirmed stillbirths in the case group and 3,180 live births in the control group, there was no significant association between influenza vaccination during pregnancy and stillbirth (343/795 [43.1%] stillbirths in the case group vs 1,407/3,180 [44.3%] live births in the control group, OR 0.94, adjusted OR 0.95, 95% CI 0.79-1.14, P=.54) and no significant association between Tdap vaccination during pregnancy and stillbirth (184/795 [23.1%] stillbirths in the case group vs 746/3,180 [23.5%] live births in the control group, OR 0.97, aOR 0.96, 95% CI 0.76-1.28, P=.91). From 2007 to 2015, the stillbirth rate in the Vaccine Safety Datalink was 5.2 per 1,000 live births and stillbirths. No association was found between vaccination during pregnancy and the odds of stillbirth. These findings support the safety of ACIP recommendations for vaccination during pregnancy.
Authors: Panagiotakopoulos, Lakshmi; Klein, Nicola P; Weintraub, Eric S; et al.
Obstet Gynecol. 2020 12;136(6):1086-1094.
Health System-Based Unhealthy Alcohol Use Screening and Treatment Comparing Demographically-Matched Participants With and Without HIV
Unhealthy alcohol use among persons living with HIV (PLWH) is linked to significant morbidity, and use of alcohol services may differ by HIV status. Our objective was to compare unhealthy alcohol use screening and treatment by HIV status in primary care. Cohort study of adult (≥18 years) PLWH and HIV-uninfected participants frequency matched 20:1 to PLWH by age, sex, and race/ethnicity who were enrolled in a large integrated healthcare system in the United States, with information ascertained from an electronic health record. Outcomes included unhealthy alcohol screening, prevalence, provider-delivered brief interventions, and addiction specialty care visits. Other predictors included age, sex, race/ethnicity, neighborhood deprivation index, depression, smoking, substance use disorders, Charlson comorbidity index, prior outpatient visits, insurance type, and medical facility. Cox proportional hazards models were used to compute hazard ratios (HR) for the outcomes of time to unhealthy alcohol use screening and time to first addiction specialty visit. Poisson regression with robust standard errors was used to compute prevalence ratios (PR) for other outcomes. 11,235 PLWH and 227,320 HIV-uninfected participants were included. By 4.5 years after baseline, most participants were screened for unhealthy alcohol use (85% of PLWH and 93% of HIV-uninfected), but with a lower rate among PLWH (adjusted HR 0.84, 95% CI 0.82 to 0.85). PLWH were less likely, compared with HIV-uninfected participants, to report unhealthy drinking among those screened (adjusted PR 0.74, 95% CI 0.69 to 0.79), and among those who screened positive, less likely to receive brief interventions (adjusted PR 0.82, 95% CI 0.75 to 0.90), but more likely (adjusted HR 1.7, 95% CI 1.2 to 2.4) to have an addiction specialty visit within 1 year. Unhealthy alcohol use was lower in PLWH, but the treatment approach by HIV status differed. PLWH reporting unhealthy alcohol use received less brief interventions and more addiction specialty care than HIV-uninfected participants.
Authors: Silverberg, Michael J; Alexeeff, Stacey E; Lam, Jennifer O; Weisner, Constance M; Sterling, Stacy A; Satre, Derek D; et al.
Alcohol Clin Exp Res. 2020 12;44(12):2545-2554. Epub 2020-11-10.
Shouting at each other into the void: A linguistic network analysis of vaccine hesitance and support in online discourse regarding California law SB277
In 2015, California passed Senate Bill 277 and became the third state in the United States to ban all nonmedical exemptions from school immunization requirements, effectively prohibiting religious and personal belief exemptions. This attracted grassroots opposition and considerable debate among vaccine hesitant factions online. This mixed-methods study used quantitative linguistic analysis, semantic network analysis, and content analysis techniques to examine 2424 online documents drawn from newspapers, blogs, health websites, government information pages, web forums, personal websites, Facebook groups, among others. The study examined which words and phrases were used most frequently by vaccine skeptics, vaccine defenders, and more neutral media accounts to illuminate how groups with different attitudes towards vaccination discuss and disseminate information about vaccines and vaccine policy online. We proposed an innovative methodology for examining online discourse surrounding vaccine hesitance, as well as for studying the online dissemination of misinformation about vaccines. Our findings highlighted discrepancies in the narratives between what vaccine supporters believe causes vaccine skepticism and the issues that vaccine skeptics actually discuss within their own digital spaces. For example, in these exchanges, the importance of parental rights overshadowed that of children’s rights; supporters of vaccines brought up autism in more distinct documents than skeptics do; distrust of government regulators and researchers seemed to unite vaccine skeptics and defenders; and politicians, doctors, and even celebrities often served as proxies in heated exchanges about factual evidence, believability, and the importance of expertise in public discourse.
Authors: DeDominicis, Kali; Buttenheim, Alison M; Howa, Amanda C; Delamater, Paul L; Salmon, Daniel; Omer, Saad B; Klein, Nicola P
Soc Sci Med. 2020 12;266:113216. Epub 2020-08-28.
Identification and description of mumps cases in a non-outbreak setting and evaluation of the effectiveness of mumps-containing vaccines over time
Mumps outbreaks among previously vaccinated young adults raise concerns regarding waning vaccine immunity. This study identified, described and assessed the changing incidence of mumps cases following mumps-containing vaccination (MMR/MMRV) in a non-mumps outbreak setting. Potential cases between 1996 and 2018 were identified by the international classification of disease codes or by mumps laboratory test orders among Kaiser Permanente Northern California members. Medical charts were reviewed to confirm diagnoses, timing relative to vaccination and clinical characteristics. Among 474 potential cases, 257 (54.2%) were confirmed after chart review. A third of the cases were <10 years old at diagnosis and 48% were over 25 years. Most cases (92.2%) had parotitis and 5% of males had orchitis. Mumps rates decreased from 8.5 to 1.8/1,000,000 person-years as time since the second MMR/MMRV dose increased from <2 years to ≥10 years. Similarly, rates decreased from 16.3 to 3/1,000,000 person-years after at least 1 dose of MMR/MMRV. Mumps rates were higher among children aged ≤10 years compared with older age groups. In conclusion, in the context of a non-outbreak setting, this study suggests that waning of vaccine immunity to mumps appeared to have minimal clinical impact.
Authors: Zerbo O; Modaressi S; Glanternik JR; Goddard K; Ross P; Lewis N; Klein NP
Hum Vaccin Immunother. 2020 12 01;16(12):3098-3102. Epub 2020-05-13.
Health care utilization and HIV clinical outcomes among newly enrolled patients following Affordable Care Act implementation in a California integrated health system: a longitudinal study
The Affordable Care Act (ACA) has increased insurance coverage for people with HIV (PWH) in the United States. To inform health policy, it is useful to investigate how enrollment through ACA Exchanges, deductible levels, and demographic factors are associated with health care utilization and HIV clinical outcomes among individuals newly enrolled in insurance coverage following implementation of the ACA. Among PWH newly enrolled in an integrated health care system (Kaiser Permanente Northern California) in 2014 (N = 880), we examined use of health care and modeled associations between enrollment mechanisms (enrolled in a Qualified Health Plan through the California Exchange vs. other sources), deductibles (none, $1-$999 and > = $1000), receipt of benefits from the California AIDS Drug Assistance Program (ADAP), demographic factors, and three-year patterns of health service utilization (primary care, psychiatry, substance treatment, emergency, inpatient) and HIV outcomes (CD4 counts; viral suppression at HIV RNA < 75 copies/mL). Health care use was greatest immediately after enrollment and decreased over 3 years. Those with high deductibles were less likely to use primary care (OR = 0.64, 95% CI = 0.49-0.84, p < 0.01) or psychiatry OR = 0.59, 95% CI = 0.37, 0.94, p = 0.03) than those with no deductible. Enrollment via the Exchange was associated with fewer psychiatry visits (rate ratio [RR] = 0.40, 95% CI = 0.18-0.86; p = 0.02), but ADAP was associated with more psychiatry visits (RR = 2.22, 95% CI = 1.24-4.71; p = 0.01). Those with high deductibles were less likely to have viral suppression (OR = 0.65, 95% CI = 0.42-1.00; p = 0.05), but ADAP enrollment was associated with viral suppression (OR = 2.20, 95% CI = 1.32-3.66, p < 0.01). Black (OR = 0.35, 95% CI = 0.21-0.58, p < 0.01) and Hispanic (OR = 0.50, 95% CI = 0.29-0.85, p = 0.01) PWH were less likely to be virally suppressed. In this sample of PWH newly enrolled in an integrated health care system in California, findings suggest that enrollment via the Exchange and higher deductibles were negatively associated with some aspects of service utilization, high deductibles were associated with worse HIV outcomes, but support from ADAP appeared to help patients achieve viral suppression. Race/ethnic disparities remain important to address even among those with access to insurance coverage.
Authors: Satre, Derek D; Parthasarathy, Sujaya; Silverberg, Michael J; Horberg, Michael; Young-Wolff, Kelly C; Williams, Emily C; Volberding, Paul; Campbell, Cynthia I
BMC Health Serv Res. 2020 Nov 11;20(1):1030. Epub 2020-11-11.
Individual and Neighborhood Factors Associated with Failure to Vaccinate against Influenza during Pregnancy
Uptake of influenza vaccine among pregnant women remains low. We investigated whether unvaccinated pregnant women were clustered geographically and determined factors associated with failure to vaccinate using spatial and multivariate logistic regression analyses. Pregnant women who were members of Kaiser Permanente Northern California in 2015 or 2016 were included in the study. More than half (53%) of the 77,607 included pregnant women were unvaccinated. Spatial analysis identified 5 clusters with a high prevalence of unvaccinated pregnant women. The proportion of unvaccinated women ranged from 57% to 75% within clusters as compared with 51% outside clusters. In covariate-adjusted analyses, residence in a cluster was associated with a 41% increase in the odds of being unvaccinated (odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.36, 1.46). The odds of being unvaccinated were greater for Black women (OR = 1.58, 95% CI: 1.49, 1.69), Hispanic women (OR = 1.15, 95% CI: 1.05, 1.25), women with subsidized health insurance (OR = 1.18, 95% CI: 1.11, 1.24), women with fewer than 5 prenatal-care visits (OR = 1.85, 95% CI: 1.60, 2.16), and neighborhoods with a high deprivation index (fourth quartile vs. first: OR = 1.14, 95% CI: 1.07, 1.21). In conclusion, unvaccinated pregnant women were clustered geographically and by key sociodemographic factors. These findings suggest that interventions to increase influenza vaccine coverage among pregnant women are needed, particularly in vulnerable populations.
Authors: Zerbo, Ousseny; Ray, G Thomas; Zhang, Lea; Goddard, Kristin; Fireman, Bruce; Adams, Alyce; Omer, Saad; Kulldorff, Martin; Klein, Nicola P
Am J Epidemiol. 2020 11 02;189(11):1379-1388.
Longitudinal Changes in Hematologic Parameters Among Transgender People Receiving Hormone Therapy
The effect of gender-affirming hormone therapy (HT) on erythropoiesis is an area of priority in transgender health research. To compare changes in hematologic parameters and rates of erythrocytosis and anemia among transgender people to those of cisgender controls. Longitudinal observational study. We compared 559 transfeminine (TF) and 424 transmasculine (TM) people enrolled in 3 integrated health care systems to matched cisgender referents. Hormone therapy receipt was ascertained from filled prescriptions. Hemoglobin (Hb) and hematocrit (Hct) levels were examined from the first blood test to HT initiation, and from the start of HT to the most recent blood test. Rates of erythrocytosis and anemia in transgender participants and referents were compared by calculating adjusted hazard ratios and 95% confidence intervals (CI). In the TF group, there was a downward trend for both Hb and Hct. The corresponding changes in the TM cohort were in the opposite direction. TM study participants experienced a 7-fold higher rate (95% CI: 4.1-13.4) of erythrocytosis relative to matched cisgender males, and an 83-fold higher rate (95% CI: 36.1-191.2) compared to cisgender females. The corresponding rates for anemia were elevated in TF subjects but primarily relative to cisgender males (hazard ratio 5.9; 95% CI: 4.6-7.5). Our results support previous recommendations that hematological parameters of transgender people receiving HT should be interpreted based on their affirmed gender, rather than their sex documented at birth. The clinical significance of erythrocytosis following testosterone therapy, as well as anemia following feminizing HT, requires further investigation.
Authors: Antun, Ana; Silverberg, Michael J; Goodman, Michael; et al.
J Endocr Soc. 2020 Nov 01;4(11):bvaa119. Epub 2020-08-25.
Beyond the HIV Care Continuum and Viral Suppression: Broadening the Scope of Quality Metrics for Total HIV Patient Care
Assessing quality care for people with HIV (PWH) should not be limited to reporting on HIV Care Continuum benchmarks, particularly viral suppression rates. At Kaiser Permanente Mid-Atlantic States (KPMAS), an integrated health system providing HIV care in the District of Columbia, Maryland, and Virginia, we created a comprehensive measure of HIV quality care, including both preventative measures and clinical outcomes. We included PWH ≥18 years old with ≥6 months KPMAS membership between 2015 and 2018. Process quality metrics (QMs) include: pneumococcal vaccination and influenza vaccination; primary care physician (PCP) and/or HIV/infectious disease (HIV/ID) visits with additional HIV/ID visit; antiretroviral treatment medication fills; and syphilis and gonorrhea/chlamydia screenings. Outcome QMs include HIV RNA <200/mL and other measurements within normal range [blood pressure, body mass index (BMI), hemoglobin, blood sugar, alanine transaminase, low-density lipoproteins, estimated glomerular filtration rate]; no hospitalization/emergency department visit; no new depression diagnosis; remaining or becoming a nonsmoker. Logistic models estimated odds of achieving QMs associated with sex, age, race/ethnicity, insurance type, and HIV risk. A total of 4996 observations were analyzed. 45.6% met all process QMs, while 19.6% met all outcome QMs. Least frequently met process QM was PCP or HIV/ID visit (74.5%); least met outcome QM was BMI (60.2%). Significantly lower odds of achieving all QMs among women {odds ratio (OR) = 0.63 [95% confidence interval (CI): 0.49-0.81]} and those with Medicaid and Medicare [vs. commercial; OR = 0.48 (95% CI: 0.30-0.76) and 0.47 (95% CI: 0.31-0.71)]. Broadening the scope of HIV patient care QMs beyond viral suppression helps identify opportunities for improvement. Successful process metrics do not necessarily coincide with greater outcome metrics.
Authors: Horberg, Michael A; Certa, Julia M; Rubenstein, Kevin B; Hurley, Leo B; Satre, Derek D; Kadlecik, Peter M; Silverberg, Michael J
AIDS Patient Care STDS. 2020 11;34(11):461-469.
Oral leukoplakia and risk of progression to oral cancer: A population-based cohort study
The optimal clinical management of oral precancer remains uncertain. We investigated the natural history of oral leukoplakia, the most common oral precancerous lesion, to estimate the relative and absolute risks of progression to cancer, the predictive accuracy of a clinician’s decision to biopsy a leukoplakia vis-à-vis progression, and histopathologic predictors of progression. We conducted a retrospective cohort study (1996-2012) of patients with oral leukoplakia (n = 4886), identified using electronic medical records within Kaiser Permanente Northern California. Among patients with leukoplakia who received a biopsy (n = 1888), we conducted a case-cohort study to investigate histopathologic predictors of progression. Analyses included indirect standardization and unweighted or weighted Cox regression. Compared with the overall Kaiser Permanente Northern California population, oral cancer incidence was substantially elevated in oral leukoplakia patients (standardized incidence ratio = 40.8, 95% confidence interval [CI] = 34.8 to 47.6; n = 161 cancers over 22 582 person-years). Biopsied leukoplakias had a higher oral cancer risk compared with those that were not biopsied (adjusted hazard ratio = 2.38, 95% CI = 1.73 to 3.28). However, to identify a prevalent or incident oral cancer, the biopsy decision had low sensitivity (59.6%), low specificity (62.1%), and moderate positive-predictive value (5.1%). Risk of progression to oral cancer statistically significantly increased with the grade of dysplasia; 5-year competing risk-adjusted absolute risks were: leukoplakia overall = 3.3%, 95% CI = 2.7% to 3.9%; no dysplasia = 2.2%, 95% CI = 1.5% to 3.1%; mild-dysplasia = 11.9%, 95% CI = 7.1% to 18.1%; moderate-dysplasia = 8.7%, 95% CI = 3.2% to 17.9%; and severe dysplasia = 32.2%, 95% CI = 8.1%-60.0%. Yet 39.6% of cancers arose from biopsied leukoplakias without dysplasia. The modest accuracy of the decision to biopsy a leukoplakia vis-à-vis presence or eventual development of oral cancer highlights the need for routine biopsy of all leukoplakias regardless of visual or clinical impression. Leukoplakia patients, particularly those with dysplasia, need to be closely monitored for signs of early cancer.
Authors: Chaturvedi AK; Udaltsova N; Engels EA; Katzel JA; Yanik EL; Katki HA; Lingen MW; Silverberg MJ
J Natl Cancer Inst. 2020 10 01;112(10):1047-1054.
SARS-CoV-2 Infection Among Hospitalized Pregnant Women: Reasons for Admission and Pregnancy Characteristics – Eight U.S. Health Care Centers, March 1-May 30, 2020
Pregnant women might be at increased risk for severe coronavirus disease 2019 (COVID-19), possibly related to changes in their immune system and respiratory physiology* (1). Further, adverse birth outcomes, such as preterm delivery and stillbirth, might be more common among pregnant women infected with SARS-CoV-2, the virus that causes COVID-19 (2,3). Information about SARS-CoV-2 infection during pregnancy is rapidly growing; however, data on reasons for hospital admission, pregnancy-specific characteristics, and birth outcomes among pregnant women hospitalized with SARS-CoV-2 infections are limited. During March 1-May 30, 2020, as part of Vaccine Safety Datalink (VSD)† surveillance of COVID-19 hospitalizations, 105 hospitalized pregnant women with SARS-CoV-2 infection were identified, including 62 (59%) hospitalized for obstetric reasons (i.e., labor and delivery or another pregnancy-related indication) and 43 (41%) hospitalized for COVID-19 illness without an obstetric reason. Overall, 50 (81%) of 62 pregnant women with SARS-CoV-2 infection who were admitted for obstetric reasons were asymptomatic. Among 43 pregnant women hospitalized for COVID-19, 13 (30%) required intensive care unit (ICU) admission, six (14%) required mechanical ventilation, and one died from COVID-19. Prepregnancy obesity was more common (44%) among pregnant women hospitalized for COVID-19 than that among asymptomatic pregnant women hospitalized for obstetric reasons (31%). Likewise, the rate of gestational diabetes (26%) among pregnant women hospitalized for COVID-19 was higher than it was among women hospitalized for obstetric reasons (8%). Preterm delivery occurred in 15% of pregnancies among 93 women who delivered, and stillbirths (fetal death at ≥20 weeks’ gestation) occurred in 3%. Antenatal counseling emphasizing preventive measures (e.g., use of masks, frequent hand washing, and social distancing) might help prevent COVID-19 among pregnant women,§ especially those with prepregnancy obesity and gestational diabetes, which might reduce adverse pregnancy outcomes.
Authors: Panagiotakopoulos, Lakshmi; Klein, Nicola P; Weintraub, Eric S; et al.
MMWR Morb Mortal Wkly Rep. 2020 Sep 23;69(38):1355-1359. Epub 2020-09-23.
Association of Mortality and Years of Potential Life Lost With Active Tuberculosis in the United States
Active tuberculosis (TB) disease leads to substantial mortality but is preventable through screening and treatment for latent TB infection. Early mortality after TB diagnosis (≤1 year) is well described, but delayed mortality (>1 year) among patients with active TB is poorly understood. To compare early and delayed mortality and years of potential life (YPL) lost among patients with active TB disease vs an age-, sex-, and year of diagnosis-matched comparison cohort without active TB disease. This retrospective cohort study, conducted in the integrated health system of Kaiser Permanente Northern California, included patients with microbiologically confirmed active TB disease from January 1, 1997, to December 31, 2017, and a control cohort matched by age, sex, and year of diagnosis. Multivariable models were used to adjust for demographic and clinical characteristics. Patients with active TB disease prior to 1997 were excluded. Data were analyzed from January 1, 2019, to January 31, 2020. Microbiologically confirmed TB disease. Early (≤1 year after TB diagnosis) and delayed (>1 year after TB diagnosis) all-cause mortality. A total of 2522 patients who had active TB from 1997 to 2017 were identified, with 17 166 person-years of follow-up. The comparison cohort included 100 880 persons with 735 726 person-years of follow-up. In the active TB and comparison cohorts, similar percentages of persons were male (56.3% vs 55.6%), aged 45 to 64 years (33.7% vs 33.7%), and aged 65 years or older (24.7% vs 24.7%). Both early mortality (7.0%) and delayed mortality (16.3%) were higher among patients with active TB disease compared with those without active TB disease (1.1% and 12.0%, respectively). Patients with active TB disease had a significantly higher risk for early (adjusted hazard ratio [aHR], 7.29; 95% CI, 6.08-8.73) and delayed (aHR, 1.78; 95% CI, 1.61-1.98) mortality compared with the comparison cohort (P < .001). Active TB disease was associated with an adjusted -7.0 (95% CI, -8.4 to -5.5) YPL lost compared with the comparison cohort. In this study, patients with active TB disease had significantly higher early and delayed all-cause mortality when adjusting for demographic and clinical characteristics. These findings suggest that TB prevention through screening and treatment of latent TB infection could reduce mortality and YPL lost due to active TB disease.
Authors: Lee-Rodriguez, Christian; Wada, Paul Y; Hung, Yun-Yi; Skarbinski, Jacek
JAMA Netw Open. 2020 09 01;3(9):e2014481. Epub 2020-09-01.
Virological Failure and Acquired Genotypic Resistance Associated With Contemporary Antiretroviral Treatment Regimens
There are few descriptions of virologic failure (VF) and acquired drug resistance (HIVDR) in large cohorts initiating contemporary antiretroviral therapy (ART). We studied all persons with HIV (PWH) in a California clinic population initiating ART between 2010 and 2017. VF was defined as not attaining virologic suppression, discontinuing ART, or virologic rebound prompting change in ART. During the study, 2315 PWH began ART. Six companion drugs were used in 93.3% of regimens: efavirenz, elvitegravir/c, dolutegravir, b-darunavir, rilpivirine, and raltegravir. During a median follow-up of 36 months, 214 (9.2%) PWH experienced VF (2.8 per 100 person-years) and 62 (2.7%) experienced HIVDR (0.8 per 100 person-years). In multivariable analyses, younger age, lower CD4 count, higher virus load, and b-atazanavir were associated with increased VF risk; lower CD4 count, higher virus load, and nevirapine were associated with increased HIVDR risk. Compared with efavirenz, dolutegravir, raltegravir, and b-darunavir were associated with reduced HIVDR risk. Risks of VF and HIVDR were not significantly associated with ART initiation year. Of the 62 PWH with HIVDR, 42 received an non-nucleoside RT inhibitor (NNRTI), 15 an integrase-strand transfer inhibitor (INSTI), and 5 a protease inhibitor (PI). Among those with HIVDR on an NNRTI or first-generation INSTI, 59% acquired dual class resistance and 29% developed tenofovir resistance; those receiving a PI or dolutegravir developed just M184V. Despite the frequent use of contemporary ART regimens, VF and HIVDR continue to occur. Further efforts are required to improve long-term ART virological responses to prevent the consequences of ongoing HIV-1 replication including virus transmission and HIVDR.
Authors: Rhee, Soo-Yon; Clutter, Dana; Hare, C Bradley; Tchakoute, Christophe T; Sainani, Kristin; Fessel, W Jeffrey; Hurley, Leo; Slome, Sally; Pinsky, Benjamin A; Silverberg, Michael J; Shafer, Robert W
2020 Sep;7(9):ofaa316. Epub 2020-08-06.
Evaluation of a Vaccine-Communication Tool for Physicians
To evaluate a Kaiser Permanente Northern California physician training tool entitled “Effective Communication without Confrontation” aimed at improving communication with vaccine-hesitant parents, building trust, and alleviating physician stress surrounding vaccination visits. Trainings were held May to July 2015. Pre- and post-training surveys assessed physician comfort and perceived effectiveness in communicating with vaccine-hesitant parents. We measured vaccination coverage at the 2-, 4-, and 6-month well-child visits, and days undervaccinated at 9 months of age. We compared vaccination rates before and after the training. Of 415 physicians who received training, 249 completed post-training surveys. Physicians reported that the training helped them feel “much more or more” comfortable talking with parents who are unsure (72.3%), want to delay (73.9%), or refuse (63.5%) vaccinations and “much more or more” effective at persuading parents who are unsure (67.5%) or want to delay vaccinations (61.4%). They reported feeling “the same or less” effective persuading parents who refuse vaccinations (66.3%). Vaccine coverage remained unchanged and high from before to after the training (95%-96%), as did parent satisfaction with his or her child’s provider (4.73/5.00). The Effective Communication without Confrontation training did not increase vaccine coverage, but did improve physicians’ comfort and perceived effectiveness communicating with most vaccine-hesitant parents and may help to ease potentially stressful vaccination visits.
Authors: Glanternik JR; McDonald JC; Yee AH; Howell Ba A; Saba KN; Mellor RG; Fireman B; Klein NP
J Pediatr. 2020 09;224:72-78.e1. Epub 2020-06-06.
Response to Brandt, Bednarz-Knoll, Kleinheinz et al
Authors: Chaturvedi AK; Udaltsova N; Engels EA; Katzel JA; Yanik EL; Katki HA; Lingen MW; Silverberg MJ
J Natl Cancer Inst. 2020 09 01;112(9):970-971.
Risk for Subdeltoid Bursitis After Influenza Vaccination: A Population-Based Cohort Study
Subdeltoid bursitis has been reported as an adverse event after intramuscular vaccination in the deltoid muscle. Most published case reports involved influenza vaccine. To estimate the risk for subdeltoid bursitis after influenza vaccination. Retrospective cohort study. The Vaccine Safety Datalink, which contains health encounter data for 10.2 million members of 7 U.S. health care organizations. Persons who received an inactivated influenza vaccine during the 2016-2017 influenza season. Potential incident cases were identified by searching administrative data for persons with a shoulder bursitis diagnostic code within 180 days after receiving an injectable influenza vaccine in the same arm. The date of reported bursitis symptom onset was abstracted from the medical record. A self-controlled risk interval analysis was used to calculate the incidence rate ratio of bursitis in a risk interval of 0 to 2 days after vaccination versus a control interval of 30 to 60 days, which represents the background rate. The attributable risk was also estimated. The cohort included 2 943 493 vaccinated persons. Sixteen cases of symptom onset in the risk interval and 51 cases of symptom onset in the control interval were identified. The median age of persons in the risk interval was 57.5 years (range, 24 to 98 years), and 69% were women. The incidence rate ratio was 3.24 (95% CI, 1.85 to 5.68). The attributable risk was 7.78 (CI, 2.19 to 13.38) additional cases of bursitis per 1 million persons vaccinated. The results may not be generalizable to vaccinations done in other types of health care settings. Although an increased risk for bursitis after vaccination was present, the absolute risk was small. Centers for Disease Control and Prevention.
Authors: Hesse EM; Navarro RA; Daley MF; Getahun D; Henninger ML; Jackson LA; Nordin J; Olson SC; Zerbo O; Zheng C; Duffy J
Ann Intern Med. 2020 08 18;173(4):253-261. Epub 2020-06-23.
Overcoming Waning Immunity in Pertussis Vaccines: Workshop of the National Institute of Allergy and Infectious Diseases
Despite high vaccine coverage in many parts of the world, pertussis is resurging in a number of areas in which acellular vaccines are the primary vaccine administered to infants and young children. This is attributed in part to the suboptimal and short-lived immunity elicited by acellular pertussis vaccines and to their inability to prevent nasal colonization and transmission of the etiologic agent Bordetella pertussis In response to this escalating public health concern, the National Institute of Allergy and Infectious Diseases held the workshop “Overcoming Waning Immunity in Pertussis Vaccines” in September 2019 to identify issues and possible solutions for the defects in immunity stimulated by acellular pertussis vaccines. Discussions covered aspects of the current problem, gaps in knowledge and possible paths forward. This review summarizes presentations and discussions of some of the key points that were raised by the workshop.
Authors: Damron, F Heath; Lu, Kristina; Harvill, Eric T; et al.
J Immunol. 2020 08 15;205(4):877-882.
Obesity and Mortality Among Patients Diagnosed With COVID-19: Results From an Integrated Health Care Organization
Obesity, race/ethnicity, and other correlated characteristics have emerged as high-profile risk factors for adverse coronavirus disease 2019 (COVID-19)-associated outcomes, yet studies have not adequately disentangled their effects. To determine the adjusted effect of body mass index (BMI), associated comorbidities, time, neighborhood-level sociodemographic factors, and other factors on risk for death due to COVID-19. Retrospective cohort study. Kaiser Permanente Southern California, a large integrated health care organization. Kaiser Permanente Southern California members diagnosed with COVID-19 from 13 February to 2 May 2020. Multivariable Poisson regression estimated the adjusted effect of BMI and other factors on risk for death at 21 days; models were also stratified by age and sex. Among 6916 patients with COVID-19, there was a J-shaped association between BMI and risk for death, even after adjustment for obesity-related comorbidities. Compared with patients with a BMI of 18.5 to 24 kg/m2, those with BMIs of 40 to 44 kg/m2 and greater than 45 kg/m2 had relative risks of 2.68 (95% CI, 1.43 to 5.04) and 4.18 (CI, 2.12 to 8.26), respectively. This risk was most striking among those aged 60 years or younger and men. Increased risk for death associated with Black or Latino race/ethnicity or other sociodemographic characteristics was not detected. Deaths occurring outside a health care setting and not captured in membership files may have been missed. Obesity plays a profound role in risk for death from COVID-19, particularly in male patients and younger populations. Our capitated system with more equalized health care access may explain the absence of effect of racial/ethnic and socioeconomic disparities on death. Our data highlight the leading role of severe obesity over correlated risk factors, providing a target for early intervention. Roche-Genentech.
Authors: Tartof SY; Skarbinski J; Murali SB; et al.
Ann Intern Med. 2020 Aug 12.
Retrospective study of the use of an influenza disease two-tiered classification system to characterize clinical severity in US children
In children <5 years, influenza is associated with higher risk of serious disease and hospitalization when compared with other age groups. Influenza vaccination reduces the risk of influenza and vaccination may attenuate the severity of disease. Recent studies in Europe suggest that classifying influenza disease as mild versus moderate-to-severe (M-S) using a novel definition may be clinically significant. We retrospectively evaluated whether this M-S definition also characterized influenza severity in a cohort of US children. We included children <18 years at Kaiser Permanente Northern California with PCR-confirmed influenza during the 2013-2014 influenza season. We classified children as M-S if they had ≥1 symptom: fever >39°C, acute otitis media, lower respiratory tract infection (LRTI), or extra-pulmonary complications; otherwise, they were classified as mild. We used multivariable log-binomial models to assess whether M-S influenza disease was associated with increased healthcare utilization. Nearly half of the 1,105 influenza positive children were classified as M-S. Children 6-35 months had the highest proportion of M-S disease (35.1%), mostly due to LRTI (63.2%) and fever (44.6%). Children ≥6 months who had M-S disease were associated with a 1.6 to 2.8 times increased likelihood of having had an emergency department or any follow-up outpatient visits. Those who had M-S disease were associated with an increased likelihood of receiving antibiotics, with the highest likelihood in children 6-35 months (RR 9.0, 95% CI 4.1, 19.8). While more studies are needed, an influenza classification system may distinguish children with more clinically significant disease.
Authors: Hsiao A; Buck PO; Yee A; Hansen J; Lewis EM; Aukes LL; Yanni E; Bekkat-Berkani R; Schuind A; Klein NP
Hum Vaccin Immunother. 2020 08 02;16(8):1753-1761. Epub 2020-02-20.
Smoking and cessation treatment among persons with and without HIV in a U.S. integrated health system
Persons with HIV (PWH) are more likely to smoke and are more susceptible to the harmful effects of smoking than persons without HIV. We examined smoking patterns and use of cessation treatment among PWH and persons without HIV in a U.S. integrated health system. We identified adults (≥18 years) with HIV and demographically-matched persons without HIV between July 2013 and December 2017. Smoking status and cessation treatment were ascertained from health records. We calculated age-standardized annual prevalence of smoking and evaluated trends using Cochran-Armitage tests and Poisson regression. Factors associated with cessation treatment during the study period, and smoking in the last year of the study, were evaluated by HIV status using multivariable Poisson models. The study included 11,235 PWH and 227,320 persons without HIV. Smoking prevalence was higher among PWH across all years but declined for both groups (from 16.6% to 14.6% in PWH and 11.6% to 10.5% in persons without HIV). Among smokers, PWH were more likely to initiate cessation treatment compared to persons without HIV (17.9% vs. 13.3%, covariate-adjusted prevalence ratio of 1.31, 95% CI = 1.15-1.50), with few differences in cessation treatment across subgroups of PWH. In 2017, smoking prevalence remained higher in PWH, especially among those who were younger or who had diagnoses of depression or substance use disorder. In a setting with access to cessation resources, smoking prevalence decreased both in PWH and persons without HIV. PWH had greater uptake of cessation treatment, which is encouraging for smoking reduction and improved health.
Authors: Lam JO; Levine-Hall T; Hood N; Alexeeff SE; Horberg MA; Young-Wolff KC; Sterling SA; Williams A; Weisner C; Satre DD; Silverberg MJ
Drug Alcohol Depend. 2020 08 01;213:108128. Epub 2020-06-18.
Discussing Cervical Cancer Screening Options: Outcomes to Guide Conversations Between Patients and Providers
Purpose. In 2018, the US Preventive Services Task Force (USPSTF) endorsed three strategies for cervical cancer screening in women ages 30 to 65: cytology every 3 years, testing for high-risk types of human papillomavirus (hrHPV) every 5 years, and cytology plus hrHPV testing (co-testing) every 5 years. It further recommended that women discuss with health care providers which testing strategy is best for them. To inform such discussions, we used decision analysis to estimate outcomes of screening strategies recommended for women at age 30. Methods. We constructed a Markov decision model using estimates of the natural history of HPV and cervical neoplasia. We evaluated the three USPSTF-endorsed strategies, hrHPV testing every 3 years and no screening. Outcomes included colposcopies with biopsy, -positive testing (a colposcopy in which no cervical intraepithelial neoplasia grade 2 or worse was found), treatments, cancers, and cancer mortality expressed per 10,000 women over a shorter-than-lifetime horizon (15-year). Results. All strategies resulted in substantially lower cancer and cancer death rates compared with no screening. Strategies with the lowest likelihood of cancer and cancer death generally had higher likelihood of colposcopy and -positive testing. Conclusions. The screening strategies we evaluated involved tradeoffs in terms of benefits and harms. Because individual women may place different weights on these projected outcomes, the optimal choice for each woman may best be discerned through shared decision making.
Authors: Holt, Hunter K; Kulasingam, Shalini; Sanstead, Erinn C; Alarid-Escudero, Fernando; Smith-McCune, Karen; Gregorich, Steven E; Silverberg, Michael J; Huchko, Megan J; Kuppermann, Miriam; Sawaya, George F
2020 Jul-Dec;5(2):2381468320952409. Epub 2020-08-19.
Adaptive Validation Design: A Bayesian Approach to Validation Substudy Design With Prospective Data Collection
An internal validation substudy compares an imperfect measurement of a variable with a gold-standard measurement in a subset of the study population. Validation data permit calculation of a bias-adjusted estimate, which has the same expected value as the association that would have been observed had the gold-standard measurement been available for the entire study population. Existing guidance on optimal sampling for validation substudies assumes complete enrollment and follow-up of the target cohort. No guidance exists for validation substudy design while cohort data are actively being collected. In this article, we use the framework of Bayesian monitoring methods to develop an adaptive approach to validation study design. This method monitors whether sufficient validation data have been collected to meet predefined criteria for estimation of the positive and negative predictive values. We demonstrate the utility of this method using the Study of Transition, Outcomes and Gender-a cohort study of transgender and gender nonconforming people. We demonstrate the method’s ability to determine efficacy (when sufficient validation data have accumulated to obtain estimates of the predictive values that fall above a threshold value) and futility (when sufficient validation data have accumulated to conclude the mismeasured variable is an untenable substitute for the gold-standard measurement). This proposed method can be applied within the context of any parent epidemiologic study design and modified to meet alternative criteria given specific study or validation study objectives. Our method provides a novel approach to effective and efficient estimation of classification parameters as validation data accrue.
Authors: Collin LJ; MacLehose RF; Ahern TP; Nash R; Getahun D; Roblin D; Silverberg MJ; Goodman M; Lash TL
Epidemiology. 2020 07;31(4):509-516.
Sensorineural hearing loss (SNHL) as an adverse event following immunization (AEFI): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data
This is a Brighton Collaboration case definition of the term “Sensorineural Hearing Loss” to be utilized in the evaluation of adverse events following immunization. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for Lassa Fever and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and define levels of diagnostic certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network.
Authors: Carol Liu YC; Ibekwe T; Kelso JM; Klein NP; Shehu N; Steuerwald W; Aneja S; Dudley MZ; Garry R; Munoz FM; Brighton Collaboration SNHL Working Group
Vaccine. 2020 06 19;38(30):4717-4731. Epub 2020-05-15.
Effectiveness of ‘catch-up’ human papillomavirus vaccination to prevent cervical neoplasia in immunosuppressed and non-immunosuppressed women
It is unknown whether the HPV vaccine is effective in immunocompromised women during catch-up ages. We performed a case-control study of 4,357 women with incident CIN2+ (cases) and 5:1 age-matched, incidence-density selected controls (N = 21,773) enrolled in an integrated health care system from 2006 to 2014. Vaccine effectiveness was estimated from multivariable conditional logistic regression models, with results stratified by immunosuppression history, defined as prior HIV infection, solid organ transplant history, or recently prescribed immunosuppressive medications. HPV vaccination resulted in a 19% reduction in CIN2+ rates for women without an immunosuppression history but a nonsignificant 4% reduction for women with an immunosuppression history. Further research is needed to evaluate whether catch-up HPV vaccine effectiveness varies by immunosuppression status, especially given the recent approval of the HPV vaccine for adults up to 45 years of age.
Authors: Silverberg MJ; Leyden WA; Lam JO; Chao CR; Gregorich SE; Huchko MJ; Kulasingam S; Kuppermann M; Smith-McCune KK; Sawaya GF
Vaccine. 2020 06 15;38(29):4520-4523. Epub 2020-05-20.
Safety of Recombinant Influenza Vaccine Compared to Inactivated Influenza Vaccine in Adults: An Observational Study
Recombinant trivalent influenza vaccine (RIV3) was initially licensed in 2013 and approved for all adults ≥18 in 2014. This study evaluated the safety of RIV3 compared with trivalent standard-dose, inactivated influenza vaccine (IIV3) in Kaiser Permanente Northern California (KPNC). This Phase 4 observational, postmarketing safety study included persons ≥18 years vaccinated with RIV3 or IIV3 in KPNC during the 2015-2016 influenza season. We compared (1) the rates of prespecified diagnoses of interest (Guillain-Barré Syndrome, pericarditis, pleural effusion, narcolepsy/cataplexy, asthma, acute hypersensitivity reactions, and fever) during various postvaccination risk intervals as well as (2) all-cause hospitalization and mortality 0-180 days after vaccination. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analyses adjusted for age, sex, race/ethnicity, month of vaccination, and concomitant receipt of other vaccinations. Comparing the 21 976 persons who received RIV3 with the 283 683 who received IIV3, there were statistically significant differences in the prespecified diagnoses of interest between the 2 groups. Specifically, RIV3 vaccination was associated with fewer fever diagnoses during the 0-41 days postvaccination (OR, 0.38; 95% CI, 0.14-0.86). Also, RIV3 was associated with fewer all-cause hospitalizations during the 0-180 days postvaccination (OR, 0.66; 95% CI, 0.61-0.73), which was mostly related to pregnancy-related hospitalizations in IIV3 recipients. There were no serious adverse events or deaths related to RIV3. This study did not identify any safety concerns regarding the use of RIV3 in adults.
Authors: Hansen J; Goddard K; Timbol J; Zhang L; Lewis N; Dunkle L; Izikson R; Klein NP
Open Forum Infect Dis. 2020 Jun;7(6):ofaa179. Epub 2020-05-20.
Comparison of Overall and Comorbidity-Free Life Expectancy Between Insured Adults With and Without HIV Infection, 2000-2016
Antiretroviral therapy (ART) has improved life expectancy for individuals with HIV infection, but recent data comparing life span and comorbidity-free years by HIV status are lacking. To quantify the gap in life span and comorbidity-free years by HIV status among adults with access to care. This matched cohort study used data from insured adults with and without HIV infection (aged ≥21 years) matched 1:10 at medical centers of Kaiser Permanente in northern and southern California and the mid-Atlantic states of Washington DC, Maryland, and Virginia from January 1, 2000, through December 31, 2016. Data were analyzed from September 1, 2019, through March 31, 2020. HIV status and, for individuals with HIV infection, ART initiation at a CD4 cell count of 500/μL or greater. Overall life expectancy and expected years free of major chronic comorbidities, including chronic liver disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and cardiovascular disease. Of 39 000 individuals with HIV infection and 387 785 matched uninfected adults, 374 421 (87.7%) were male, with a mean (SD) age of 41.4 (10.8) years. Among 359 244 individuals with known race/ethnicity, 90 177 (25.1%) were non-Hispanic black and 87 191 (24.3%) were Hispanic. From 2000 to 2003, overall life expectancy at age 21 years of age was 37.6 years among individuals with HIV infection and 59.7 years among uninfected adults, (difference, 22.1 years; 95% CI, 20.2-24.0 years). From 2014 to 2016, overall life expectancy at 21 years of age among individuals with HIV infection increased to 56.0 years compared with 65.1 years among uninfected adults (difference, 9.1 years; 95% CI, 7.9-10.2 years). During 2011 to 2016, individuals with HIV infection who initiated ART with a CD4 cell count of 500/μL or greater had a life expectancy at 21 years of age of 57.4 years compared with 64.2 years among uninfected adults (difference, 6.8 years; 95% CI, 5.0-8.5 years). From 2000 to 2003, the expected number of comorbidity-free years remaining at 21 years of age was 11.3 for individuals with HIV infection and 26.6 years for uninfected adults (difference, 15.3 years; 95% CI, 13.9-16.6 years). This difference in comorbidity-free years persisted over time but decreased to 9.5 years (95% CI, 7.7-11.2 years) for individuals with HIV infection who initiated ART at a CD4 cell count of 500/μL or greater. The results suggest that life expectancy of adults with HIV infection may be near that of life expectancy of individuals without HIV infection, but greater attention is needed to prevention of comorbidities among individuals with HIV infection.
Authors: Marcus JL; Leyden WA; Alexeeff SE; Anderson AN; Hechter RC; Hu H; Lam JO; Towner WJ; Yuan Q; Horberg MA; Silverberg MJ
JAMA Netw Open. 2020 06 01;3(6):e207954. Epub 2020-06-01.
Changes in Days of Unhealthy Alcohol Use and Antiretroviral Therapy Adherence, HIV RNA Levels, and Condomless Sex: A Secondary Analysis of Clinical Trial Data
In a sample of people with HIV (PWH) enrolled in an alcohol intervention trial and followed for 12 months, we examined the association of changes in days (i.e., decrease, increase, no change [reference]) of unhealthy drinking (consuming ≥ 4/≥ 5 drinks for women/men) with antiretroviral therapy adherence (≥ 95% adherent), viral suppression (HIV RNA < 75 copies/mL), condomless sex with HIV-negative/unknown status partners, and dual-risk outcome (HIV RNA ≥ 75 copies/mL plus condomless sex). The sample included 566 PWH (96.8% male; 63.1% White; 93.9% HIV RNA < 75 copies/mL) who completed baseline, 6-, and 12-month assessments. Decrease in days of unhealthy drinking was associated with increased likelihood of viral suppression (odds ratio [OR] 3.78; 95% confidence interval [CI] 1.06, 13.51, P = .04) versus no change. Increase in days of unhealthy drinking was associated with increased likelihood of condomless sex (OR 3.13; 95% CI 1.60, 6.12, P < .001). Neither increase nor decrease were associated with adherence or dual-risk outcome. On a continuous scale, for each increase by 1 day of unhealthy drinking in the prior month, the odds of being 95% adherent decreased by 6% (OR 0.94, 95% CI 0.88, 1.00, P = 0.04).
Authors: Satre DD; Sarovar V; Leyden W; Hare CB; Catz SL; Bryant KJ; Williams EC; Hojilla JC; Horberg MA; Silverberg MJ
AIDS Behav. 2020 Jun;24(6):1784-1792.
Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Invasive Pneumococcal Disease After Introduction Into Routine Pediatric Use
In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced 7-valent PCV (PCV7) for protection against invasive pneumococcal disease (IPD). This study used laboratory surveillance data to examine the effect of PCV13 on IPD before and after PCV13 introduction among children aged 6 weeks to
Authors: Baxter R; Aukes L; Pelton SI; Yee A; Klein NP; Gruber WC; Scott DA; Center KJ
J Pediatric Infect Dis Soc. 2020 May 16.
Alcohol and drug use, partner PrEP use and STI prevalence among people with HIV
People with HIV (PWH) have a high burden of bacterial sexually transmitted infections (STIs). We examined the relationship of alcohol and drug use and partner pre-exposure prophylaxis (PrEP) use to STI prevalence in a cohort of PWH with a history of unhealthy alcohol use. We analysed data from a primary care-based alcohol intervention study at Kaiser Permanente Northern California (KPNC). Participants were recruited between April 2013 and May 2015 and were followed for up to 24 months. We linked participant responses to questions from the 24?month follow-up interview, including alcohol and drug use and partner PrEP use, with STI test results (ie, syphilis, chlamydia, gonorrhoea) in the KPNC electronic health record. Prevalence ratios (PR) were estimated using Poisson models fitted with robust variance estimators to evaluate the association of substance use and partner use of PrEP with STIs. In the analytic sample (n=465), the median age was 52 years (IQR 45-59); 67% were white; 95% were men who have sex with men. Thirty-two per cent of participants had HIV-positive partners only; 31% had HIV-negative partners with at least one on PrEP in the previous year and 37% had HIV-negative partners without any on PrEP. Twenty-three per cent reported alcohol and drug use prior to sex in the last 6?months. Eight per cent of participants had an STI. Partner PrEP use (adjusted PR (aPR) 2.99 (95% CI 1.11 to 8.08)) was independently associated with higher STI prevalence. Participants who reported use of alcohol (aPR 1.53 (0.61 to 3.83)), drugs (aPR 1.97 (0.71 to 5.51)) or both (aPR 1.93 (0.75 to 4.97)) prior to sex had a higher STI prevalence. The higher prevalence of STIs among PWH with unhealthy alcohol use who have partners on PrEP suggests that this subgroup may be a high-yield focus for targeted outreach, STI screening and sexual health counselling.
Authors: Hojilla JC; Marcus J; Volk JE; Leyden W; Hare CB; Hechter RC; Edelman EJ; Silverberg M; Satre DD
Sex Transm Infect. 2020 05;96(3):184-188. Epub 2019-08-23.
Immunogenicity and Safety of a Measles-Mumps-Rubella Vaccine Administered as a First Dose to Children Aged 12 to 15 Months: A Phase III, Randomized, Noninferiority, Lot-to-Lot Consistency Study
MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose. In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines. Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected. If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.
Authors: Klein NP; Henry O; et al.
J Pediatric Infect Dis Soc. 2020 Apr 30;9(2):194-201.
Epidemiology and clinical outcomes of hospitalizations for acute respiratory or febrile illness and laboratory-confirmed influenza among pregnant women during six influenza seasons, 2010-2016
Pregnant women are at increased risk of seasonal influenza hospitalizations, but data about the epidemiology of severe influenza among pregnant women remain largely limited to pandemics. To describe the epidemiology of hospitalizations for acute respiratory infection or febrile illness (ARFI) and influenza-associated ARFI among pregnant women, administrative and electronic health record data were analyzed from retrospective cohorts of pregnant women hospitalized with ARFI who had testing for influenza viruses by reverse-transcription polymerase chain reaction (RT-PCR) in Australia, Canada, Israel, and the United States during 2010-2016. Of 18 048 ARFI-coded hospitalizations, 1064 (6%) included RT-PCR testing for influenza viruses, 614 (58%) of which were influenza positive. Of 614 influenza-positive ARFI hospitalizations, 35% were in women with low socioeconomic status, 20% with underlying conditions, and 67% in their third trimesters. The median length of influenza-positive hospitalizations was 2 days (interquartile range, 1-4), 18% (95% confidence interval [CI], 15%-21%) resulted in delivery, 10% (95% CI, 8%-12%) included a pneumonia diagnosis, 5% (95% CI, 3%-6%) required intensive care, 2% (95% CI, 1%-3%) included a sepsis diagnosis, and <1% (95% CI, 0%-1%) resulted in respiratory failure. Our findings characterize seasonal influenza hospitalizations among pregnant women and can inform assessments of the public health and economic impact of seasonal influenza on pregnant women.
Authors: Dawood FS; Klein NP; Fell DB; et al.
J Infect Dis. 2020 04 27;221(10):1703-1712.
Addressing Problems With Alcohol and Other Substances Among Older Adults During the COVID-19 Pandemic
Authors: Satre DD; Hirschtritt ME; Silverberg MJ; Sterling SA
Am J Geriatr Psychiatry. 2020 Apr 22.
If Influenza Vaccines Wane Can We Delay Vaccination Without Compromising Coverage?
Authors: Klein NP; Fireman B
Clin Infect Dis. 2020 04 10;70(8):1560-1561.
Parental Risk Factors for Fever in their Children 7-10 Days After the First Dose of Measles-Containing Vaccines
We evaluated whether parental clinical conditions were associated with fever after a first dose of measles-containing vaccine (MCV) in the child in a cohort study including 244,125 children born in Kaiser Permanente Northern California between 2009 and 2016 who received MCV between ages 1 and 2 years. Each child was linked with his/her mother and father when possible. Parental clinical conditions present before and after their child’s birth were identified. We defined fever in the children as clinic and emergency department visits with a fever code 7-10 days after a first dose of MCV (“MCV-associated fever”). We evaluated parental clinical conditions associated with MCV-associated fever using multivariate logistic regression analyses. After adjusting for multiple factors, including healthcare utilization, maternal fever [odds ratio (OR) = 1.19, 95% confidence interval (CI) 1.06-1.32], fever after MCV (OR = 5.90, 95% CI 1.35-25.78), respiratory infections (OR = 1.20, 95% CI 1.10-1.31), migraine (OR = 1.14, 95% CI 1.05-1.24), syncope (OR 1.14, 95% CI 1.01-1.27), and essential thrombocythemia (OR = 1.93, 95% CI 1.15-3.25) were significantly associated with MCV-associated fever. Paternal respiratory infections (OR = 1.15, 95% CI 1.05-1.27), fever associated with respiratory infections (OR = 1.47, 95% CI 1.23-1.76), and vitiligo (OR = 1.63, 95% CI 1.06-2.53) were significantly associated with MCV-associated fever. Parental clinical conditions, specifically fever alone and fever associated with respiratory infection, are associated with fever in their child 7-10 days after MCV.
Authors: Zerbo O; Modaressi S; Goddard K; Lewis E; Bok K; Gans H; Klein NP
Hum Vaccin Immunother. 2020 04 02;16(4):875-880. Epub 2019-11-08.
Depletion of Susceptibles Bias in Analyses of Intra-season Waning of Influenza Vaccine Effectiveness
Bias arises in studies of waning vaccine effectiveness when higher-risk individuals are depleted from the at-risk population at different rates between study groups. We examined how this bias arises and how to avoid it. A reanalysis of data from California confirmed a finding of intra-season waning of influenza vaccine effectiveness.
Authors: Ray GT; Lewis N; Klein NP; Daley MF; Lipsitch M; Fireman B
Clin Infect Dis. 2020 03 17;70(7):1484-1486.
Characterizing the Human Immunodeficiency Virus Care Continuum Among Transgender Women and Cisgender Women and Men in Clinical Care: A Retrospective Time-series Analysis
Prior studies suggest that transgender women (TW) with human immunodeficiency virus (HIV) are less likely to be virally suppressed than cisgender women (CW) and cisgender men (CM). However, prior data are limited by small sample sizes and cross-sectional designs. We sought to characterize the HIV care continuum comparing TW to CW and CM in the United States and Canada. We analyzed annual HIV care continuum outcomes by gender status from January 2001 through December 2015 among adults (aged ≥18 years) in 15 clinical cohorts. Outcomes were retention in care and viral suppression. The study population included TW (n = 396), CW (n = 14 094), and CM (n = 101 667). TW had lower proportions retained in care than CW and CM (P < .01). Estimates of retention in care were consistently lower in TW, with little change over time within each group. TW and CW had similar proportions virally suppressed over time (TW, 36% in 2001 and 80% in 2015; CW, 35% in 2001 and 83% in 2015) and were lower than CM (41% in 2001 and 87% in 2015). These differences did not reach statistical significance after adjusting for age, race, HIV risk group, and cohort. TW experience challenges with retention in HIV care. However, TW who are engaged in care achieve viral suppression that is comparable to that of CW and CM of similar age, race, and HIV risk group. Further research is needed to understand care engagement disparities.
Authors: Poteat T; Silverberg MJ; Althoff KN; et al.
Clin Infect Dis. 2020 03 03;70(6):1131-1138.
Association of immunosuppression and HIV viremia with anal cancer risk in persons living with HIV in the United States and Canada
People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. We studied 102 777 PLWH during 1996-2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for <50 vs ≥500 cells/µL, 13.4; 95% confidence interval [CI], 3.5-51.0) and proportion of time CD4 <200 cells/µL from approximately 8.5 to 4.5 years in the past (a cumulative measure; HR for 100% vs 0%, 3.1; 95% CI, 1.5-6.6). Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.
Authors: Hernández-Ramírez RU; Neugebauer RS; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; et al.
Clin Infect Dis. 2020 03 03;70(6):1176-1185.
Human Papillomavirus Vaccine Effectiveness Against HPV Infection: Evaluation of One, Two, and Three Doses
Highly effective human papillomavirus (HPV) vaccines are used in many national programs in 3- or 2-dose schedules. We examined HPV vaccine effectiveness against HPV prevalence by number of doses. We collected residual liquid-based cytology samples from US women aged 20-29 years who were screened for cervical cancer. Women continuously enrolled from 2006 through the specimen collection date were analyzed. Specimens were tested using the Linear Array assay. We analyzed prevalence of quadrivalent HPV vaccine (4vHPV) types (HPV 6,11,16,18) and other HPV-type categories and determined prevalence ratios (PRs) and 95% confidence intervals (CIs) for 1, 2, and 3 compared with no vaccine doses. Among 4269 women, 1052 (24.6%) were unvaccinated, 2610 (61.1%) received 3 doses, 304 (7.1%) received 2 doses, and 303 (7.1%) received 1 dose. The 4vHPV-type prevalence was 7.4% among unvaccinated women compared with 1.7%, 1.0%, and 1.0% among 1-, 2-, and 3-dose recipients. Among women vaccinated at ≤18 years, adjusted PRs for 1, 2, and 3 doses were 0.06 (95% CI, 0.01-0.42), 0.05 (95% CI, 0.01-0.39), and 0.06 (95% CI, 0.04-0.12). Among women who received their first dose at age ≤18, estimated HPV vaccine effectiveness was high regardless of number of doses.
Authors: Markowitz LE; Klein NP; Unger ER; et al.
J Infect Dis. 2020 03 02;221(6):910-918.
Order of Live and Inactivated Vaccines and Risk of Non-vaccine-targeted Infections in US Children 11-23 Months of Age
Some findings from observational studies have suggested that recent receipt of live vaccines may be associated with decreased non-vaccine-targeted infection risk and mortality. Our objective was to estimate risk of non-vaccine-targeted infections based on most recent vaccine type (live vaccines only, inactivated vaccines only or both concurrently) received in US children 11-23 months of age. We conducted a retrospective cohort study within the Vaccine Safety Datalink. We examined electronic health record and immunization data from children born in 2003-2013 who received 3 diphtheria-tetanus-acellular pertussis vaccines before their first birthday. We modeled vaccine type as a time-varying exposure and estimated risk of non-vaccine-targeted infections identified in emergency department and inpatient settings, adjusting for multiple confounders. Among 428,608 children, 48.9% were female, 4.9% had ≥1 immunization visit with live vaccines only and 10.3% had a non-vaccine-targeted infection. In males, lower risk of non-vaccine-targeted infections was observed following last receipt of live vaccines only or live and inactivated vaccines concurrently as compared with last receipt of inactivated vaccines only [live vaccines-only adjusted hazard ratio (aHR) = 0.83, 95% confidence interval (CI): 0.72-0.94; live and inactivated vaccines concurrently aHR: 0.91, 95% CI: 0.88-0.94]. Among females, last receipt of live and inactivated vaccines concurrently was significantly associated with non-vaccine-targeted infection risk (aHR = 0.94, 95% CI: 0.91-0.97 vs. last receipt of inactivated vaccines only). We observed modest associations between live vaccine receipt and non-vaccine-targeted infections. In this observational study, multiple factors, including healthcare-seeking behavior, may have influenced results.
Authors: Newcomer SR; Zerbo O; Glanz JM; et al.
Pediatr Infect Dis J. 2020 03;39(3):247-253.
Fever After Influenza, Diphtheria-Tetanus-Acellular Pertussis, and Pneumococcal Vaccinations
Administering inactivated influenza vaccine (IIV), 13-valent pneumococcal conjugate vaccine (PCV13), and diphtheria-tetanus-acellular pertussis (DTaP) vaccine together has been associated with increased risk for febrile seizure after vaccination. We assessed the effect of administering IIV at a separate visit from PCV13 and DTaP on postvaccination fever. In 2017-2018, children aged 12 to 16 months were randomly assigned to receive study vaccines simultaneously or sequentially. They had 2 study visits 2 weeks apart; nonstudy vaccines were permitted at visit 1. The simultaneous group received PCV13, DTaP, and quadrivalent IIV (IIV4) at visit 1 and no vaccines at visit 2. The sequential group received PCV13 and DTaP at visit 1 and IIV4 at visit 2. Participants were monitored for fever (≥38°C) and antipyretic use during the 8 days after visits. There were 110 children randomly assigned to the simultaneous group and 111 children to the sequential group; 90% received ≥1 nonstudy vaccine at visit 1. Similar proportions of children experienced fever on days 1 to 2 after visits 1 and 2 combined (simultaneous [8.1%] versus sequential [9.3%]; adjusted relative risk = 0.87 [95% confidence interval 0.36-2.10]). During days 1 to 2 after visit 1, more children in the simultaneous group received antipyretics (37.4% vs 22.4%; P = .020). In our study, delaying IIV4 administration by 2 weeks in children receiving DTaP and PCV13 did not reduce fever occurrence after vaccination. Reevaluating this strategy to prevent fever using an IIV4 with a different composition in a future influenza season may be considered.
Authors: Walter EB; Klein NP; Wodi AP; Rountree W; Todd CA; Wiesner A; Duffy J; Marquez PL; Broder KR
Pediatrics. 2020 03;145(3). Epub 2020-02-06.
Evaluating screening participation, follow-up and outcomes for breast, cervical and colorectal cancer in the PROSPR consortium
Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the Population-based Research Optimizing Screening through Personalized Regimens consortium. We describe how selected metrics map to a trans-organ conceptual model of the screening process. For each cancer type, we calculated calendar year 2013 metrics for the screen-eligible target population (breast: ages 40-74 years; cervical: ages 21-64 years; colorectal: ages 50-75 years). Metrics for screening participation, timely diagnostic evaluation, and diagnosed cancers in the screened and total populations are presented for the total eligible population and stratified by age group and cancer type. The overall screening-eligible populations in 2013 were 305 568 participants for breast, 3 160 128 for cervical, and 2 363 922 for colorectal cancer screening. Being up-to-date for testing was common for all three cancer types: breast (63.5%), cervical (84.6%), and colorectal (77.5%). The percentage of abnormal screens ranged from 10.7% for breast, 4.4% for cervical, and 4.5% for colorectal cancer screening. Abnormal breast screens were followed up diagnostically in almost all (96.8%) cases, and cervical and colorectal were similar (76.2% and 76.3%, respectively). Cancer rates per 1000 screens were 5.66, 0.17, and 1.46 for breast, cervical, and colorectal cancer, respectively. Comprehensive assessment of metrics by the Population-based Research Optimizing Screening through Personalized Regimens consortium enabled systematic identification of screening process steps in need of improvement. We encourage widespread use of common metrics to allow interventions to be tested across cancer types and health-care settings.
Authors: Barlow WE; Corley DA; Silverberg MJ; Tiro JA; et al.
J Natl Cancer Inst. 2020 03 01;112(3):238-246.
Trivalent inactivated influenza vaccine (IIV3) during pregnancy and six-month infant development
Despite recommendations by professional organizations that all pregnant women receive inactivated influenza vaccine, safety concerns remain a barrier. Our objective was to assess the effect of trivalent influenza vaccines (IIV3) during pregnancy on parent report 6-month infant development. We conducted a multi-site prospective birth cohort study during the 2010-2011 influenza season and followed pregnant women and their newborns through 6 months of age. Information on IIV3 during pregnancy was ascertained from the EHR and self-report. The Ages and Stages Questionnaire-3 (ASQ-3) was completed by the mother to assess 6-month infant neurodevelopment in five domains (communication, gross motor, fine motor, problem-solving, and personal adaptive skills). Scores for each domain above the cut-off point indicating typical development were categorized as “on schedule” while scores in the zones indicating the need for either monitoring or further assessment were categorized as “not on schedule”. Multivariable logistic regression was conducted. Of the 1225 infant-mother pairs, 65% received IIV3 during pregnancy. In bivariate analysis, infants of women who received IIV3 during pregnancy were moderately-less likely to need monitoring or further assessment in the personal social domain compared with infants of unvaccinated women (10.0% vs. 14.1%, p = 0.033; crude OR (cOR): 0.68(95%CI:0.48,0.97)). However, after controlling for potential confounders, the findings were no longer statistically significant (aOR:0.72,95%CI: 0.49,1.06,p = 0.46). No significant unadjusted or adjusted associations emerged in any other ASQ-3 domain. There was no significant association between IIV3 exposure during pregnancy and 6-month infant development. Studies of IIV3 during pregnancy to assess longer-term developmental outcomes are indicated.
Authors: Avalos LA; Zerbo O; Li DK; et al.
Vaccine. 2020 02 28;38(10):2326-2332. Epub 2020-02-05.
Survey of influenza vaccine knowledge, attitudes, and beliefs among pregnant women in the 2016-17 season
Influenza vaccination coverage among pregnant women in the United States is suboptimal. We surveyed women who were pregnant during the 2016-17 influenza season to assess knowledge and attitudes regarding influenza vaccination. We identified and sampled pregnant women to include approximately equal numbers of vaccinated and unvaccinated women from strata defined by vaccination status and trimester from four integrated health systems in the Vaccine Safety Datalink (VSD). Potential participants were contacted via mail and telephone to complete a standardized survey. Characteristics and responses of women vaccinated and unvaccinated during pregnancy were compared. The survey was completed by 510 (48%) of 1062 contacted women; 500 were included in the analysis. Vaccine receipt while pregnant was associated with primigravida status (p = 0.02), college degree (p = 0.01), employment in health care (p < 0.01), and history of routine annual influenza vaccination (p < 0.01). Among 330 vaccinated women, the primary reasons for vaccination included protection of self and baby from influenza (n = 233, 71%), and medical professional recommendation (n = 46, 14%). Multiple reasons were given for nonvaccination, but concern about 'negative effects' was cited most often (n = 44, 29%). Vaccinated women were significantly more likely to believe that influenza vaccines are safe and effective, and to recognize the potential for harm from influenza infection. Nearly all women reported receiving at least one influenza vaccination recommendation from a healthcare provider. Vaccinated pregnant women were more likely to receive routine annual influenza vaccine compared to those not vaccinated. Recommendations by obstetric providers should be supplemented with efforts to encourage women of childbearing age to receive annual vaccination.
Authors: King JP; Hanson KE; Donahue JG; Glanz JM; Klein NP; Naleway AL; DeStefano F; Weintraub E; Belongia EA
Vaccine. 2020 02 24;38(9):2202-2208. Epub 2020-01-25.
Homeschooling parents in California: Attitudes, beliefs and behaviors associated with child’s vaccination status
Senate Bill 277 (SB277) banned nonmedical exemptions from school-entry vaccination requirements for children attending classroom-based schools in California, but excluded homeschooled children from vaccination requirements. Thus, it was hypothesized that more parents would choose to homeschool to avoid vaccination requirements in response to SB277. There is limited literature on the vaccine attitudes, beliefs, and behaviors among the homeschooling population in the US, despite an overall increase in homeschooling nationwide and documented vaccine-preventable disease outbreaks within the homeschooled child population. Between November 2018 and January 2019, we conducted a cross-sectional online survey among homeschooling parents with at least one child in grades K-8 who is currently enrolled in one of the legally-acceptable mechanisms to homeschool in California: (1) home-based private school satellite program (PSP), or (2) public or charter independent study program (ISP) with no classroom-based instruction. Among 140 homeschooling parents from 8 schools in California, 71% reported that their youngest child in grade K-8 was up-to-date on immunizations at kindergarten-entry and 56% reported that they made the decision to homeschool their child after the implementation of SB277. Compared to homeschooling parents whose child was up-to-date at kindergarten entry, homeschooling parents whose child was not up-to-date at kindergarten entry reported higher concerns over vaccine safety and effectiveness, more frequently cited immunization mandates as a reason to homeschool, and were more likely to report having considered moving out of California due to immunization mandates. There was variation in vaccine attitudes and beliefs within the homeschooling population in this sample. Immunization mandates were a factor in the decision to homeschool for some parents in this sample, supporting the hypothesis that vaccine-hesitant parents considered homeschooling as a way to avoid immunization mandates such as SB277. Future studies should explore the complexities around vaccine attitudes, beliefs and behaviors among homeschooling populations.
Authors: Mohanty S; Joyce CM; Delamater PL; Klein NP; Salmon D; Omer SB; Buttenheim AM
Vaccine. 2020 02 18;38(8):1899-1905. Epub 2020-01-22.
Life Expectancy of Insured People With and Without Hepatitis C Virus Infection, 2007-2017
Among 25 291 and 4 921 830 people with and without hepatitis C, life expectancy at age 20 increased 1.8 years and 0.3 years from the interferon to interferon-free era, respectively. Increases were highest for racial and/or ethnic minority groups with hepatitis C.
Authors: Marcus JL; Lam JO; Quesenberry CP; Silverberg MJ; et al.
Open Forum Infect Dis. 2020 Feb;7(2):ofaa044. Epub 2020-02-05.
Cervical cancer risk in women living with HIV across four continents: A multicohort study
We compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. We analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. We used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. We included 64,231 women from 45 countries. During 320,141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100,000 pys were 447 in South Africa (95% confidence interval [CI]: 382-523), 136 in Latin America (95% CI: 85-219), 76 in North America (95% CI: 48-119) and 66 in Europe (95% CI: 57-77). Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (>50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/μl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities.
Authors: Rohner E; Silverberg MJ; Bohlius J; et al.
Int J Cancer. 2020 02 01;146(3):601-609. Epub 2019-06-19.
Prevalence of Spontaneous Clearance of Hepatitis C Virus Infection Doubled From 1998 to 2017
Strategic planning for hepatitis C virus (HCV) screening and treatment requires up-to-date information on the prevalence of HCV spontaneous clearance. Published estimates of HCV spontaneous clearance range from 15% to 60%.1-3 We conducted an observational study over 20 years to evaluate trends in the prevalence of HCV spontaneous clearance. Our goals were to estimate the proportion of HCV-antibody-positive patients who were viremic, and to identify factors associated with viremia, thus facilitating prediction of the number of patients needing treatment.
Authors: Seo S; Silverberg MJ; Marcus JL; et al.
Clin Gastroenterol Hepatol. 2020 02;18(2):511-513. Epub 2019-04-19.
Burden of Active Tuberculosis in an Integrated Health Care System, 1997-2016: Incidence, Mortality, and Excess Health Care Utilization
Active tuberculosis (TB) is preventable. To quantify the potential value of prevention, we assessed active TB burden in a large health system from 1997 to 2016. Compared with a matched non-TB cohort, patients with active TB had higher mortality (8.4% vs 1.3%), mean number of hospitalizations (0.55 vs 0.10), emergency department visits (0.78 vs 0.28), and outpatient visits (14.6 vs 5.9) in the first year. TB-associated hospital use (mean number of hospitalizations and total length of stay) increased from 1997-2000 compared with 2013-2016 despite decreasing active TB incidence. Active TB is associated with high mortality and health care utilization and has remained stable or increased over time.
Authors: Wada PY; Lee-Rodriguez C; Hung YY; Skarbinski J
Open Forum Infect Dis. 2020 Jan;7(1):ofaa015. Epub 2020-01-12.
Vaccine effectiveness of cell-culture relative to egg-based inactivated influenza vaccine during the 2017-18 influenza season
There is concern that influenza vaccine effectiveness (VE) may be attenuated by passage in eggs during manufacture. We compared quadrivalent cell-culture vaccine with egg-based vaccines, most of which were trivalent, against influenza A and B during 2017-2018 when A(H3N2) and B/Yamagata (present only in quadrivalent vaccines) predominated. We retrospectively examined risk of PCR-confirmed influenza A and B in members of Kaiser Permanente Northern California aged 4-64 years. We estimated the relative VE (rVE) of cell-culture vaccine versus egg-based vaccines, and the absolute VE (aVE) of each vaccine comparing vaccinated to unvaccinated individuals. Analyses used Cox regression with a calendar timeline, stratified by birth year, and adjusted for demographics, co-morbidities and utilization. One-third (1,016,965/3,053,248) of the population was vaccinated; 932,545 (91.7% of vaccinees) received egg-based and 84,420 (8.3%) received cell-culture vaccines. The rVE against influenza A was 8.0% (95% CI: -10, 23); aVE was 31.7% (CI: 18.7, 42.6) for cell-culture and 20.1% (CI: 14.5, 25.4) for egg-based vaccines. The rVE against influenza B was 39.6% (CI: 27.9, 49.3); aVE was 40.9% (CI: 30, 50.1) for cell-culture and 9.7% (CI 3.5, 15.6) for egg-based trivalent vaccines. Inclusion of the B/Yamagata lineage in the quadrivalent cell-based vaccine provided better protection against influenza B but vaccine effectiveness against influenza A was low for both the cell-culture vaccine and the egg-based vaccines. Improving influenza vaccines requires ongoing comparative vaccine effectiveness monitoring.
Authors: Klein NP; Fireman B; Goddard K; Zerbo O; Asher J; Zhou J; King J; Lewis N
PLoS One. 2020;15(2):e0229279. Epub 2020-02-26.
LIFE EXPECTANCY DISPARITIES AMONG ADULTS WITH HIV IN THE UNITED STATES AND CANADA: THE IMPACT OF A REDUCTION IN DRUG- AND ALCOHOL-RELATED DEATHS USING THE LIVES SAVED SIMULATION (LISSO) MODEL
Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities.
Authors: Althoff KN; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA; et al.
Am J Epidemiol. 2019 12 31;188(12):2097-2109.
Chorioamnionitis: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data
Authors: Kachikis A; Klein NP; Brighton Collaboration Chorioamnionitis Working Group; et al.
Vaccine. 2019 12 10;37(52):7610-7622.
Near Real-Time Surveillance to Assess the Safety of the 9-Valent Human Papillomavirus Vaccine
Human papillomavirus is the most common sexually transmitted infection in the United States and causes certain anogenital and oropharyngeal cancers. The 9-valent human papillomavirus vaccine (9vHPV) provides protection against additional types not included in the quadrivalent vaccine. We conducted near real-time vaccine safety surveillance for 24 months after the vaccine became available in the Vaccine Safety Datalink. Immunizations and adverse events were extracted weekly from October 2015 to October 2017 from standardized data files for persons 9 to 26 years old at 6 Vaccine Safety Datalink sites. Prespecified adverse events included anaphylaxis, allergic reaction, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, injection site reaction, pancreatitis, seizure, stroke, syncope, and venous thromboembolism. The observed and expected numbers of events after 9vHPV were compared weekly by using sequential methods. Both historical and concurrent comparison groups were used to identify statistical signals for adverse events. Unexpected signals were investigated by medical record review and/or additional analyses. During 105 weeks of surveillance, 838 991 doses of 9vHPV were administered. We identified unexpected statistical signals for 4 adverse events: appendicitis among boys 9 to 17 years old after dose 3; pancreatitis among men 18 to 26 years old; and allergic reactions among girls 9 to 17 years old and women 18 to 26 years old after dose 2. On further evaluation, which included medical record review, temporal scan analysis, and additional epidemiological analyses, we did not confirm signals for any adverse events. After 2 years of near real-time surveillance of 9vHPV and several prespecified adverse events, no new safety concerns were identified.
Authors: Donahue JG; Klein NP; Belongia EA; et al.
Pediatrics. 2019 12;144(6). Epub 2019-11-18.
Assessment of Exemptions From Vaccination in California, 2015 to 2027
Authors: Delamater PL; Buttenheim AM; Klein NP; Mohanty S; Salmon DA; Omer SB
Ann Intern Med. 2019 Nov 05.
Uptake and safety of hepatitis A vaccination during pregnancy: A Vaccine Safety Datalink study
Infection with hepatitis A virus (HAV) during pregnancy, although uncommon, is associated with gestational complications and pre-term labor. Hepatitis A vaccine (HepA) is recommended for anyone at increased risk for contracting hepatitis A, including women at risk who are also pregnant. Limited data are available on the safety of maternal HepA vaccination. Assess the frequency of maternal HepA receipt and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. A retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live births from 2004 through 2015 was included. Pregnancies with HepA exposure were compared to those with other vaccine exposures, and to those with no vaccine exposures. Risk factors for contracting hepatitis A were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were evaluated according to maternal HepA exposure status. Adjusted odds ratio (OR) were used to describe the association. Among 666,233 pregnancies in the study period, HepA was administered at a rate of 1.7 per 1000 (n = 1140), most commonly within the first six weeks of pregnancy. Less than 3% of those exposed to HepA during pregnancy had an ICD-confirmed risk factor. There were no significant associations between HepA exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, and low birthweight. There was a statistically significant association between HepA exposure during pregnancy and small-for-gestational age (SGA) infants (aOR 1.32, [95% CI 1.09, 1.60], p = 0.004). The rate of maternal HepA vaccination was low and rarely due to documented risk factors for vaccination. HepA vaccination during pregnancy was not associated with an increased risk for a range of adverse events examined among pregnancies resulting in live births, but an identified association between maternal HepA and SGA infant outcomes, while likely due to unmeasured confounding, warrants further exploration.
Authors: Groom HC; Klein NP; Naleway AL; et al.
Vaccine. 2019 10 16;37(44):6648-6655. Epub 2019-09-20.
Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012-13, 2013-14, and 2014-15
A recent study reported an association between inactivated influenza vaccine (IIV) and spontaneous abortion (SAB), but only among women who had also been vaccinated in the previous influenza season. We sought to estimate the association between IIV administered in three recent influenza seasons and SAB among women who were and were not vaccinated in the previous influenza season. We conducted a case-control study over three influenza seasons (2012-13, 2013-14, 2014-15) in the Vaccine Safety Datalink (VSD). Cases (women with SAB) and controls (women with live births) were matched on VSD site, date of last menstrual period, age group, and influenza vaccination status in the previous influenza season. Of 1908 presumptive cases identified from the electronic record, 1236 were included in the main analysis. Administration of IIV was documented in several risk windows, including 1-28, 29-56, and >56 days before the SAB date. Among 627 matched pairs vaccinated in the previous season, no association was found between vaccination in the 1-28 day risk window and SAB (adjusted odds ratio (aOR) 0.9; 95% confidence interval (CI) 0.6-1.5). The season-specific aOR ranged from 0.5 to 1.7 with all CIs including the null value of 1.0. Similarly, no association was found among women who were not vaccinated in the previous season; the season-specific aOR in the 1-28 day risk window ranged from 0.6 to 0.7 and the 95% CI included 1.0 in each season. There was no association found between SAB and influenza vaccination in the other risk windows, or when vaccine receipt was analyzed relative to date of conception. During these seasons we found no association between IIV and SAB, including among women vaccinated in the previous season. These findings lend support to current recommendations for influenza vaccination at any time during pregnancy, including the first trimester.
Authors: Donahue JG; Klein NP; Belongia EA; et al.
Vaccine. 2019 10 16;37(44):6673-6681. Epub 2019-09-17.
Prevalence of human papillomavirus (HPV)-vaccine types by race/ethnicity and sociodemographic factors in women with high-grade cervical intraepithelial neoplasia (CIN2/3/AIS), Alameda County, California, United States
We evaluated racial/ethnic differences in prevalence of oncogenic HPV types targeted by the quadrivalent HPV vaccine (16/18) and nonavalent HPV vaccine (31/33/45/52/58) in women diagnosed with CIN2/3/AIS after quadrivalent HPV vaccine introduction (2008-2015). Typing data from 1810 cervical tissue specimen from HPV-IMPACT (Alameda County, California, US), a population-based CIN2/3/AIS surveillance effort, were analyzed. Using log-binomial regression, we calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) comparing type prevalence by race/ethnicity, adjusted for health insurance, age, CIN2/3/AIS grade, and time period, overall and in the "early vaccine era" (2008-2011) and "later vaccine era" (2012-2015). Overall, oncogenic HPV16/18 prevalence was significantly lower among black (43%) and Hispanic (43%) women compared with white (52%) women (aPR (95% CI): 0.80 (0.70, 0.93) and 0.80 (0.70, 0.91), respectively). In 2008-2011, proportion of HPV16/18 detected was significantly lower in black (47%), Hispanic (46%), and Asian (42%) women compared to white (58%) women (aPR (95% CI): 0.80 (0.67, 0.96), 0.75 (0.63, 0.90), and 0.73 (0.58, 0.90), respectively). There were no significant differences in 2012-2015. Between the two eras, HPV16/18 prevalence declined in white (-11%), black (-9%), and Hispanic (-6%) women, and increased in Asian women (12%). Decreasing HPV 16/18 prevalence in CIN2/3/AIS lesions in white, black, and Hispanic women may suggest benefit from quadrivalent vaccination. In our unadjusted analysis of HPV31/33/45/52/58, prevalence did not differ significantly by race/ethnicity, but was significantly higher among Hispanic women (32%) compared to white women (27%) after adjustment (aPR (95%CI): 1.22 (1.02, 1.47). Prevalence was also non-significantly higher among black (32%) and Asian (33%) women. This analysis suggests that the nonavalent vaccine’s potential for impact against cervical precancers will not be lower in women of color compared to white women. These data underscore the importance of equitable vaccination in facilitating continued declines of vaccine-preventable HPV types among all women.
Authors: Saadeh K; Park I; Gargano JW; Whitney E; Querec TD; Hurley L; Silverberg M
Vaccine. 2019 Oct 11.
Use of electronic health record data and machine learning to identify candidates for HIV pre-exposure prophylaxis: a modelling study
The limitations of existing HIV risk prediction tools are a barrier to implementation of pre-exposure prophylaxis (PrEP). We developed and validated an HIV prediction model to identify potential PrEP candidates in a large health-care system. Our study population was HIV-uninfected adult members of Kaiser Permanente Northern California, a large integrated health-care system, who were not yet using PrEP and had at least 2 years of previous health plan enrolment with at least one outpatient visit from Jan 1, 2007, to Dec 31, 2017. Using 81 electronic health record (EHR) variables, we applied least absolute shrinkage and selection operator (LASSO) regression to predict incident HIV diagnosis within 3 years on a subset of patients who entered the cohort in 2007-14 (development dataset), assessing ten-fold cross-validated area under the receiver operating characteristic curve (AUC) and 95% CIs. We compared the full model to simpler models including only men who have sex with men (MSM) status and sexually transmitted infection (STI) positivity, testing, and treatment. Models were validated prospectively with data from an independent set of patients who entered the cohort in 2015-17. We computed predicted probabilities of incident HIV diagnosis within 3 years (risk scores), categorised as low risk (<0·05%), moderate risk (0·05% to <0·20%), high risk (0·20% to <1·0%), and very high risk (≥1·0%), for all patients in the validation dataset. Of 3 750 664 patients in 2007-17 (3 143 963 in the development dataset and 606 701 in the validation dataset), there were 784 incident HIV cases within 3 years of baseline. The LASSO procedure retained 44 predictors in the full model, with an AUC of 0·86 (95% CI 0·85-0·87) for incident HIV cases in 2007-14. Model performance remained high in the validation dataset (AUC 0·84, 0·80-0·89). The full model outperformed simpler models including only MSM status and STI positivity. For the full model, flagging 13 463 (2·2%) patients with high or very high HIV risk scores in the validation dataset identified 32 (38·6%) of the 83 incident HIV cases, including 32 (46·4%) of 69 male cases and none of the 14 female cases. The full model had equivalent sensitivity by race whereas simpler models identified fewer black than white HIV cases. Prediction models using EHR data can identify patients at high risk of HIV acquisition who could benefit from PrEP. Future studies should optimise EHR-based HIV risk prediction tools and evaluate their effect on prescription of PrEP. Kaiser Permanente Community Benefit Research Program and the US National Institutes of Health.
Authors: Marcus JL; Hurley LB; Krakower DS; Alexeeff S; Silverberg MJ; Volk JE
Lancet HIV. 2019 10;6(10):e688-e695. Epub 2019-07-05.
Infection and Fever in Pregnancy and Autism Spectrum Disorders: Findings from the Study to Explore Early Development
Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res 2019, 12: 1551-1561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD.
Authors: Croen LA; Zerbo O; Ames JL; et al.
Autism Res. 2019 10;12(10):1551-1561. Epub 2019-07-17.
Interventions to Reduce Unhealthy Alcohol Use among Primary Care Patients with HIV: the Health and Motivation Randomized Clinical Trial
Unhealthy alcohol use has adverse effects on HIV treatment. Screening, brief intervention, and referral to treatment (SBIRT) has some evidence of efficacy but may not be sufficient for those with low motivation or comorbid substance use. To examine the effectiveness of motivational interviewing (MI) and emailed feedback (EF) among primary care HIV-positive patients, compared with treatment as usual care (UC) only, which included SBIRT. Randomized clinical trial. Six hundred fourteen adult HIV-positive patients in Kaiser Permanente Northern California who reported prior-year unhealthy alcohol use. Participants were randomized to either three sessions of MI (one in person and two by phone), information regarding alcohol risks via EF through a patient portal, or UC alone. MI and EF participants who reported unhealthy alcohol use at 6 months were offered additional MI and EF treatment, respectively. Participant-reported unhealthy alcohol use (defined as ≥ 4/≥ 5 drinks per day for women/men), alcohol problems at 12 months, based on blinded telephone interviews. Secondary outcomes included drug use and antiretroviral (ART) adherence. At 12 months, there were no overall group differences, but in all three arms, there were declines in unhealthy alcohol use and alcohol-related problems (p < 0.001). Participants reporting low motivation to reduce drinking at baseline were less likely to report unhealthy alcohol use if they received MI vs. EF and UC (p = 0.013). At 6 months, reported illegal drug use/misuse of prescription drugs other than marijuana was lower in the MI arm than EF or UC (p = 0.012). There were no differences in ART adherence between groups. In a randomized trial of HIV-positive patients using two behavioral interventions compared with SBIRT alone, participants in all three conditions reduced unhealthy alcohol use. MI may provide added benefit for patients with low motivation or who report illegal drug use/misuse of prescription drugs. NCT01671501 ( ClinicalTrials.gov ).
Authors: Satre DD; Lam JO; Weisner CM; Sterling SA; Silverberg MJ; et al.
J Gen Intern Med. 2019 10;34(10):2054-2061. Epub 2019-06-11.
Implementing electronic substance use disorder and depression and anxiety screening and behavioral interventions in primary care clinics serving people with HIV: Protocol for the Promoting Access to Care Engagement (PACE) trial
Substance use disorders (SUDs) and psychiatric disorders are common among people with HIV (PWH) and lead to poor outcomes. Yet these conditions often go unrecognized and untreated in primary care. The Promoting Access to Care Engagement (PACE) trial currently in process examines the impact of self-administered electronic screening for SUD risk, depression and anxiety in three large Kaiser Permanente Northern California primary care clinics serving over 5000 PWH. Screening uses validated measures (Tobacco, Alcohol, Prescription medication, and other Substance use [TAPS]; and the Adult Outcomes Questionnaire [AOQ], which includes the Patient Health Questionnaire [PHQ-9] and Generalized Anxiety Disorder [GAD-2]) delivered via three modalities (secure messaging, tablets in waiting rooms, and desktop computers in exam rooms). Results are integrated automatically into the electronic health record. Based on screening results and physician referrals, behavioral health specialists embedded in primary care initiate motivational interviewing- and cognitive behavioral therapy-based brief treatment and link patients to addiction and psychiatry clinics as needed. Analyses examine implementation (screening and treatment rates) and effectiveness (SUD, depression and anxiety symptoms; HIV viral control) outcomes using a stepped-wedge design, with a 12-month intervention phase implemented sequentially in the clinics, and a 24-month usual care period prior to implementation in each clinic functioning as sequential observational phases for comparison. We also evaluate screening and treatment costs and implementation barriers and facilitators. The study examines innovative, technology-facilitated strategies for improving assessment and treatment in primary care. Results may help to inform substance use, mental health, and HIV services. NCT03217058.
Authors: Satre DD; Weisner CM; Silverberg MJ; et al.
Contemp Clin Trials. 2019 09;84:105833. Epub 2019-08-22.
Determinants of Liver Complications Among HIV/Hepatitis B Virus-Coinfected Patients
Hepatitis B virus (HBV) infection is a leading cause of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) in HIV. Factors contributing to the high rates of liver complications among HIV/HBV-coinfected individuals remain unknown. North American AIDS Cohort Collaboration on Research and Design. We performed a retrospective cohort study among HIV/HBV-coinfected patients in 10 US and Canadian cohorts of the North American AIDS Cohort Collaboration on Research and Design that validated ESLD (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, and/or hepatic encephalopathy) and HCC diagnoses from 1996 to 2010. Multivariable Cox regression was used to examine adjusted hazard ratios [aHRs with 95% confidence interval (CIs)] of liver complications (first occurrence of ESLD or HCC) associated with hypothesized determinants and with increasing durations of HIV suppression (≤500 copies/mL). Among 3573 HIV/HBV patients with 13,790 person-years of follow-up, 111 liver complications occurred (incidence rate = 8.0 [95% CI: 6.6 to 9.7] events/1000 person-years). Rates of liver complication were increased with non-black/non-Hispanic race [aHR = 1.76 (1.13-2.74)], diabetes mellitus [aHR = 2.07 (1.20-3.57)], lower time-updated CD4 cell count [<200 cells/mm: aHR = 2.59 (1.36-4.91); 201-499 cells/mm: aHR = 1.75 (1.01-3.06) versus ≥500 cells/mm], heavy alcohol use [aHR = 1.58 (1.04-2.39)], and higher FIB-4 at start of follow-up [>3.25: aHR = 9.79 (5.73-16.74); 1.45-3.25: aHR = 3.20 (1.87-5.47) versus FIB-4 <1.45]. HIV suppression for ≥6 months was associated with lower liver complication rates compared with those with unsuppressed HIV [aHR = 0.56 (0.35-0.91)]. Non-black/non-Hispanic race, diabetes, lower CD4 cell count, heavy alcohol use, and advanced liver fibrosis were determinants of liver complications among HIV/HBV patients. Sustained HIV suppression should be a focus for HIV/HBV-coinfected patients to reduce the risks of ESLD/HCC.
Authors: Lo Re V; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of IeDEA; et al.
J Acquir Immune Defic Syndr. 2019 09 01;82(1):71-80.
Mental and Physical Quality of Life by Age Groups in People Living With HIV
Quality of life (QoL) is relevant to people living with HIV (PLWH) with increased life expectancy because of antiretroviral therapy. Our cross-sectional study examined associations between sociodemographic, HIV-related and psychological variables, and QoL, overall and by age. PLWH (n = 614) completed questionnaires at enrollment in an alcohol treatment study. QoL was assessed by the 12-item Short Form Survey, which includes physical and mental domains. Linear regression models evaluated the association of age and other factors with mental and physical QoL. PLWH younger than 50 years (n = 310) reported poorer mental QoL but better physical QoL compared to older PLWH (n = 304). Poorer mental QoL was associated with substance use, depression, and anxiety. Poorer physical QoL was associated with depression and history of injection drug use. We identified age-group differences in QoL for this primary care-based sample. Health care providers can use our findings to guide patient-centered care.
Authors: Jang HJ; Satre DD; Leyden W; Leibowitz A; Silverberg MJ
J Assoc Nurses AIDS Care. 2019 Sep-Oct;30(5):500-510.
Reply to Skowronski, De Serres and Orenstein
Authors: Thompson MG; Jackson ML; Regan A; Katz MA; Kwong JC; Ball SW; Simmonds K; Klein NP; Naleway A
Clin Infect Dis. 2019 08 30;69(6):1085-1086.
Long-term effectiveness of zoster vaccine live for postherpetic neuralgia prevention
Postherpetic neuralgia (PHN) occurs in 5-30% of individuals with herpes zoster (HZ) and is characterized by long-lasting pain. Zoster vaccine live (ZVL) is licensed for people 50 years and older to prevent HZ and PHN. This study evaluated vaccine effectiveness (VE) of ZVL against PHN. We conducted an open cohort study within Kaiser Permanente Northern California with continuous accrual of people as they became age-eligible for ZVL. We defined PHN using a PHN diagnosis between 90 and 365 days after an incident episode of HZ. We estimated VE against PHN using Cox regression with a calendar timeline stratified by year of birth and adjusted for sex, race, influenza vaccination, outpatient visit frequency, comorbidities, and immune compromise status. From 2007 to 2016, 1·5 million people entered the study population and 33% received ZVL. During 7·6 million person-years of follow-up, there were 62,205 HZ cases, 4150 (6·7%) of which went on to develop PHN. Overall VE for PHN was 64·8% (95% CI 61·3, 68). VE was 82·8% (95% CI 77·6, 86·7) during the first year after vaccination, 58·3% (95% CI 50.1, 65.2) during the third year, and then waned more gradually to 48·7% (95% CI 30·2, 62·3) during the eighth year. VE in persons vaccinated when aged 80 years or older was similar to VE in younger vaccinees. VE in persons vaccinated when immune compromised was similar to VE in immune competent. Overall, ZVL was 65% effective against PHN. It was effective in all age groups and provided moderate protection through 8 years.
Authors: Klein NP; Bartlett J; Fireman B; Marks MA; Hansen J; Lewis E; Aukes L; Saddier P
Vaccine. 2019 08 23;37(36):5422-5427. Epub 2019-07-10.
Antibody persistence and booster response following MenACWY-CRM vaccination in children as assessed by two different assay methods
The quadrivalent meningococcal conjugate vaccine MenACWY-CRM has been shown to be immunogenic and well-tolerated in infants and toddlers. We evaluated antibody persistence for up to 4 years after vaccination with MenACWY-CRM in the first years of life and response to a booster dose administered at 60 months of age. This was phase 3b, open-label, multicenter extension trial (NCT01148017). We assessed by hSBA and rSBA the persistence of antibody responses to serogroups ACWY in 203 healthy 60-month-olds receiving 4 doses of MenACWY-CRM during infancy (ACWY-4 group), or 2 doses at 12/13 and 15 months or 1 dose at 18 months of age (ACWY-2 group). We administered a MenACWY-CRM dose to 224 primed and 45 naïve 60-month-olds and evaluated safety and antibody response 1 month later. Antibody persistence measured by both assays was higher in primed than naïve 60-month-olds. The percentages of primed children with hSBA titers ≥8 was low for serogroup A (6-25%) and moderate for serogroups C (27-43%), Y (69-74%) and W (56-69%). For all serogroups, hSBA antibody geometric mean titers (GMTs) tended to be higher in the ACWY-2 than the ACWY-4 group. Post-booster/single dose, ≥96% of primed and ≥73% of naïve children had hSBA titers ≥8 against each serogroup, and hSBA GMTs were higher in primed children. The booster dose was well-tolerated and no safety concern was identified. We further assessed persistence using rSBA across different age groups and detected no overall correlation between rSBA and hSBA titers. Primary vaccination of infants/toddlers with MenACWY-CRM resulted in moderate antibody persistence against serogroups C, W and Y for up to 4 years after the last priming dose. Regardless of priming schedule, a MenACWY-CRM booster dose at 60 months of age induced a robust immune response against all serogroups and was well-tolerated in all children.
Authors: Klein NP; Block SL; Essink B; Barbi S; Smolenov I; Keshavan P
Vaccine. 2019 07 26;37(32):4460-4467. Epub 2019-07-03.
An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk: The Early Markers for Autism Study
The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes. Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis. Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups. Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.
Authors: Heuer LS; Croen LA; Jones KL; Yoshida CK; Hansen RL; Yolken R; Zerbo O; DeLorenze G; Kharrazi M; Ashwood P; Van de Water J
Biol Psychiatry. 2019 May 15.
The impact of reactogenicity after the first dose of recombinant zoster vaccine upon the physical functioning and quality of life of older adults: an open phase III trial
Herpes zoster and its related complications are associated with significant medical burden, which negatively affects quality of life and daily functioning of the patients. The recently licensed recombinant zoster vaccine (RZV) offers high efficacy but is associated with local and systemic reactions. This study assessed the impact of RZV on the quality of life and daily functioning of participants and implications for caregivers. Four hundred and one adults aged 50 years or older received single RZV doses at 0 and 2 months in this open-label, single-arm, multicenter study (NCT02979639). Change in mean SF-36 Physical Functioning score following first-dose administration, quality of life, reactogenicity, safety, productivity loss, and health care resource utilization was assessed. The current analysis was performed post-vaccine dose-1; safety follow-up will continue until 1 year post-dose-2. The most common solicited local symptoms were injection-site pain (77.5%), redness (23.0%), and swelling (13.3%); the most frequent solicited systemic reactions were fatigue (33.5%), headache (28.3%), and myalgia (26.8%). Grade 3 reactogenicity occurred in 9.5% of participants and was associated with a transient clinically important decrease in SF-36 Physical Functioning score (affecting activities such as walking, carrying groceries, climbing stairs) on Days 1 and 2 post-first vaccination. No clinically meaningful reductions in mean SF-36 Physical Functioning scale scores from pre- to post-RZV dose-1 were observed (mean +1.9 points, primary end point), and no overall quality-adjusted-life-year loss was recorded post-dose-1. Five participants reported lost workdays; caregiver workload was not increased. Overall, the physical functioning and quality of life of older adults were not affected by a first RZV dose. The observed reactogenicity was consistent with previous studies.
Authors: Schmader KE; Klein NP; Curran D; et al.
J Glaucoma. 2019 05;28(5):473-480.
Associations of Statewide Legislative and Administrative Interventions With Vaccination Status Among Kindergartners in California
California implemented 3 interventions to increase uptake of vaccines. In 2014, Assembly bill 2109 tightened requirements for obtaining a personal belief exemption. A 2015 campaign provided educational materials to school staff on the proper application of conditional admission for kindergartners who were not up to date on required vaccinations. In 2016, Senate bill 277 eliminated personal belief exemptions. Prior research has not evaluated these 3 interventions together with regard to the vaccination status of students. To assess the changes in the yearly rates of kindergartners who were not up to date on required vaccinations who were entering school during the period of the interventions, by focusing on geographic clustering and the potential contacts of these kindergartners. Observational study that used cross-sectional school-entry data from 2000-2017 to calculate the rates of kindergartners attending California schools who were not up to date on required vaccinations. Assembly bill 2109, a conditional admission education program, and Senate bill 277. The primary outcome was the yearly rate of kindergartners without up-to-date vaccination status. The secondary outcomes were (1) the modified aggregation index, which was used to assess the potential within-school contacts among kindergartners without up-to-date vaccination status, (2) the number of geographic clusters of schools with rates for kindergartners without up-to-date vaccination status that were higher than the rates for schools located outside the cluster, and (3) the number of schools located inside the geographic clusters. In California between 2000 and 2017, 9 323 315 children started attending kindergarten and 721 593 were not up to date on required vaccinations. Prior to the interventions, the statewide rate of kindergartners without up-to-date status for required vaccinations increased from 7.80% during 2000 to 9.84% during 2013 and then decreased after the interventions to 4.87% during 2017. The percentage chance for within-school contact among kindergartners without up-to-date vaccination status decreased from 26.02% during 2014 to 4.56% (95% CI, 4.21%-4.99%) during 2017. During 2012-2013, there were 124 clusters that contained 3026 schools with high rates of kindergartners without up-to-date vaccination status. During 2014-2015, there were 93 clusters that contained 2290 schools with high rates of kindergartners without up-to-date vaccination status. During 2016-2017, there were 110 clusters that contained 1613 (95% CI, 1565-1691) schools. In California, statewide legislative and educational interventions were associated with a decrease in the yearly rates of kindergartners without up-to-date vaccination status. These interventions also were associated with reductions in the number of schools inside the clusters with high rates of kindergartners without up-to-date vaccination status and the potential for contact among these kindergartners.
Authors: Pingali SC; Delamater PL; Buttenheim AM; Salmon DA; Klein NP; Omer SB
JAMA. 2019 07 02;322(1):49-56.
Incidence of Herpes Zoster Among Children: 2003-2014
After the 1996 introduction of routine varicella vaccination in the United States, most studies evaluating pediatric herpes zoster (HZ) incidence reported lower incidence over time, with varying degrees of decline. Using the combined databases of 6 integrated health care organizations, we examined HZ incidence in children over a 12-year period in the varicella vaccine era. This study included children aged 0 through 17 years from 2003 through 2014. Using electronic medical records, we identified HZ cases through International Classification of Diseases, Ninth Revision diagnosis code 053. We calculated HZ incidence rates per 100 000 person years of health plan membership for all children and among children who were vaccinated versus unvaccinated. We calculated rates for the 12-year period and examined temporal trends. Among children who were vaccinated, we compared HZ rates by month and year of age at vaccination. The study included 6 372 067 children with ≥1 month of health plan membership. For the 12-year period, the crude HZ incidence rate for all subjects was 74 per 100 000 person years, and the rate among children who were vaccinated was 38 per 100 000 person years, which was 78% lower than that among children who were unvaccinated (170 per 100 000 person years; P < .0001). Overall HZ incidence declined by 72% (P < .0001) from 2003 through 2014. Annual rates in children who were vaccinated were consistently lower than in children who were unvaccinated. With this population-based study, we confirm the decline in pediatric HZ incidence and the significantly lower incidence among children who are vaccinated, reinforcing the benefit of routine varicella vaccination to prevent pediatric HZ.
Authors: Weinmann S; Klein NP; Chun C; et al.
Pediatrics. 2019 07;144(1). Epub 2019-06-10.
Acellular Pertussis Vaccine Effectiveness Over Time
To determine pertussis risk by diphtheria-tetanus-acellular pertussis (DTaP) vaccination status and time since last DTaP dose. Children born at Kaiser Permanente Northern California between 1999 and 2016 were followed from 3 months of age until they tested positive for pertussis; disenrolled from Kaiser Permanente Northern California; received the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed vaccine; turned 11 years of age, or the end of the study period. DTaP vaccination status was categorized on the basis of the number of doses received in relation to the number of doses expected according to the Advisory Committee on Immunization Practice-recommended ages. Among 469 982 children ages 3 months to 11 years, we identified 738 pertussis cases. A total of 99 cases were unvaccinated, 36 were undervaccinated, 515 were fully vaccinated, and 88 were fully vaccinated plus 1 dose. Pertussis risk was 13 times higher among unvaccinated (adjusted hazard ratio [aHR] = 13.53; 95% confidence interval [CI] 10.64-17.21) compared with fully vaccinated children and 1.9 times higher (aHR = 1.86; 95% CI 1.32-2.63) among undervaccinated children. Among vaccinated children ages 19 to <84 months, pertussis risk was 5 times higher (aHR = 5.04; 95% CI 1.84-13.80) ≥3 years vs <1 year after vaccination. Among children ages 84 to 132 months, risk was 2 times higher (aHR = 2.32; 95% CI 0.97-5.59) ≥6 years vs <3 years after vaccination. Undervaccinated and especially unvaccinated children were at greater risk of pertussis. However, most pertussis cases occurred among children age-appropriately vaccinated who were further away from their last DTaP dose, suggesting that suboptimal vaccine effectiveness played a major role in recent pertussis epidemics.
Authors: Zerbo O; Bartlett J; Goddard K; Fireman B; Lewis E; Klein NP
Pediatrics. 2019 07;144(1). Epub 2019-06-10.
Colorectal Cancer Screening in People With and Without HIV in an Integrated Health Care Setting
As people with HIV (PWH) live longer, age-appropriate colorectal cancer (CRC) screening is increasingly important. Limited data exist on CRC screening and outcomes comparing PWH and persons without HIV. Large integrated health care system. This study included PWH and demographically matched persons without HIV who were aged 50-75 years during 2005-2016 and had no previous CRC screening. We evaluated time to first CRC screening (fecal test, sigmoidoscopy, or colonoscopy). We also assessed detection of adenoma and CRC with sigmoidoscopy or colonoscopy by HIV status, accounting for CRC risk factors including sex, age, race/ethnicity, number of outpatient visits, smoking, body mass index, type-2 diabetes, and inflammatory bowel disease. Among PWH, we evaluated whether CD4 count (<200/200-499/≥500 cells/µL) was associated with adenoma and CRC. Among 3177 PWH and 29,219 persons without HIV, PWH were more likely to be screened (85.6% vs. 79.1% within 5 years, P < 0.001). Among those with sigmoidoscopy or colonoscopy, adenoma was detected in 161 (19.6%) PWH and 1498 (22.6%) persons without HIV, and CRC was detected in 4 (0.5%) PWH and 69 (1.0%) persons without HIV. In adjusted analyses, we found no difference in prevalence of either adenoma or CRC by HIV status (adjusted prevalence ratio = 0.97, 95% confidence interval: 0.83 to 1.12). Lower CD4 count did not increase likelihood of adenoma or CRC. Within an integrated health care system with an organized CRC screening program, we found no disparities in CRC screening uptake or outcomes among people with and without HIV, and CD4 count did not influence CRC risk among PWH.
Authors: Lam JO; Hurley LB; Udaltsova N; Alexeeff SE; Klein DB; Corley DA; Silverberg MJ
J Acquir Immune Defic Syndr. 2019 07 01;81(3):284-291.
Estimated Quality of Life and Economic Outcomes Associated With 12 Cervical Cancer Screening Strategies: A Cost-effectiveness Analysis
Many cervical cancer screening strategies are now recommended in the United States, but the benefits, harms, and costs of each option are unclear. To estimate the cost-effectiveness of 12 cervical cancer screening strategies. The cross-sectional portion of this study enrolled a convenience sample of 451 English-speaking or Spanish-speaking women aged 21 to 65 years from September 22, 2014, to June 16, 2016, identified at women’s health clinics in San Francisco. In this group, utilities (preferences) were measured for 23 cervical cancer screening-associated health states and were applied to a decision model of type-specific high-risk human papillomavirus (hrHPV)-induced cervical carcinogenesis. Test accuracy estimates were abstracted from systematic reviews. The evaluated strategies were cytologic testing every 3 years for women aged 21 to 65 years with either repeat cytologic testing in 1 year or immediate hrHPV triage for atypical squamous cells of undetermined significance (ASC-US), cytologic testing every 3 years for women age 21 to 29 years followed by cytologic testing plus hrHPV testing (cotesting), or primary hrHPV testing alone for women aged 30 to 65 years. Screening frequency, abnormal test result management, and the age to switch from cytologic testing to hrHPV testing (25 or 30 years) were varied. Analyses were conducted from both the societal and health care sector perspectives. Utilities for 23 cervical cancer screening-associated health states (cross-sectional study) and quality-adjusted life-years (QALYs) and total costs for each strategy. Utilities were measured in a sociodemographically diverse group of 451 women (mean [SD] age, 38.2 [10.7] years; 258 nonwhite [57.2%]). Cytologic testing every 3 years with repeat cytologic testing for ASC-US yielded the most lifetime QALYs and conferred more QALYs at higher costs ($2166 per QALY) than the lowest-cost strategy (cytologic testing every 3 years with hrHPV triage of ASC-US). All cytologic testing plus hrHPV testing (cotesting) and primary hrHPV testing strategies provided fewer QALYs at higher costs. Adding indirect costs did not change the conclusions. In sensitivity analyses, hrHPV testing every 5 years with genotyping triage beginning at age 30 years was the lowest-cost strategy when hrHPV test sensitivity was markedly higher than cytologic test sensitivity or when hrHPV test cost was equated to the lowest reported cytologic test cost ($14). Cytologic testing every 3 years for women aged 21 to 29 years with either continued cytologic testing every 3 years or switching to a low-cost hrHPV test every 5 years confers a reasonable balance of benefits, harms, and costs. Comparative modeling is needed to confirm the association of these novel utilities with cost-effectiveness.
Authors: Sawaya GF; Sanstead E; Alarid-Escudero F; Smith-McCune K; Gregorich SE; Silverberg MJ; Leyden W; Huchko MJ; Kuppermann M; Kulasingam S
JAMA Intern Med. 2019 07 01;179(7):867-878.
Early outcomes of a high-resolution anoscopy-based anal cancer screening program among people with HIV enrolled in an integrated healthcare system
Few studies have examined outcomes of high-resolution anoscopy (HRA)-based screening for people with HIV infection (PWH), a population at increased risk for anal cancer. Large integrated health care system. Cohort study of 13,552 people with HIV infection, comparing incidences of anal cancer and advanced anal cancer (higher stage, recurrence, death, or surgical salvage) before and after HRA became available (2008). Calendar time was divided as 1998-2007, 2008-2010, and 2011-2012. Rate ratios (RRs) were obtained from Poisson regression models with adjustment for baseline demographic and health variables. Cohort cases during 2008-2012 were included in a nested case-control study, evaluating association of screening with anal cancer (33 cases, 330 controls) and advanced anal cancer (19 cases, 190 controls). Odds ratios (ORs) for receipt of screening were obtained from conditional logistic regression models with adjustment for baseline demographic and health history variables. Compared with 1998-2007 (pre-HRA), 2008-2010 adjusted RRs were 1.32 [95% confidence intervals (CI): 0.77 to 2.27; P = 0.31] for anal cancer and 2.11 (95% CI: 0.99 to 4.48; P = 0.053) for advanced anal cancer; and 2011-2012 adjusted RRs were 0.35 (95% CI: 0.12 to 0.99; P = 0.048) for anal cancer and 0.23 (95% CI: 0.03 to 1.77; P = 0.16) for advanced anal cancer. Individual history of screening did not reach statistical significance for anal cancer (OR 1.7; 0.6-4.6) or advanced anal cancer (OR 0.44; 0.1-3.8). Despite the possible effect of secular trends, we found 2008-2012 incidence trends for anal cancer and advanced anal cancer that seem consistent with expected findings of a beneficial screening program.
Authors: Barnell GM; Merchant M; Lam JO; Silverberg MJ
J Acquir Immune Defic Syndr. 2019 07 01;81(3):292-299.
Short-term outcomes for lung cancer resection surgery in HIV infection
Lung cancer is the leading cause of cancer death in people living with HIV (PWH). Surgical resection is a key component of potentially curative treatment regimens for early-stage lung cancers, but its safety is unclear in the setting of HIV. From a national cohort, we assessed potential differences in the risk of major lung cancer surgery complications by HIV status. We linked clinical and cancer data from the Veterans Aging Cohort Study (VACS) and Veterans Affairs Corporate Data Warehouse to outcomes from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) and identified 8371 patients (137 PWH, 8234 uninfected) who underwent lung cancer surgeries between 2000 and 2016. We compared rates of 15 major short-term surgical complications by HIV status. Use of surgical resection for early-stage lung cancer did not differ by HIV status. Lung cancer surgery postoperative (30-day) mortality was 2.0% for PWH and did not differ by HIV status (P?=?0.9). Pneumonia was the most common complication for both PWH and uninfected veterans, but did not differ significantly in prevalence between groups (11.0% for PWH versus 9.4%; P?=?0.5). The frequency of complications did not differ by HIV status for any complication (all P?>?0.3). There were no significant predictors of postoperative complications for PWH. In a national antiretroviral-era cohort of lung cancer patients undergoing surgical lung resection, short-term outcomes after surgery did not differ significantly by HIV status. Concerns regarding short-term surgical complications should have limited influence on treatment decisions for PWH with lung cancer.
Authors: Sigel KM; Silverberg MJ; Crothers K; et al.
AIDS. 2019 07 01;33(8):1353-1360.
Elimination of Nonmedical Immunization Exemptions in California and School-Entry Vaccine Status
California implemented Senate Bill 277 (SB277) in 2016, becoming the first state in nearly 30 years to eliminate nonmedical exemptions from immunization requirements for schoolchildren. Our objectives were to determine (1) the impacts of SB277 on the percentage of kindergarteners entering school not up-to-date on vaccinations and (2) if geographic patterns of vaccine refusal persisted after the implementation of the new law. At the state level, we analyzed the magnitude and composition of the population of kindergarteners not up-to-date on vaccinations before and after the implementation of SB277. We assessed correlations between previous geographic patterns of nonmedical exemptions and patterns of the remaining entry mechanisms for kindergarteners not up-to-date after the law’s implementation. In the first year after SB277 was implemented, the percentage of kindergartners entering school not up-to-date on vaccinations decreased from 7.15% to 4.42%. The conditional entrance rate fell from 4.43% to 1.91%, accounting for much of this decrease. Other entry mechanisms for students not up-to-date, including medical exemptions and exemptions for independent study or homeschooled students, largely replaced the decrease in the personal belief exemption rate from 2.37% to 0.56%. In the second year, the percentage of kindergartners not up-to-date increased by 0.45%, despite additional reductions in conditional entrants and personal belief exemptions. The correlational analysis revealed that previous geographic patterns of vaccine refusal persisted after the law’s implementation. Although the percentage of incoming kindergarteners up-to-date on vaccinations in California increased after the implementation of SB277, we found evidence for a replacement effect.
Authors: Delamater PL; Pingali SC; Buttenheim AM; Salmon DA; Klein NP; Omer SB
Pediatrics. 2019 06;143(6). Epub 2019-05-21.
Vaccine safety in HIV-infected adults within the Vaccine Safety Datalink Project
We evaluate safety of routine vaccination among adults infected with human immunodeficiency virus (HIV) in five healthcare organizations in the United States. We conducted a retrospective cohort study of HIV-infected adults who received inactivated influenza vaccines, hepatitis B vaccines, pneumococcal vaccines, or tetanus, diphtheria, and acellular pertussis vaccines between 2002 and 2013. We conducted self-controlled case series analysis to estimate the relative risk (RR) for 11 pre-specified adverse events (AEs) requiring medical attention. Among 20,417 HIV-infected adults (90.2% male), a total of 137,674 vaccine doses were administered. Based on ICD-9 codes, we detected an increased risk of cellulitis and infection (RR: 1.18, 95% CI: 1.03-1.35) among all patients, and an increased risk of stroke/cerebrovascular diseases among patients with an HIV viral load >10,000 copies/ml (adjusted RR: 3.94, 95% CI: 1.32-11.72). Further analyses on chart confirmed cases of stroke/cerebrovascular diseases indicated no statistically significant increased risk (adjusted RR: 1.72, 95% CI: 0.41-7.24). There was no evidence of increased risk for other AEs following routine vaccination in HIV-infected adults. Routinely administered vaccines are generally safe for HIV-infected adults.
Authors: Hechter RC; Qian L; Tartof SY; Sy LS; Klein NP; Weintraub E; Mercado C; Naleway A; McLean HQ; Jacobsen SJ
Vaccine. 2019 May 31;37(25):3296-3302. Epub 2019-05-04.
Intra-season Waning of Influenza Vaccine Effectiveness
In the United States, it is recommended that healthcare providers offer influenza vaccination by October, if possible. However, if the vaccine’s effectiveness soon begins to wane, the optimal time for vaccination may be somewhat later. We examined whether the effectiveness of influenza vaccine wanes during the influenza season with increasing time since vaccination. We identified persons who were vaccinated with inactivated influenza vaccine from 1 September 2010 to 31 March 2017 and who were subsequently tested for influenza and respiratory syncytial virus (RSV) by a polymerase chain reaction test. Test-confirmed influenza was the primary outcome and days-since-vaccination was the predictor of interest in conditional logistic regression. Models were adjusted for age and conditioned on calendar day and geographic area. RSV was used as a negative-control outcome. Compared with persons vaccinated 14 to 41 days prior to being tested, persons vaccinated 42 to 69 days prior to being tested had 1.32 (95% confidence interval [CI], 1.11 to 1.55) times the odds of testing positive for any influenza. The odds ratio (OR) increased linearly by approximately 16% for each additional 28 days since vaccination. The OR was 2.06 (95% CI, 1.69 to 2.51) for persons vaccinated 154 or more days prior to being tested. No evidence of waning was found for RSV. Our results suggest that effectiveness of inactivated influenza vaccine wanes during the course of a single season. These results may lead to reconsideration of the optimal timing of seasonal influenza vaccination.
Authors: Ray GT; Lewis N; Klein NP; Daley MF; Wang SV; Kulldorff M; Fireman B
Clin Infect Dis. 2019 05 02;68(10):1623-1630.
Mind the gap: observation windows to define periods of event ascertainment as a quality control method for longitudinal electronic health record data
Use of electronic health records (EHRs) in health research may lead to the false assumption of complete event ascertainment. We estimated “observation windows” (OWs), defined as periods within which the assumption of complete ascertainment of events is more likely to hold, as a quality control approach to reducing the likelihood of this false assumption. We demonstrated the impact of OWs on estimating the rates of type II diabetes mellitus (diabetes) from HIV clinical cohorts. Data contributed by 16 HIV clinical cohorts to the NA-ACCORD were used to identify and evaluate OWs for an operationalized definition of diabetes occurrence as a case study. Procedures included (1) gathering cohort-level data; (2) visualizing and summarizing gaps in observations; (3) systematically establishing start and stop dates during which the assumption of complete ascertainment of diabetes events was reasonable; and (4) visualizing the diabetes OWs relative to the cohort open and close dates to identify immortal person-time. We estimated diabetes occurrence event rates and 95% confidence intervals in the most recent decade that data were available (January 1, 2007, to December 31, 2016). The number of diabetes events decreased by 17% with the use of the diabetes OWs; immortal person-time was removed decreasing total person-years by 23%. Consequently, the diabetes rate increased from 1.23 (95% confidence interval [1.20, 1.25]) per 100 person-years to 1.32 [1.29, 1.35] per 100 person-years with the use of diabetes OWs. As the use of EHR-curated data for event-driven health research continues to expand, OWs have utility as a quality control approach to complete event ascertainment, helping to improve accuracy of estimates by removing immortal person-time when ascertainment is incomplete.
Authors: Althoff KN; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design; et al.
Ann Epidemiol. 2019 05;33:54-63. Epub 2019-03-04.
Barriers to preexposure prophylaxis use among individuals with recently acquired HIV infection in Northern California
Barriers to HIV preexposure prophylaxis (PrEP) use have not been well-characterized in people who became HIV-infected, all of whom could have benefited from PrEP. We invited Kaiser Permanente Northern California members diagnosed with HIV during 2014-2016, following a negative HIV test in the prior year, to complete a survey assessing barriers to PrEP use before HIV diagnosis. Of 268 patients surveyed, 122 (46%) responded. Median age was 36, most (84%) were men who have sex with men, and 64% were of minority racial/ethnic background. Thirty-six (30%) had discussed PrEP with a provider, of whom 10 were diagnosed with HIV at PrEP intake. Overall, only 5 (4.1%) had used PrEP, and all 5 discontinued before diagnosis. Among all respondents, the most common barrier to PrEP use was lack of PrEP awareness (51%). Among those aware of PrEP, the most common barriers were cost/insurance concerns (36%) and perceived low risk for HIV (24%). Lack of PrEP awareness ranged from 39% among those aged 25-34 to 88% among those aged <25 (P?=?0.011), and from 33% among Hispanics to 69% among Blacks (P?=?0.055). Increasing awareness and affordability of PrEP, and facilitating accurate assessment of HIV risk, are critical to reducing missed opportunities for PrEP.
Authors: Marcus JL; Hurley LB; Dentoni-Lasofsky D; Ellis CG; Silverberg MJ; Slome S; Snowden JM; Volk JE
AIDS Care. 2019 05;31(5):536-544. Epub 2018-10-10.
Influenza Vaccine Effectiveness in Preventing Influenza-associated Hospitalizations During Pregnancy: A Multi-country Retrospective Test Negative Design Study, 2010-2016
To date, no study has examined influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalizations during pregnancy. The Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) consisted of public health or healthcare systems with integrated laboratory, medical, and vaccination records in Australia, Canada (Alberta and Ontario), Israel, and the United States (California, Oregon, and Washington). Sites identified pregnant women aged 18 through 50 years whose pregnancies overlapped with local influenza seasons from 2010 through 2016. Administrative data were used to identify hospitalizations with acute respiratory or febrile illness (ARFI) and clinician-ordered real-time reverse transcription polymerase chain reaction (rRT-PCR) testing for influenza viruses. Overall IVE was estimated using the test-negative design and adjusting for site, season, season timing, and high-risk medical conditions. Among 19450 hospitalizations with an ARFI discharge diagnosis (across 25 site-specific study seasons), only 1030 (6%) of the pregnant women were tested for influenza viruses by rRT-PCR. Approximately half of these women had pneumonia or influenza discharge diagnoses (54%). Influenza A or B virus infections were detected in 598/1030 (58%) of the ARFI hospitalizations with influenza testing. Across sites and seasons, 13% of rRT-PCR-confirmed influenza-positive pregnant women were vaccinated compared with 22% of influenza-negative pregnant women; the adjusted overall IVE was 40% (95% confidence interval = 12%-59%) against influenza-associated hospitalization during pregnancy. Between 2010 and 2016, influenza vaccines offered moderate protection against laboratory-confirmed influenza-associated hospitalizations during pregnancy, which may further inform the benefits of maternal influenza vaccination programs.
Authors: Thompson MG; Klein NP; PREVENT Workgroup; et al.
Clin Infect Dis. 2019 04 24;68(9):1444-1453.
National and International Dimensions of Human Immunodeficiency Virus-1 Sequence Clusters in a Northern California Clinical Cohort
Recent advances in high-throughput molecular epidemiology are transforming the analysis of viral infections. Human immunodeficiency virus (HIV)-1 pol sequences from a Northern Californian cohort (NCC) of 4553 antiretroviral-naive individuals sampled between 1998 and 2016 were analyzed together with 140 000 previously published global pol sequences. The HIV-TRAnsmission Cluster Engine (HIV-TRACE) was used to infer a transmission network comprising links between NCC and previously published sequences having a genetic distance ≤1.5%. Twenty-five percent of NCC sequences were included in 264 clusters linked to a published sequence, and approximately one third of these (8.0% of the total) were linked to 1 or more non-US sequences. The largest cluster, containing 512 NCC sequences (11.2% of the total), comprised the subtype B lineage that traced its origin to the earliest North American sequences. Approximately 5 percent of NCC sequences belonged to a non-B subtype, and these were more likely to cluster with a non-US sequence. Twenty-two NCC sequences belonged to 1 of 4 large clusters containing sequences from rapidly growing regional epidemics: CRF07_BC (East Asia), subtype A6 (former Soviet Union), a Japanese subtype B lineage, and an East/Southeast Asian CRF01_AE lineage. Bayesian phylogenetics suggested that most non-B sequences resulted from separate introductions but that local spread within the largest CRF01_AE cluster occurred twice. The NCC contains national and international links to previously published sequences including many to the subtype B strain that originated in North America and several to rapidly growing Asian epidemics. Despite their rapid regional growth, the Asian epidemic strains demonstrated limited NCC spread.
Authors: Rhee SY; Magalis BR; Hurley L; Silverberg MJ; Marcus JL; Slome S; Kosakovsky Pond SL; Shafer RW
Open Forum Infect Dis. 2019 Apr;6(4):ofz135. Epub 2019-03-14.
Association of immunosuppression and HIV viraemia with non-Hodgkin lymphoma risk overall and by subtype in people living with HIV in Canada and the USA: a multicentre cohort study
Research is needed to better understand relations between immunosuppression and HIV viraemia and risk for non-Hodgkin lymphoma, a common cancer in people living with HIV. We aimed to identify key CD4 count and HIV RNA (viral load) predictors of risk for non-Hodgkin lymphoma, overall and by subtype. We studied people living with HIV during 1996-2014 from 21 Canadian and US cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. To determine key independent predictors of risk for non-Hodgkin lymphoma, we assessed associations with time-updated recent, past, cumulative, and nadir or peak measures of CD4 count and viral load, using demographics-adjusted, cohort-stratified Cox models, and we compared models using Akaike’s information criterion. Of 102 131 people living with HIV during the study period, 712 people developed non-Hodgkin lymphoma. The key independent predictors of risk for overall non-Hodgkin lymphoma were recent CD4 count (ie, lagged by 6 months; <50 cells per μL vs ≥500 cells per μL, hazard ratio [HR] 3·2, 95% CI 2·2-4·7) and average viral load during a 3-year window lagged by 6 months (a cumulative measure; ≥100 000 copies per mL vs ≤500 copies per mL, HR 9·6, 95% CI 6·5-14·0). These measures were also the key predictors of risk for diffuse large B-cell lymphoma (recent CD4 count <50 cells per μL vs ≥500 cells per μL, HR 2·4, 95% CI 1·4-4·2; average viral load ≥100 000 copies per mL vs ≤500 copies per mL, HR 7·5, 95% CI 4·5-12·7). However, recent CD4 count was the sole key predictor of risk for CNS non-Hodgkin lymphoma (<50 cells per μL vs ≥500 cells per μL, HR 426·3, 95% CI 58·1-3126·4), and proportion of time viral load was greater than 500 copies per mL during the 3-year window (a cumulative measure) was the sole key predictor for Burkitt lymphoma (100% vs 0%, HR 41·1, 95% CI 9·1-186·6). Both recent immunosuppression and prolonged HIV viraemia have important independent roles in the development of non-Hodgkin lymphoma, with likely subtype heterogeneity. Early and sustained antiretroviral therapy to decrease HIV replication, dampen B-cell activation, and restore overall immune function is crucial for preventing non-Hodgkin lymphoma. National Institutes of Health, Centers for Disease Control and Prevention, US Agency for Healthcare Research and Quality, US Health Resources and Services Administration, Canadian Institutes of Health Research, Ontario Ministry of Health and Long Term Care, and the Government of Alberta.
Authors: Hernández-Ramírez RU; Neugebauer RS; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; et al.
Lancet HIV. 2019 04;6(4):e240-e249. Epub 2019-02-27.
Long term risk of developing type 1 diabetes after HPV vaccination in males and females
Despite minimal evidence, public concerns that the human papillomavirus (HPV) vaccine can cause autoimmune diseases (AD) persist. We evaluated whether HPV vaccine is associated with a long-term increased risk of diabetes mellitus type 1 (DM1). This was a retrospective cohort study in which we identified all potential DM1 cases from Kaiser Permanente Northern California (KPNC) members who were between 11 and 26 years old any time after June 2006 through December 2015. We chart reviewed a random sample of 100 DM1 cases to confirm diagnosis and to develop a computer algorithm that reliably determined symptom onset date. Our DM1 Analysis Population comprised all individuals who met membership criteria and who were age and sex eligible to have received HPV vaccine. We adjusted for age, sex, race, Medicaid, and years of prior KPNC membership by stratification using a Cox multiplicative hazards model with a calendar timeline. Our DM1 analysis included 911,648 individuals. Of 2613 DM1 cases identified, 338 remained in the analysis after applying our algorithm, HPV vaccine eligibility and membership criteria. Over the 10 years of the study period, comparing vaccinated with unvaccinated persons, we did not find an increased risk of DM1 associated with HPV vaccine receipt (hazard ratio 1.21, 95% Confidence Interval 0.94, 1.57). We found no increased risk for development of DM1 following HPV vaccination. Our study provides reassurance that during the 10-year time period after HPV vaccine was introduced, there was no substantial increased risk for DM1 following HPV vaccination.
Authors: Klein NP; Goddard K; Lewis E; Ross P; Gee J; DeStefano F; Baxter R
Vaccine. 2019 03 28;37(14):1938-1944. Epub 2019-03-01.
Adverse childhood experiences, mental health, substance use, and HIV-related outcomes among persons with HIV
While persons with HIV (PWH) have benefited from significant advances in treatment and resulting longevity, mental health problems remain elevated in this population. Adverse childhood experiences (ACEs) are common among PWH and may negatively affect mental health and HIV-related outcomes. We examined the association between ACEs, depression and anxiety symptoms, substance use, antiretroviral therapy (ART) adherence, and HIV-clinical indicators in a sample of 584 PWH at risk for unhealthy alcohol use enrolled in a primary care-based alcohol intervention study. The sample was 96.9% male, 63.0% non-Hispanic white, with an average age of 49.0 years. ACEs were highly prevalent: 82.5% reported ≥1 ACE, including 34.2% reporting 1-2 ACEs, 25.0% reporting 3-4 ACEs, and 23.3% reporting ≥5 ACEs. Adjusting for demographics, having 1-2, 3-4 or ≥5 ACEs was significantly associated with anxiety (ORs (95%CI): 3.41 (1.13-10.33), 4.36 (1.42-3.36), and 3.96 (1.28-12.19), respectively) and poorer mental health quality of life (Betas (SE): -3.21 (1.40), -6.23 (1.51), and -7.09 (1.54), respectively), but not with other outcomes. Trauma-informed interventions to reduce anxiety and improve mental health quality of life in PWH may reduce the negative health sequelae of ACEs.
Authors: Young-Wolff KC; Sarovar V; Sterling SA; Leibowitz A; McCaw B; Hare CB; Silverberg MJ; Satre DD
AIDS Care. 2019 Mar 19:1-9.
Comparison of msp genotyping and a 24 SNP molecular assay for differentiating Plasmodium falciparum recrudescence from reinfection
Current World Health Organization guidelines for conducting anti-malarial drug efficacy clinical trials recommend genotyping Plasmodium falciparum genes msp1 and msp2 to distinguish recrudescence from reinfection. A more recently developed potential alternative to this method is a molecular genotyping assay based on a panel of 24 single nucleotide polymorphism (SNP) markers. Performance parameters of these two genotyping methods were compared using data from two recently completed drug efficacy trials. Blood samples from two anti-malarial therapeutic trials were analysed by both msp genotyping and the 24 SNP assay. Additionally, to conserve time and resources, the statistical program R was used to select the most informative SNPs for a set of unrelated Malawian samples to develop a truncated SNP-based assay for the region surrounding Blantyre, Malawi. The ability of this truncated assay to distinguish reinfection from recrudescence when compared to the full 24 SNP assay was then analysed using data from the therapeutic trials. A total of 360 samples were analysed; 66 for concordance of msp and SNP barcoding methodologies, and 294 for assessing the most informative of the 24 SNP markers. SNP genotyping performed comparably to msp genotyping, with only one case of disagreement among the 50 interpretable results, where the SNP assay identified the sample as reinfection and the msp typing as recrudescence. Furthermore, SNP typing was more robust; only 6% of samples were uninterpretable by SNP typing, compared to 19.7% when msp genotyping was used. For discriminating reinfection from recrudescence, a truncated 6 SNP assay was found to perform at 95.1% the accuracy of the full 24 SNP bar code. The use of SNP analysis has similar sensitivity to the standard msp genotyping in determining recrudescence from reinfection. Although more expensive, SNP typing is faster and less work intensive. Limiting the assay to those SNPs most informative in the geographical region of interest may further decrease the workload and the cost, making this technique a feasible and affordable alternative in drug efficacy trials.
Authors: Fulakeza J; McNitt S; Vareta J; Saidi A; Mvula G; Taylor T; Mathanga DP; Small DS; Skarbinski J; Gutman JR; Seydel K
Malar J. 2019 Mar 18;18(1):84. Epub 2019-03-18.
Cervical Cancer Screening Research in the PROSPR I Consortium: Rationale, Methods, and Baseline Findings from a U.S. Cohort
Little is known about the effect of evolving risk-based cervical cancer screening and management guidelines on United States (US) clinical practice and patient outcomes. We describe the National Cancer Institute’s Population-based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium, methods and baseline findings from its cervical sites: Kaiser Permanente Washington, Kaiser Permanente Northern California, Kaiser Permanente Southern California, Parkland Health & Hospital System/University of Texas Southwestern (Parkland-UTSW) and New Mexico HPV Pap Registry housed by University of New Mexico (UNM-NMHPVPR). Across these diverse healthcare settings, we collected data on human papillomavirus (HPV) vaccinations, screening tests/results, diagnostic and treatment procedures/results and cancer diagnoses on nearly 4.7 million women aged 18-89 years from 2010 to 2014. We calculated baseline (2012 for UNM-NMHPVPR; 2010 for other sites) frequencies for sociodemographics, cervical cancer risk factors and key screening process measures for each site’s cohort. Healthcare delivery settings, cervical cancer screening strategy, race/ethnicity and insurance status varied among sites. The proportion of women receiving a Pap test during the baseline year was similar across sites (26.1-36.1%). Most high-risk HPV tests were performed either reflexively or as cotests, and utilization pattern varied by site. Prevalence of colposcopy or biopsy was higher at Parkland-UTSW (3.6%) than other sites (1.3-1.4%). Incident cervical cancer was rare. HPV vaccination among age-eligible women not already immunized was modest across sites (0.1-7.2%). Cervical PROSPR I makes available high-quality, multilevel, longitudinal screening process data from a large and diverse cohort of women to evaluate and improve the effectiveness of US cervical cancer screening delivery.
Authors: Kamineni A; Silverberg MJ; Corley DA; PROSPR consortium; et al.
Int J Cancer. 2019 03 15;144(6):1460-1473. Epub 2018-12-20.
Health Care Service Utilization and Cost Among Adults with Autism Spectrum Disorders in a U.S. Integrated Health Care System
To compare health care utilization patterns and cost among insured adults with autism spectrum disorder (ASD), adults with attention-deficit and hyperactivity disorder (ADHD), and adults with neither condition (general population [GP] controls). We conducted a case-control study among adults (≥18 years) who were members of Kaiser Permanente Northern California (KPNC) for at least 9 months each year from 2008 to 2012. Cases (N = 1507) were adults with an ASD diagnosis (ICD-9-CM 299.0-299.8) recorded in the electronic medical record on at least two separate occasions by December 31, 2012. Two control groups, adults with ADHD (N = 9042) defined by ICD-9-CM code 314 and GP (N = 15,070), were randomly selected and frequency matched to cases on gender and age. Health care utilization and cost data were obtained from KPNC databases for the year 2012. Compared with adults with ADHD, adults with ASD had significantly higher utilization of outpatient visits for primary care (74.2% vs. 66.6%), mental health (43.3% vs. 33.2%), and laboratory services (60.9% vs. 54.4%). Hospitalizations for ambulatory care sensitive diagnoses (5.4% vs. 2.3%) were less frequent overall but more common among adults with ASD than with ADHD. Group differences were larger comparing adults with ASD with GP controls. Gynecology visits and screening for cervical cancer were significantly less common among women with ASD than among women with ADHD (35% vs. 50%) or GP (35% vs. 49%). Total annual mean healthcare costs for adults with ASD were 20% higher than costs for adults with ADHD and double costs for GP. Adults with ASD had significantly higher rates of utilization across most health care service areas compared with adults with ADHD or GP; however, women with ASD were significantly less likely to have gynecology visits and have screening for cervical cancer. We conducted a study among adults (≥18 years) who were members of Kaiser Permanente Northern California (KPNC) from 2008 to 2012. We compared how often people attended different types of health care and costs of health care among adults with autism spectrum disorder (ASD), adults with attention-deficit and hyperactivity disorder (ADHD), and adults with neither condition (general population [GP] controls). The study included 1507 adults with ASD, 9042 with ADHD but not ASD, and 15,070 GP controls with no ASD or ADHD. Health care and cost data were obtained from KPNC databases for the year 2012. The study found that adults with ASD used more outpatient visits for primary care, mental health, and laboratory services than adults with ADHD. Gynecology visits and screening for cervical cancer were less common among women with ASD than among women with ADHD or GP. Health care costs for adults with ASD were higher than costs for adults with ADHD and costs for GP. In conclusion, adults with ASD had higher rates of use of most health care service areas than adults with ADHD or GP; however, women with ASD were less likely to have gynecology visits and have screening for cervical cancer.
Authors: Zerbo, Ousseny; Qian, Yinge; Ray, Thomas; Sidney, Steve; Rich, Steve; Massolo, Maria; Croen, Lisa A
Autism Adulthood. 2019 Mar 01;1(1):27-36. Epub 2019-03-11.
Viral suppression among persons in HIV care in the United States during 2009-2013: sampling bias in Medical Monitoring Project surveillance estimates
To assess sampling bias in national viral suppression (VS) estimates derived from the Medical Monitoring Project (MMP) resulting from use of an abbreviated (four-month) annual sampling period. We aimed to improve VS estimates using cohort data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and a novel cohort-adjustment method. Using full calendar years of NA-ACCORD data, we assessed timing of HIV care attendance (inside vs. exclusively outside MMP’s four-month sampling period), VS status at last test (<200 vs. ?200 copies/mL), and associated demographics. These external estimates were used to standardize MMP to NA-ACCORD data with multivariable regression models of care attendance and VS, yielding adjusted 2009-2013 VS estimates with 95% confidence intervals. Weighted percentages of VS among persons in HIV care were 67% in 2009 and 77% in 2013. These estimates are slightly lower than previously published MMP estimates (72% and 80% in 2009 and 2013, respectively). The number of persons receiving HIV care was previously underestimated by 20%, because patients receiving care exclusively outside the MMP sampling period did not contribute toward the weighted population estimate. Careful examination of national surveillance estimates using data triangulation and novel methodologies can improve the robustness of VS estimates.
Authors: Bradley H; Silverberg MJ; Rosenberg ES; et al.
Ann Epidemiol. 2019 03;31:3-7. Epub 2018-11-22.
Safety and Immunogenicity of a Full-Dose Split-Virion Inactivated Quadrivalent Influenza Vaccine in Healthy Children 6 to 35 Months of Age: A Randomized Controlled Clinical Trial
For children <3 years of age, a half dose of inactivated influenza vaccine (7.5 μg hemagglutinin per strain) has been used for more than 30 years, but several studies indicate that a full dose (15 μg hemagglutinin per strain) can be used in this population without increasing the rate of fever or other reactions. Here, we compare the safety and immunogenicity of full and half doses of quadrivalent, split-virion, inactivated influenza vaccine (IIV4) in children 6-35 months of age. In this phase IV, randomized, observer-blinded, multi-center study, healthy children 6-35 months of age were randomized 1:1 to be vaccinated with a half or full dose of IIV4 (NCT02915302). The primary objective was to demonstrate that the rate of any fever (≥38.0°C) up to 7 days after a full dose of IIV4 was noninferior to the rate of fever after a half dose. The study included 1950 children. Noninferiority in the rate of fever was demonstrated for the full dose versus the half dose of IIV4 (difference in rate = 0.84%; 95% confidence interval, -2.13% to 3.80%). Solicited reactions and unsolicited adverse events were similar between the dose groups. No vaccine-related serious adverse events were reported. Noninferiority of both hemagglutination inhibition geometric mean titers and seroconversion rates was demonstrated for all 4 vaccine strains for the full dose versus the half dose. In children 6-35 months of age, a full dose of IIV4 was immunogenic and had a safety profile comparable to that of a half dose, with no new safety concerns observed.
Authors: Robertson CA; Mercer M; Selmani A; Klein NP; Jeanfreau R; Greenberg DP
Pediatr Infect Dis J. 2019 03;38(3):323-328.
One Size Fits (n)One: The Influence of Sex, Age, and Sexual Human Immunodeficiency Virus (HIV) Acquisition Risk on Racial/Ethnic Disparities in the HIV Care Continuum in the United States
The United States National HIV/AIDS Strategy established goals to reduce disparities in retention in human immunodeficiency virus (HIV) care, antiretroviral therapy (ART) use, and viral suppression. The impact of sex, age, and sexual HIV acquisition risk (ie, heterosexual vs same-sex contact) on the magnitude of HIV-related racial/ethnic disparities is not well understood. We estimated age-stratified racial/ethnic differences in the 5-year restricted mean percentage of person-time spent in care, on ART, and virally suppressed among 19 521 women (21.4%), men who have sex with men (MSM; 59.0%), and men who have sex with women (MSW; 19.6%) entering HIV care in the North American AIDS Cohort Collaboration on Research and Design between 2004 and 2014. Among women aged 18-29 years, whites spent 12.0% (95% confidence interval [CI], 1.1%-20.2%), 9.2% (95% CI, .4%-20.4%), and 13.5% (95% CI, 2.7%-22.5%) less person-time in care, on ART, and virally suppressed, respectively, than Hispanics. Black MSM aged ≥50 years spent 6.3% (95% CI, 1.3%-11.7%), 11.0% (95% CI, 4.6%-18.1%), and 9.7% (95% CI, 3.6%-16.8%) less person-time in these stages, respectively, than white MSM ≥50 years of age. Among MSM aged 40-49 years, blacks spent 9.8% (95% CI, 2.4%-16.5%) and 11.9% (95% CI, 3.8%-19.3%) less person-time on ART and virally suppressed, respectively, than whites. Racial/ethnic differences in HIV care persist in specific populations defined by sex, age, and sexual HIV acquisition risk. Clinical and public health interventions that jointly target these demographic factors are needed.
Authors: Desir FA; Silverberg M; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) Region of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortium; et al.
Clin Infect Dis. 2019 02 15;68(5):795-802.
Contributions of traditional and HIV-related risk factors on non-AIDS-defining cancer, myocardial infarction, and end-stage liver and renal diseases in adults with HIV in the USA and Canada: a collaboration of cohort studies
Adults with HIV have an increased burden of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease. The objective of this study was to estimate the population attributable fractions (PAFs) of preventable or modifiable HIV-related and traditional risk factors for non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes. We included participants receiving care in academic and community-based outpatient HIV clinical cohorts in the USA and Canada from Jan 1, 2000, to Dec 31, 2014, who contributed to the North American AIDS Cohort Collaboration on Research and Design and who had validated non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, or end-stage renal disease outcomes. Traditional risk factors were tobacco smoking, hypertension, elevated total cholesterol, type 2 diabetes, renal impairment (stage 4 chronic kidney disease), and hepatitis C virus and hepatitis B virus infections. HIV-related risk factors were low CD4 count (<200 cells per μL), detectable plasma HIV RNA (>400 copies per mL), and history of a clinical AIDS diagnosis. PAFs and 95% CIs were estimated to quantify the proportion of outcomes that could be avoided if the risk factor was prevented. In each of the study populations for the four outcomes (1405 of 61 500 had non-AIDS-defining cancer, 347 of 29 515 had myocardial infarctions, 387 of 35 044 had end-stage liver disease events, and 255 of 35 620 had end-stage renal disease events), about 17% were older than 50 years at study entry, about 50% were non-white, and about 80% were men. Preventing smoking would avoid 24% (95% CI 13-35) of these cancers and 37% (7-66) of the myocardial infarctions. Preventing elevated total cholesterol and hypertension would avoid the greatest proportion of myocardial infarctions: 44% (30-58) for cholesterol and 42% (28-56) for hypertension. For liver disease, the PAF was greatest for hepatitis C infection (33%; 95% CI 17-48). For renal disease, the PAF was greatest for hypertension (39%; 26-51) followed by elevated total cholesterol (22%; 13-31), detectable HIV RNA (19; 9-31), and low CD4 cell count (13%; 4-21). The substantial proportion of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes that could be prevented with interventions on traditional risk factors elevates the importance of screening for these risk factors, improving the effectiveness of prevention (or modification) of these risk factors, and creating sustainable care models to implement such interventions during the decades of life of adults living with HIV who are receiving care. National Institutes of Health, US Centers for Disease Control and Prevention, the US Agency for Healthcare Research and Quality, the US Health Resources and Services Administration, the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long Term Care, and the Government of Alberta.
Authors: Althoff KN; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design; et al.
Lancet HIV. 2019 02;6(2):e93-e104. Epub 2019-01-22.
Exploring California’s new law eliminating personal belief exemptions to childhood vaccines and vaccine decision-making among homeschooling mothers in California
California’s Senate Bill 277 (SB-277) law eliminated the personal belief exemption to school immunization requirements. A potential consequence may be that parents choose homeschooling to avoid immunization. Vaccine attitudes and behaviors have not been well studied among the home-schooling population. This study explored the effect of SB-277 and vaccine decision-making among California home schoolers. Purposive and snowball sampling were used recruit home-schooling parents through home-schooling Facebook groups based on home school type in high-exemption regions in California for in-depth interviews. Participants had to have a child in a legalized form of homeschooling in California in grades kindergarten-twelfth grade. Twenty-four mothers were interviewed. Participants were categorized based on self-reported vaccine attitudes and behavior into three groups: Confident and Accepting, Hesitant and Accepting, and Skeptical and Refusing. All reported the belief that SB-277 is an infringement on parental rights but was not currently impacting them. Confident and Accepting mothers (n?=?10) generally believed vaccinations were safe, effective, and posed a lower risk than vaccine preventable disease (VPD). Hesitant and Accepting mothers (n?=?5) expressed varying confidence levels in the belief that vaccinations were safe and effective, were not confident in the belief that vaccination posed lower risks than VPD risk, and risk perception affected vaccine decision-making. Skeptical and Refusing mothers (n?=?9) generally believed that vaccinations were unsafe and ineffective, refused select vaccines, believed that vaccination posed a more serious risk than VPD risks, and belief of vaccine harm was a salient factor in vaccine decision-making. Home-schooling mothers were concerned about SB-277 but did not report that it was directly impacting their children, their vaccine decisions, or reason to home school. Vaccine attitudes and beliefs among homeschooling mothers broadly fell into categories similar to parents of non-home-schooled children. Future quantitative studies should measure vaccine hesitancy and refusal prevalence and potential confounders.
Authors: McDonald P; Limaye RJ; Omer SB; Buttenheim AM; Mohanty S; Klein NP; Salmon DA
Value Health. 2019 06;22(6):648-655. Epub 2019-05-17.
Estimating Vaccine Effectiveness Against Hospitalized Influenza During Pregnancy: Multicountry Protocol for a Retrospective Cohort Study
Although pregnant women are believed to have elevated risks of severe influenza infection and are targeted for influenza vaccination, no study to date has examined influenza vaccine effectiveness (IVE) against laboratory-confirmed influenza-associated hospitalizations during pregnancy, primarily because this outcome poses many methodological challenges. The Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) was formed in 2016 as an international collaboration with the Centers for Disease Control and Prevention; Abt Associates; and study sites in Australia, Canada, Israel, and the United States. The primary goal of this collaboration is to estimate IVE in preventing acute respiratory or febrile illness (ARFI) hospitalizations associated with laboratory-confirmed influenza virus infection during pregnancy. Secondary aims include (1) describing the incidence, clinical course, and severity of influenza-associated ARFI hospitalization during pregnancy; (2) comparing the characteristics of ARFI-hospitalized pregnant women who were tested for influenza with those who were not tested; (3) describing influenza vaccination coverage in pregnant women; and (4) comparing birth outcomes among women with laboratory-confirmed influenza-associated hospitalization versus other noninfluenza ARFI hospitalizations. For an initial assessment of IVE, sites identified a retrospective cohort of pregnant women aged from 18 to 50 years whose pregnancies overlapped with local influenza seasons from 2010 to 2016. Pregnancies were defined as those that ended in a live birth or stillbirth of at least 20 weeks gestation. The analytic sample for the primary IVE analysis was restricted to pregnant women who were hospitalized for ARFI during site-specific influenza seasons and clinically tested for influenza virus infection using real-time reverse transcription polymerase chain reaction. We identified approximately 2 million women whose pregnancies overlapped with influenza seasons; 550,344 had at least one hospitalization during this time. After restricting to women who were hospitalized for ARFI and tested for influenza, the IVE analytic sample included 1005 women. In addition to addressing the primary question about the effectiveness of influenza vaccination, PREVENT data will address other important knowledge gaps including understanding the incidence, clinical course, and severity of influenza-related hospitalizations during pregnancy. The data infrastructure and international partnerships created for these analyses may be useful and informative for future influenza studies. DERR1-10.2196/11333.
Authors: Naleway AL; Klein NP; Thompson MG; et al.
JMIR Res Protoc. 2019 Jan 21;8(1):e11333. Epub 2019-01-21.
Similar relative risks of seizures following measles containing vaccination in children born preterm compared to full-term without previous seizures or seizure-related disorders
Febrile seizures are associated with the first dose of measles-containing vaccines and the risk increases with chronologic age during the second year of life. We used the Vaccine Safety Datalink (VSD) to determine if the relative increase in risk of seizures following receipt of measles-containing vaccine differs by gestational age at birth. Children were eligible if they received their first dose of measles-containing vaccine at age 12 through 23?months from January 2003 through September 2015. Children were excluded if they had a history of seizure or conditions strongly related to seizure prior to 12?months of age. Seizures were identified by diagnostic codes in the inpatient or emergency department settings. Using risk-interval analysis, we estimated the incidence rate ratio (IRR) for seizures in the 7 through 10?days (risk period) vs 15 through 42?days (control period) following receipt of measles-containing vaccines in children born preterm (<37?weeks gestation age) and those born full-term (?37?weeks). There were 532,375 children (45,343 preterm and 487,032 full-term) who received their first dose of measles-containing vaccine at age 12 through 23?months. The IRRs of febrile seizures 7 through 10?days compared with 15 through 42?days after receipt of measles-containing vaccine were 3.9 (95% CI: 2.5-6.0) in preterm children and 3.2 (2.7-3.7) in full-term children; the ratio of IRRs: was 1.2 (0.76-1.9), p?=?0.41. IRRs were also similar across gestational age groups, by vaccine type received (measles-mumps-rubella [MMR] or measles-mumps-rubella-varicella [MMRV]) and age at vaccination (12-15 or 16-23?months). Vaccination with a measles-containing vaccine in the second year of life is associated with a similar relative risk of a first seizure in children born preterm as in those who were born full-term.
Authors: McClure DL; Jacobsen SJ; Klein NP; Naleway AL; Kharbanda EO; Glanz JM; Jackson LA; Weintraub ES; McLean HQ
Vaccine. 2019 01 03;37(1):76-79. Epub 2018-11-23.
Impact of an electronic medical record reminder on hepatitis B vaccine initiation and completion rates among insured adults with diabetes mellitus
The Advisory Committee on Immunization Practices recommends Hepatitis B (HepB) vaccine for previously unvaccinated adults <60 years with diabetes mellitus. This observational retrospective cohort study assessed the impact of implementing electronic provider reminders on HepB vaccine initiation and 3-dose series completion rates among insured adults with diabetes aged 19-59 years old. Difference-in-difference (DID) analyses compared changes in vaccine initiation and completion rates (ratio of the rate ratio [RRR] and 95% confidence interval [CI]) during 12 months pre- and post-implementation between intervention and control sites. We examined trends in vaccine initiation and completion rates by plotting monthly rates during the study period. We also calculated the overall HepB vaccine coverage rates with 95% CI among all adults with diabetes aged 19-59 years old at the start and end date of the study period. Baseline HepB vaccine initiation and completion rates were similar at both the intervention and control sites. Gender, age, and race/ethnicity distributions within both sites were similar during the 12 months pre- and post-implementation. DID analyses demonstrated statistically significant differences in the changes of the annual vaccine initiation rates (RRR: 70.7, 95% CI: 62.8-79.6) and the third dose completion rates (RRR = 18.7, 95% CI: 14.2-24.8) between the two sites. The coverage increased significantly at the intervention site while it remained low at the control site. Use of provider reminders is highly effective in increasing both HepB vaccine initiation and series completion rates among adults with diabetes.
Authors: Hechter RC; Klein NP; Tseng HF; et al.
Vaccine. 2019 01 03;37(1):195-201. Epub 2018-06-27.
Evaluation of two frailty indices, with practical application in a vaccine clinical trial
Frail older adults are at increased risk of poor clinical outcomes. Frailty assessment is therefore important in clinical trials to understand the benefits and harms of interventions. However, consensus is lacking on how frailty should be assessed.We developed a prospectively specified index using a battery of formal tests and instruments and a retrospectively generated index using medical comorbidities and patient reported outcomes (PROs) within an adjuvanted recombinant zoster vaccine (RZV) trial (NCT02979639). For both frailty indices (FIs), a total deficit score was calculated as the accumulation of deficits and participants were categorized as non-frail, pre-frail and frail. We assessed (1) the feasibility and validity of both FIs; (2) the impact of RZV vaccine reactogenicity by frailty status on Short Form-36 [SF-36] physical functioning (PF) scores.Of 401 participants, aged ≥50 years, 236 (58.9%) were categorized non-frail, 143 (35.7%), pre-frail, and 22 (5.5%) frail using the prospective FI. Corresponding numbers for the retrospective FI were 192 (47.9%), 169 (42.1%) and 40 (10.0%), respectively. Strong concordance was observed between the frailty status assessments (P < .001). The proportion defined as frail increased from 1.5%, to 10.4% in participants aged 50-59, and ≥70 years, respectively, for the prospective FI. Corresponding numbers for the retrospective FI were 3.7%, and 17.2%, respectively. RZV vaccination was associated with a transient, non-clinically meaningful, decrease on the SF-36 PF score in frail participants.Both frailty indices provided similar results. The retrospectively generated FI offers the advantage of being easier to incorporate into vaccine clinical trials of older adults.
Authors: Curran D; Andrew MK; Levin MJ; Turriani E; Matthews S; Fogarty C; Klein NP; Grupping K; Oostvogels L; Schmader KE
Hum Vaccin Immunother. 2019;15(12):2960-2968. Epub 2019-06-21.
Healthcare Effectiveness Data and Information Set (HEDIS) measures of alcohol and drug treatment initiation and engagement among people living with the human immunodeficiency virus (HIV) and patients without an HIV diagnosis
Background: Problematic use of alcohol and other drugs (AOD) is highly prevalent among people living with the human immunodeficiency virus (PLWH), and untreated AOD use disorders have particularly detrimental effects on human immunodeficiency virus (HIV) outcomes. The Healthcare Effectiveness Data and Information Set (HEDIS) measures of treatment initiation and engagement are important benchmarks for access to AOD use disorder treatment. To inform improved patient care, we compared HEDIS measures of AOD use disorder treatment initiation and engagement and health care utilization among PLWH and patients without an HIV diagnosis. Methods: Patients with a new AOD use disorder diagnosis documented between October 1, 2014, and August 15, 2015, were identified using electronic health records (EHR) and insurance claims data from 7 health care systems in the United States. Demographic characteristics, clinical diagnoses, and health care utilization data were also obtained. AOD use disorder treatment initiation and engagement rates were calculated using HEDIS measure criteria. Factors associated with treatment initiation and engagement were examined using multivariable logistic regression models. Results: There were 469 PLWH (93% male) and 86,096 patients without an HIV diagnosis (60% male) in the study cohort. AOD use disorder treatment initiation was similar in PLWH and patients without an HIV diagnosis (10% vs. 11%, respectively). Among those who initiated treatment, few engaged in treatment in both groups (9% PLWH vs. 12% patients without an HIV diagnosis). In multivariable analysis, HIV status was not significantly associated with either AOD use disorder treatment initiation or engagement. Conclusions: AOD use disorder treatment initiation and engagement rates were low in both PLWH and patients without an HIV diagnosis. Future studies need to focus on developing strategies to efficiently integrate AOD use disorder treatment with medical care for HIV.
Authors: Hechter RC; Weisner C; Campbell CI; Satre DD; et al.
Subst Abus. 2019;40(3):302-310. Epub 2019-03-25.
Patient characteristics associated with treatment initiation and engagement among individuals diagnosed with alcohol and other drug use disorders in emergency department and primary care settings
Background: Treatment initiation and engagement rates for alcohol and other drug (AOD) use disorders differ depending on where the AOD use disorder was identified. Emergency department (ED) and primary care (PC) are 2 common settings where patients are identified; however, it is unknown whether characteristics of patients who initiate and engage in treatment differ between these settings. Methods: Patients identified with an AOD disorder in ED or PC settings were drawn from a larger study that examined Healthcare Effectiveness Data and Information Set (HEDIS) AOD treatment initiation and engagement measures across 7 health systems using electronic health record data (n = 54,321). Multivariable generalized linear models, with a logit link, clustered on health system, were used to model patient factors associated with initiation and engagement in treatment, between and within each setting. Results: Patients identified in the ED had higher odds of initiating treatment than those identified in PC (adjusted odds ratio [aOR] = 1.89, 95% confidence interval [CI] = 1.73-2.07), with no difference in engagement between the settings. Among those identified in the ED, compared with patients aged 18-29, older patients had higher odds of treatment initiation (age 30-49: aOR = 1.25, 95% CI = 1.12-1.40; age 50-64: aOR = 1.42, 95% CI = 1.26-1.60; age 65+: aOR = 1.27, 95% CI = 1.08-1.49). However, among those identified in PC, compared with patients aged 18-29, older patients were less likely to initiate (age 30-49: aOR = 0.81, 95% CI = 0.71-0.94; age 50-64: aOR = 0.68, 95% CI = 0.58-0.78; age 65+: aOR = 0.47, 95% CI = 0.40-0.56). Women identified in ED had lower odds of initiating treatment (aOR = 0.80, 95% CI = 0.72-0.88), whereas sex was not associated with treatment initiation in PC. In both settings, patients aged 65+ had lower odds of engaging compared with patients aged 18-29 (ED: aOR = 0.61, 95% CI = 0.38-0.98; PC: aOR = 0.42, 95% CI = 0.26-0.68). Conclusion: Initiation and engagement in treatment differed by sex and age depending on identification setting. This information could inform tailoring of future AOD interventions.
Authors: Kline-Simon AH; Campbell CI; Weisner C; Sterling SA; Yarborough BJH; et al.
Subst Abus. 2019;40(3):278-284. Epub 2019-01-31.
The association between medical comorbidity and Healthcare Effectiveness Data and Information Set (HEDIS) measures of treatment initiation and engagement for alcohol and other drug use disorders
Background: Medical comorbidity may influence treatment initiation and engagement for alcohol and other drug (AOD) use disorders. We examined the association between medical comorbidity and Healthcare Effectiveness Data and Information Set (HEDIS) treatment initiation and engagement measures.Methods: We used electronic health record and insurance claims data from 7 US health care systems to identify patients with AOD use disorders between October 1, 2014, and August 15, 2015 (N = 86,565). Among patients identified with AOD use disorders in outpatient and emergency department (ED) settings, we examined how Charlson/Deyo comorbidity index scores and medical complications of AOD use were associated with treatment initiation. Among those who initiated treatment in inpatient and outpatient/ED settings, we also examined how comorbidity and AOD use-related medical complications were associated with treatment engagement. Analyses were conducted using generalized estimating equation logistic regression modeling.Results: Among patients identified as having an AOD diagnosis in outpatient and ED settings (n = 69,965), Charlson/Deyo comorbidity index scores of 2 or more were independently associated with reduced likelihood of initiation (risk ratio [RR] = 0.80, 95% confidence interval [CI] = 0.74, 0.86; reference score = 0), whereas prior-year diagnoses of cirrhosis (RR = 1.25, 95% CI = 1.12, 1.35) and pancreatic disease (RR = 1.34, 95% CI = 1.15, 1.56) were associated with greater likelihood of initiation. Among those who were identified in outpatient/ED settings and initiated, higher comorbidity scores were associated with lower likelihood of engagement (score 1: RR = 0.85, 95% CI = 0.76, 0.94; score 2+: RR = 0.61, 95% CI = 0.53, 0.71).Conclusion: Medical comorbidity was associated with lower likelihood of initiating or engaging in AOD treatment, but cirrhosis and pancreatic disease were associated with greater likelihood of initiation. Interventions to improve AOD treatment initiation and engagement for patients with comorbidities are needed, such as integrating medical and AOD treatment.
Authors: Binswanger IA; Campbell CI; Satre DD; Weisner C; Lapham GT; et al.
Subst Abus. 2019;40(3):292-301. Epub 2019-01-24.
Factors associated with Healthcare Effectiveness Data and Information Set (HEDIS) alcohol and other drug measure performance in 2014-2015
Background: Only 10% of patients with alcohol and other drug (AOD) disorders receive treatment. The AOD Initiation and Engagement in Treatment (AOD-IET) measure was added to the national Healthcare Effectiveness Data and Information Set (HEDIS) to improve access to care. This study identifies factors related to improving AOD-IET rates. Methods: We include data from 7 health systems with differing geographic, patient demographic, and organizational characteristics; all used a common Virtual Data Warehouse containing electronic health records and insurance claims data. Multilevel logistic regression models examined AOD-IET among adults (18+). Results: A total of 86,565 patients had an AOD diagnosis qualifying for the HEDIS denominator. Initiation rates varied from 26% to 46%; engagement rates varied from 14% to 29%. Women versus men (odds ratio [OR] = 0.81, 95% confidence interval [CI] = 0.76-0.86); Hispanics (OR = 0.85, 95% CI = 0.79-0.91), black/African Americans (OR = 0.82, 95% CI = 0.75-0.90), and Asian Americans (OR = 0.83, 95% CI = 0.72-0.95) versus whites; and patients aged 65+ versus 18-29 (OR = 0.82, 95% CI = 0.74-0.90) had lower odds of initiation. Patients aged 30-49 versus 18-29 (OR = 1.11, 95% CI = 1.04-1.19) and those with prior psychiatric (OR = 1.26, 95% CI = 1.18-1.35) and medical (OR = 1.18, 95% CI = 1.10-1.26) conditions had higher odds of engagement. Identification in primary care versus other departments was related to lower odds of initiation (emergency department [ED]: OR = 1.55, 95% CI = 1.45-1.66; psychiatry/AOD treatment: OR = 3.58, 95% CI = 3.33-3.84; other outpatient: OR = 1.19, 95% CI = 1.06-1.32). Patients aged 30-49 versus 18-29 had higher odds of engagement (OR = 1.26, 95% CI = 1.10-1.43). Patients aged 65+ versus 18-29 (OR = 0.51, 95% CI = 0.43-0.62) and black/African Americans versus whites (OR = 0.64, 95% CI = 0.53-0.77) had lower odds. Those initiating treatment in psychiatry/AOD treatment versus primary care (OR = 7.02, 95% CI = 5.93-8.31) had higher odds of engagement; those in inpatient (OR = 0.40, 95% CI = 0.32-0.50) or other outpatient (OR = 0.73, 95% CI = 0.59-0.91) settings had lower odds. Discussion: Rates of initiation and engagement varied but were low. Findings identified age, race/ethnicity, co-occurring conditions, and department of identification as key factors associated with AOD-IET. Focusing on these could help programs develop interventions that facilitate AOD-IET for those less likely to receive care.
Authors: Weisner C; Campbell CI; Sterling SA; Satre DD; Kline-Simon AH; et al.
Subst Abus. 2019;40(3):318-327. Epub 2019-01-24.
The prevalence of Healthcare Effectiveness Data and Information Set (HEDIS) initiation and engagement in treatment among patients with cannabis use disorders in 7 US health systems
Background: Cannabis use disorders (CUDs) have increased with more individuals using cannabis, yet few receive treatment. Health systems have adopted the Healthcare Effectiveness Data and Information Set (HEDIS) quality measures of initiation and engagement in alcohol and other drug (AOD) dependence treatment, but little is known about the performance of these among patients with CUDs. Methods: This cohort study utilized electronic health records and claims data from 7 health care systems to identify patients with documentation of a new index CUD diagnosis (no AOD diagnosis ≤60 days prior) from International Classification of Diseases, Ninth revision, codes (October 1, 2014, to August 31, 2015). The adjusted prevalence of each outcome (initiation, engagement, and a composite of both) was estimated from generalized linear regression models, across index identification settings (inpatient, emergency department, primary care, addiction treatment, and mental health/psychiatry), AOD comorbidity (patients with CUD only and CUD plus other AOD diagnoses), and patient characteristics. Results: Among 15,202 patients with an index CUD diagnosis, 30.0% (95% confidence interval [CI]: 29.2-30.7%) initiated, 6.9% (95% CI: 6.2-7.7%) engaged among initiated, and 2.1% (95% CI: 1.9-2.3%) overall both initiated and engaged in treatment. The adjusted prevalence of outcomes varied across index identification settings and was highest among patients diagnosed in addiction treatment, with 25.0% (95% CI: 22.5-27.6%) initiated, 40.9% (95% CI: 34.8-47.0%) engaged, and 12.5% (95% CI: 10.0-15.1%) initiated and engaged. The adjusted prevalence of each outcome was generally highest among patients with CUD plus other AOD diagnosis at index diagnosis compared with those with CUD only, overall and across index identification settings, and was lowest among uninsured and older patients. Conclusion: Among patients with a new CUD diagnosis, the proportion meeting HEDIS criteria for initiation and/or engagement in AOD treatment was low and demonstrated variation across index diagnosis settings, AOD comorbidity, and patient characteristics, pointing to opportunities for improvement.
Authors: Lapham GT; Campbell CI; Yarborough BJH; Hechter RC; Ahmedani BK; Haller IV; Kline-Simon AH; Satre DD; Loree AM; Weisner C; Binswanger IA
Subst Abus. 2019;40(3):268-277. Epub 2019-01-18.
Psychiatric comorbidity and Healthcare Effectiveness Data and Information Set (HEDIS) measures of alcohol and other drug treatment initiation and engagement across 7 health care systems
Background: Psychiatric comorbidity is common among patients with alcohol and other drug (AOD) use disorders. To better understand how psychiatric comorbidity influences AOD treatment access in health care systems, the present study examined treatment initiation and engagement among a large, diverse sample of patients with comorbid psychiatric and AOD use disorders. Methods: This study utilized data from a multisite observational study examining Healthcare Effectiveness Data and Information Set (HEDIS) measures of initiation and engagement in treatment (IET) among patients with AOD use disorders from 7 health care systems. Participants were aged 18 or older with at least 1 AOD index diagnosis between October 1, 2014, and August 15, 2015. Data elements extracted from electronic health records and insurance claims data included patient demographic characteristics, ICD-9 (International Classification of Diseases, Ninth Revision) diagnostic codes, and procedure codes. Descriptive analyses and multivariate logistic regression models were used to examine the relationship between patient-level factors and IET measures. Results: Across health care systems, out of a total of 86,565 patients who had at least 1 AOD index diagnosis during the study period, 66.2% (n = 57,335) patients also had a comorbid psychiatric disorder. Among patients with a comorbid psychiatric disorder, 34.9% (n = 19,998) initiated AOD treatment, and of those, 10.3% (n = 2,060) engaged in treatment. After adjusting for age, sex, and race/ethnicity, patients with comorbid psychiatric disorders were more likely to initiate (odds ratio [OR] = 3.20, 95% confidence interval [CI] = 3.08, 3.32) but no more likely to engage (OR = 0.56, 95% CI = 0.51, 0.61) in AOD treatment, compared with those without a comorbid psychiatric disorder. Conclusions: Findings suggest that identification of comorbid psychiatric disorders may increase initiation in AOD treatment. However, innovative efforts are needed to enhance treatment engagement both generally and especially for individuals without diagnosed psychiatric conditions.
Authors: Loree AM; Satre DD; Campbell CI; Weisner C; Ahmedani BK; et al.
Subst Abus. 2019;40(3):311-317. Epub 2019-01-25.
Predictors of Healthcare Effectiveness Data and Information Set (HEDIS) treatment initiation and engagement among patients with opioid use disorder across 7 health systems
Background: The prevalence of opioid use disorder (OUD) has increased rapidly in the United States and improving treatment access is critical. Among patients with OUD, we examined factors associated with the Healthcare Effectiveness Data and Information Set (HEDIS) performance measures of alcohol and other drug (AOD) treatment initiation and engagement. Methods: Electronic health record and claims data between October 1, 2014, and August 15, 2015, from 7 health systems were used to identify patients (n = 11,490) with a new index OUD diagnosis (no AOD diagnosis prior <60 days) based on International Classification of Diseases (ICD)-9 codes. Multivariable generalized linear models with a logit link clustered on health system were used to examine the associations of patient demographic and clinical characteristics, and department of index diagnosis, with HEDIS measures of treatment initiation and engagement. Results: The prevalence of OUD among all AOD diagnoses varied across health systems, as did rates of AOD initiation (5.7%-21.6%) and engagement (7.6%-24.6%). Those diagnosed in the emergency department (adjusted odds ratio [aOR] = 1.58, 95% confidence interval [CI] = 1.27,1.97) or psychiatry/AOD treatment (aOR = 2.92, 95% CI = 2.47,3.46) were more likely to initiate treatment compared with primary care. Older patients were less likely to initiate (age 50-64 vs. age 18-29: aOR = 0.42, 95% CI = 0.35, 0.51; age 65+ vs. age 18-29: aOR = 0.34, 95% CI = 0.26, 0.43), as were women (aOR = 0.72, 95% CI = 0.62, 0.85). Patients diagnosed in psychiatry/AOD treatment (aOR = 2.67, 95% CI = 1.98, 3.60) compared with primary care were more likely to engage in treatment. Those identified in an inpatient setting (aOR = 0.19, 95% CI = 0.14, 0.27 vs. primary care), those with medical comorbidity (aOR = 0.70, 95% CI = 0.52, 0.95), and older patients (age 50-64 vs. 18-29: aOR = 0.64, 95% CI = 0.46, 0.88; age 65+ vs. 18-29: aOR = 0.36, 95% CI = 0.22, 0.57) were less likely to engage in treatment. Conclusions: Rates of initiation and engagement for OUD patients vary widely with noticeable room for improvement, particularly in this critical time of the opioid crisis. Targeting patient and system factors may improve health system performance, which is key to improving patient outcomes.
Authors: Campbell CI; Weisner C; Binswanger IA; Lapham GT; Ahmedani BK; Yarborough BJH; Haller IV; Altschuler A; Hechter RC; Loree AM; Kline-Simon AH
Subst Abus. 2019;40(3):328-334. Epub 2019-01-24.
Immunogenicity and safety following primary and booster vaccination with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine: a randomized trial in the United States
Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and HibA or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ HibB, DTaP-HBV-IPV+ HibA boosted with DTaP+ HibA, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15-18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ HibA co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (? 94.8%), DTaP-HBV-IPV+ HibA (? 98.1%) or DTaP-IPV/Hib+ HBV (? 97.8%) groups. We observed robust immune responses post-booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines.
Authors: Klein NP; Abu-Elyazeed R; Cheuvart B; Janssens W; Mesaros N
Hum Vaccin Immunother. 2019;15(4):809-821. Epub 2019-01-04.
Coadministration of 13-valent pneumococcal conjugate and quadrivalent inactivated influenza vaccines in adults previously immunized with polysaccharide pneumococcal vaccine 23: a randomized clinical trial
Immune responses to 13-valent pneumococcal conjugate vaccine (PCV13) and quadrivalent inactivated influenza vaccine (QIV) in older adults may vary with coadministration and previous pneumococcal polysaccharide vaccination. This study assessed safety and noninferiority of immune responses to coadministered PCV13 and QIV compared with each vaccine given alone. Adults ?50 years old preimmunized with ?1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) ?1 year before enrollment were randomized 1:1 to receive PCV13+QIV then placebo 1 month later or placebo+QIV then PCV13 1 month later. Administration of PCV13 and placebo was blinded; QIV was administered open-label. Pneumococcal serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after PCV13, and influenza hemagglutination inhibition assay GMTs 1 month after QIV were measured. Prespecified noninferiority was demonstrated by a lower bound of the 2-sided 95% CI for geometric mean ratios >0.5. Safety endpoints included proportions of subjects with adverse and serious adverse events. Of 882 randomized subjects, 846 comprised the evaluable immunogenicity population. Immune responses to all 13 pneumococcal serotypes and all 4 influenza strains 1 month after PCV13+QIV were noninferior to responses 1 month after each vaccine given alone. No safety concerns were identified. Immune responses to coadministered PCV13 and QIV were noninferior to responses after each vaccine given alone, although generally lower for coadministered PCV13. PCV13 and QIV can be administered concomitantly to adults ?50 years of age preimmunized with PPSV23.
Authors: Thompson AR; Klein NP; Schmöele-Thoma B; et al.
Hum Vaccin Immunother. 2019;15(2):444-451. Epub 2018-10-25.
Recurrence after hospitalization for acute coronary syndrome among HIV-infected and HIV-uninfected individuals
We evaluated the association of HIV infection and immunodeficiency with acute coronary syndrome (ACS) recurrence, and with all-cause mortality as a secondary outcome, after hospitalization for ACS among HIV-infected and HIV-uninfected individuals. We conducted a retrospective cohort study within Kaiser Permanente Northern California of HIV-infected and HIV-uninfected adults discharged after ACS hospitalization [types: ST-elevation myocardial infarction (STEMI), non-STEMI, or unstable angina] during 1996-2010. We compared the outcomes of ACS recurrence and all-cause mortality within 3 years, both overall by HIV status and stratified by recent CD4 count, with HIV-uninfected individuals as the reference group. Hazard ratios (HRs) were obtained from Cox regression models with adjustment for age, sex, race/ethnicity, year, ACS type, smoking, and cardiovascular risk factors. Among 226 HIV-infected and 86 321 HIV-uninfected individuals with ACS, HIV-infected individuals had a similar risk of ACS recurrence compared with HIV-uninfected individuals [HR 1.08; 95% confidence interval (CI) 0.76-1.54]. HIV infection was independently associated with all-cause mortality after ACS hospitalization overall (HR 2.52; 95% CI 1.81-3.52). In CD4-stratified models, post-ACS mortality was higher for HIV-infected individuals with CD4 counts of 201-499 cells/?L (HR 2.64; 95% CI 1.66-4.20) and < 200 cells/?L (HR 5.41; 95% CI 3.14-9.34), but not those with CD4 counts ? 500 cells/?L (HR 0.67; 95% CI 0.22-2.08), compared with HIV-uninfected individuals (P trend < 0.001). HIV infection and immunodeficiency were not associated with recurrence of ACS after hospitalization. All-cause mortality was higher among HIV-infected compared with HIV-uninfected individuals, but there was no excess mortality risk among HIV-infected individuals with high CD4 counts.
Authors: Marcus JL; Zaroff J; Go AS; Quesenberry CP; Lo JC; Silverberg MJ; et al.
HIV Med. 2019 01;20(1):19-26. Epub 2018-09-04.
Immunogenicity and safety of the Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine co-administered with human rotavirus, hepatitis A and 13-valent pneumococcal conjugate vaccines: results from a phase III, randomized, multicenter study in infants
This phase III, open-label, randomized study (NCT01978093) evaluated the immunogenicity and safety of co-administered Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (Hib-MenCY-TT) with human rotavirus vaccine (HRV), hepatitis A vaccine (HAV) and 13-valent pneumococcal conjugate vaccine (PCV13). We randomized 600 infants (1:1) to receive 4 doses of Hib-MenCY-TT at 2, 4, 6 and 12-15 months of age or 3 doses of Hib vaccine conjugated to N. meningitidis outer membrane protein complex (Hib-OMP) at 2, 4 and 12-15 months of age. All infants received HRV at 2 and 4 months of age, PCV13 at 2, 4, 6 and 12-15 months of age, HAV at 12-15 and 18-21 months of age, and diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months of age. We measured immune responses against HRV, HAV and Hib with enzyme-linked immunosorbent assays, and against MenC/MenY with serum bactericidal assays using human complement. The 4-dose vaccination series with Hib-MenCY-TT induced a robust immune response against Hib, which was non-inferior to that induced by a 3-dose vaccination series with Hib-OMP, and against MenC and MenY. Hib-MenCY-TT did not interfere with immune responses to concomitantly administered HRV, PCV13 and HAV. We did not identify any safety concern. In conclusion, we showed that 4-dose vaccination series with Hib-MenCY-TT during infancy did not interfere with immune responses of co-administered HRV, PCV13 and HAV, induced robust immune responses against Hib, MenC and MenY, and had a clinically acceptable safety profile.
Authors: Klein NP; Abu-Elyazeed R; Baine Y; Cheuvart B; Silerova M; Mesaros N
Hum Vaccin Immunother. 2019;15(2):327-338. Epub 2018-10-05.
Comment on “The impact of past vaccination coverage and immunity on pertussis resurgence”
Limitations in the data used for a recent modeling study of pertussis resurgence in the US may explain why the results were not consistent with several observational studies demonstrating a shorter duration of protection after acellular pertussis vaccine administration.
Authors: Winter K; Klein NP; Ackley S; Cherry JD
Science. 2019 04 26;364(6438):341-342.
Respiratory Syncytial Virus Hospitalization during Pregnancy in Four High-income Countries, 2010-2016
Few studies have addressed respiratory syncytial virus (RSV) infection during pregnancy. Among 846 pregnant women hospitalized with respiratory illness and tested for RSV, 21 (2%) were RSV positive, of whom 8 (38%) were diagnosed with pneumonia. Despite study limitations, these data can help inform decisions about RSV prevention strategies.
Authors: Regan AK; Klein NP; PREVENT Group; et al.
Clin Infect Dis. 2018 11 28;67(12):1915-1918.
A framework for research on vaccine effectiveness
The need for a systematic approach to research on vaccine effectiveness (VE) is increasing with growing numbers of vaccines and complexity of immunization programs. The diverse scientific fields that investigate how vaccines work and why they fail continue to evolve, yet definitions related to such advances have not kept pace. Researchers in disciplines ranging from basic science through immunopathology, clinical and epidemiological research, and mathematical modelling need more precise definitions to promote communication and interdisciplinary VE research to ensure that studies are designed to appropriately address relevant questions. To meet these aims, we suggest standardized definitions, consider models of vaccine failure, and offer general approaches for incorporation into study design. We further propose a framework for conducting VE research that builds on the traditional epidemiological triad of host, pathogen and environment, and also includes additional elements such as characteristics of both the vaccine and vaccinee, the effect of time on likelihood of exposure and protection, and the impact of environment and pathogen, as well as how outcomes of interest and study design may impact observed vaccine effectiveness. The framework is relevant to researchers in all disciplines who investigate the effectiveness of vaccines and vaccination programs and why they may fail. Stronger research in this field will help policy makers optimise decision-making on vaccination programs, ensuring we maximize the health benefits of vaccines. It is also important for clinicians communicating the benefits of vaccines to the public.
Authors: Crowcroft NS; Klein NP
Vaccine. 2018 11 19;36(48):7286-7293. Epub 2018-10-26.
Impact of Alternative Encounter Types on HIV Viral Suppression Rates in an Integrated Health System
Kaiser Permanente Mid-Atlantic States (KPMAS) members are increasingly utilizing electronic encounter types, such as telephone appointments and secure messaging for healthcare purposes, although their impact on health outcomes is unknown. We evaluated whether use of alternative encounters by adult human immunodeficiency virus (HIV)-infected patients affected the likelihood of achieving viral suppression (VS). Our study population of 3114 patients contributed 6520 patient-years between 2014 and 2016. We compared VS (HIV RNA <200 copies/mL) by number of in-person visits (1 or ≥2), with further stratification for additional phone and/or e-mail encounters (none, phone only, e-mail only, and both phone and e-mail). Rate ratios (RRs) for VS by number of in-person visits and encounter types were obtained from Poisson modeling, adjusting for age, sex, race/ethnicity, and HIV risk. Compared to those with ≥2 visits, patients with one in-person visit alone were significantly less likely to achieve VS (RR = 0.93; 95% confidence interval, CI: [0.87-1.00]), as were those with one in-person visit plus a telephone encounter (0.93; [0.90-0.97]). We did not find significant differences in VS comparing patients with one in-person visit plus e-mail only (RR = 1.00; 95% CI: [0.97-1.02]) or plus e-mail and telephone (0.99; [0.97-1.01]) to those with ≥2 in-person visits. If supplemented by e-mail communications (with or without telephone contact), patients with one in-person visit per year had similar estimated rates of VS compared with ≥2 in-person visits. More research is needed to know if these findings apply to other care systems.
Authors: Horberg MA; Blank JG; Rubenstein KB; Certa JM; Hurley LB; Kadlecik PM; Klein DB; Silverberg MJ
AIDS Patient Care STDS. 2018 11;32(11):425-431.
Acceptability of high-resolution anoscopy for anal cancer screening in HIV-infected patients
HIV-infected individuals are at increased risk of anal cancer. Screening for anal cancer precursors using high-resolution anoscopy (HRA) may be clinically beneficial. In this study, we examined patient tolerability of this procedure. The acceptability of HRA was evaluated among HIV-infected patients who completed a first-time HRA between July 2008 and December 2013 at Kaiser Permanente Northern California. We reviewed electronic medical records to identify lack of HRA acceptability, which was defined as receipt of HRA with sedation, dispensation of opioid analgaesia, and/or an urgent care visit following HRA, and to evaluate factors associated with patients not returning for a recommended repeat HRA (proxy for HRA acceptability). HRA acceptability was also assessed via a survey mailed to patients who completed HRA between January 2014 and August 2014. Logistic regression was used to model lack of acceptability of initial HRA and likelihood of not returning for a repeat HRA. Of 1857 HIV-infected patients, 94 were prescribed opioids and one had an urgent care visit. Lack of HRA acceptability was more likely in patients with pre-existing anal conditions [e.g. warts or fissure; adjusted odds ratio (aOR) 4.02; 95% confidence interval (CI) 2.4-6.7], those who had ever smoked (aOR 1.6; 95% CI 1.0-2.5) and women (aOR 5.3; 95% CI 1.6-17.5). Fifty per cent of patients returned for a repeat HRA, with younger patients less likely to return (per 10-year age interval, aOR 0.8; 95% CI 0.7-0.9). Of 48 survey respondents, 91.7% reported acceptable pain levels and all reported willingness to return for a repeat HRA. HRA was generally well tolerated and may be an acceptable screening approach for patients at high risk of anal cancer.
Authors: Lam JO; Barnell GM; Merchant M; Ellis CG; Silverberg MJ
HIV Med. 2018 11;19(10):716-723. Epub 2018-08-06.
Association of raltegravir use with long-term health outcomes in HIV-infected patients: an observational post-licensure safety study in a large integrated healthcare system
Raltegravir became the first integrase inhibitor to gain FDA approval; but with limited evidence documenting long-term risks in real world care, especially for major health outcomes of interest. Assess raltegravir safety in clinical practice within an integrated health system. We conducted a cohort study of HIV-infected adults within Kaiser Permanente California from 2005 to 2013. We compared patients initiating raltegravir during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005-2007) and a concurrent cohort that did not initiate raltegravir (2007-2013). We used multivariate Cox proportional hazard regression to obtain hazard ratios (HR) for pre-specified incident health outcomes, employing propensity scores to adjust for potential confounding. The population included 8,219 HIV-infected adults (raltegravir cohort N = 1,757; 4,798 patient-years), with greater years known HIV-infected among raltegravir patients. The raltegravir cohort had increased HR for AIDS-defining (HR 2.69 [1.53-4.71]; HR 1.85 [1.21-2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29-3.94]; HR 1.88 [1.26-2.78]) relative to both comparison cohorts. Compared to the historical cohort we found no significant difference in all-cause mortality; the raltegravir cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02-2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events. The potentially elevated risk for malignancy and mortality with raltegravir and residual confounding merits further investigation. We demonstrate the value of observational cohorts for monitoring post-licensure medication safety.
Authors: Horberg MA; Oakes AH; Hurley LB; Towner WJ; Chao CR; Silverberg MJ; Chantra JQ; Ellis CG; Quesenberry CP
HIV Clin Trials. 2018 10;19(5):177-187. Epub 2018-10-27.
Uptake and safety of Hepatitis B vaccination during pregnancy: A Vaccine Safety Datalink study
Hepatitis B virus (HBV) infection acquired during pregnancy can pose a risk to the infant at birth that can lead to significant and lifelong morbidity. Hepatitis B vaccine (HepB) is recommended for anyone at increased risk for contracting HBV infection, including pregnant women. Limited data are available on the safety of HepB administration during pregnancy. To assess the frequency of maternal HepB receipt among pregnant women and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. We examined a retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live birth outcomes from 2004 through 2015. Eligible pregnancies in women aged 12-55 years who were continuously enrolled from 6 months pre-pregnancy to 6 weeks postpartum in VSD integrated health systems were included. We compared pregnancies with HepB exposure to those with other vaccine exposures, and to those with no vaccine exposures. High-risk conditions for contracting HBV infection were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were also evaluated according to maternal HepB exposure status. Among over 650,000 pregnancies in the study period, HepB was administered at a rate of 2.1 per 1000 pregnancies (n = 1399), commonly within the first 5 weeks of pregnancy. Less than 3% of the HepB-exposed group had a high-risk ICD-9 code indicating need for HepB; this was similar to the rate among HepB unvaccinated groups. There were no significant associations between HepB exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, low birthweight or small for gestational age infants. Most women who received maternal HepB did not have high-risk indications for vaccination. No increased risk for the adverse events that were examined were observed among women who received maternal HepB or their offspring.
Authors: Groom HC; Klein NP; Naleway AL; et al.
Vaccine. 2018 10 01;36(41):6111-6116. Epub 2018-09-05.
Reduced cancer survival among adults with HIV and an AIDS-defining illnesses despite no difference in cancer stage at diagnosis
It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI. PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included. Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant. PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes.
Authors: Grover S; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design; et al.
J Acquir Immune Defic Syndr. 2018 12 01;79(4):421-429.
Factors Affecting Vaccination in Children and Their Siblings After Autism Spectrum Disorder Diagnosis-Reply
Authors: Zerbo O; Klein NP
JAMA Pediatr. 2018 10 01;172(10):985-986.
Epidemiology, detection, and management of tuberculosis among end-stage renal disease patients
Tuberculosis (TB) remains an important problem among end-stage renal disease (ESRD) patients. We reviewed the epidemiology of TB and ESRD, investigations of TB exposures in US dialysis facilities, and published guidelines to inform screening and treatment practices among US ESRD patients. Compared to TB in the general population, ESRD patients have 6-25-fold higher TB incidence rates, and mortality during treatment is 2-3-fold higher. Most TB cases among ESRD patients (~90%) occur among non-US-born persons, and an analysis of genotyping data suggests that 80% of all cases result from latent TB infection (LTBI) reactivation. Published TB contact investigations in dialysis facilities have reported cases among ESRD patients and healthcare workers. However, transmission of TB is rare: there were no reports of secondary cases of TB because of exposure to an index-case patient and there were few TB infections, which was demonstrated by low occurrence of newly positive tuberculin skin tests (12%-16%) and conversions (8%-17%) among contacts. Targeted TB education, screening, and treatment for ESRD patients at highest risk for TB exposure (eg, non-US-born persons), using interferon-gamma release assays and short course LTBI regimens (ie, isoniazid-rifapentine weekly for 12 weeks or rifampin daily for 4 months) may be an effective overall strategy for reducing TB burden in ESRD patients.
Authors: Okada RC; Barry PM; Skarbinski J; Chitnis AS
Infect Control Hosp Epidemiol. 2018 11;39(11):1367-1374. Epub 2018-09-20.
Agreement between medical records and self-reports: Implications for transgender health research
A key priority of transgender health research is the evaluation of long-term effects of gender affirmation treatment. Thus, accurate assessment of treatment receipt is critical. The data for this analysis came from an electronic medical records (EMR) based cohort of transgender individuals. A subset of cohort members were also asked to complete a self-administered survey. Information from the EMR was compared with survey responses to assess the extent of agreement regarding transmasculine (TM)/transfeminine (TF) status, hormone therapy receipt, and type of surgery performed. Logistic regression models were used to assess whether participant characteristics were associated with disagreement between data sources. Agreement between EMR and survey-derived information was high regarding TM/TF status (99%) and hormone therapy receipt (97%). Lower agreement was observed for chest reconstruction surgery (72%) and genital reconstruction surgery (84%). Using survey responses as the “gold standard”, both chest and genital reconstruction surgeries had high specificity (95 and 93%, respectively), but the corresponding sensitivities were low (49 and 68%, respectively). A lower proportion of TM had concordant results for chest reconstruction surgery (64% versus 79% for TF) while genital reconstruction surgery concordance was lower among TF (79% versus 89% for TM). For both surgery types, agreement was highest among the youngest participants. Our findings offer assurance that EMR-based data appropriately classify cohort participants with respect to their TM/TF status or hormone therapy receipt. However, current EMR data may not capture the complete history of gender affirmation surgeries. This information is useful in future studies of outcomes related to gender affirming therapy.
Authors: Gerth J; Hunkeler EM; Silverberg MJ; Goodman M; et al.
Rev Endocr Metab Disord. 2018 09;19(3):263-269.
Development and Calibration of a Mathematical Model of Anal Carcinogenesis for High-Risk HIV-Infected Men
Men who have sex with men who are living with HIV are at highest risk for anal cancer. Our objective was to use empirical data to develop a comprehensive disease simulation model that reflects the most current understanding of anal carcinogenesis, which is uniquely positioned to evaluate future anal cancer screening strategies and provide insight on the unobservable course of the disease. North America. The individual-based simulation model was calibrated leveraging primary data from empirical studies, such as a longitudinal HIV-positive men who have sex with men cohort study [Human Immunodeficiency and Papilloma Virus Research Group (HIPVIRG); n = 247] and the North American AIDS Cohort Collaboration on Research and Design [(NA-ACCORD); n = 13,146]. We used the model to infer unobservable progression probabilities from high-grade precancer to invasive anal cancer by CD4 nadir and human papillomavirus (HPV) genotype. The calibrated model had good correspondence to data on genotype- and age-specific HPV prevalence; genotype frequency in precancer and cancer; and age- and nadir CD4-specific cancer incidence. The model-projected progression probabilities differed substantially by HPV genotype and nadir CD4 status. For example, among individuals with CD4 nadir <200, the median monthly progression probability from a high-grade lesion to invasive cancer was 0.054% (ie, 6.28% 10-year probability) and 0.004% (ie, 0.48% 10-year probability) for men with an HPV-16 infection versus without a detectable HPV infection, respectively. We synthesized existing evidence into a state-of-the-art anal cancer disease simulation model that will be used to quantify the tradeoffs of harms and benefits of alternative strategies, understand critical uncertainties, and inform national anal cancer prevention policy.
Authors: Burger EA; Dyer MA; Sy S; Palefsky JM; de Pokomandy A; Coutlee F; Silverberg MJ; Kim JJ
J Acquir Immune Defic Syndr. 2018 09 01;79(1):10-19.
Factors associated with hazardous alcohol use and motivation to reduce drinking among HIV primary care patients: Baseline findings from the Health & Motivation study
Limited primary care-based research has examined hazardous drinking risk factors and motivation to reduce use in persons with HIV (PWH). We computed prevalence ratios (PR) for factors associated with recent (<30 days) hazardous alcohol use (i.e., 4+/5+ drinks in a single day for women/men), elevated Alcohol Use Disorders Identification Test (AUDIT) scores, and importance and confidence (1-10 Likert scales) to reduce drinking among PWH in primary care. Of 614 participants, 48% reported recent hazardous drinking and 12% reported high alcohol use severity (i.e., AUDIT zone 3 or higher). Factors associated with greater alcohol severity included moderate/severe anxiety (PR: 2.07; 95% CI: 1.18, 3.63), tobacco use (PR: 1.79; 1.11, 2.88), and other substance use (PR: 1.72; 1.04, 2.83). Factors associated with lower alcohol severity included age 50-59 years (PR: 0.46; 0.22, 2.00) compared with age 20-39 years, and having some college/college degree (PR: 0.61; 0.38, 0.97) compared with ≤high school. Factors associated with greater importance to reduce drinking (scores >5) included: moderate/severe depression (PR: 1.43; 1.03, 2.00) and other substance use (PR: 1.49; 1.11, 2.01). Lower importance was associated with incomes above $50,000 (PR: 0.65; 0.46, 0.91) and marijuana use (PR: 0.65; 0.49, 0.87). HIV-specific factors (e.g., CD4 and HIV RNA levels) were not associated with alcohol outcomes. This study identified modifiable participant characteristics associated with alcohol outcomes in PWH, including anxiety and depression severity, tobacco use, and other substance use.
Authors: Silverberg MJ; Leyden WA; Leibowitz A; Hare CB; Jang HJ; Sterling S; Catz SL; Parthasarathy S; Horberg MA; Satre DD
Addict Behav. 2018 09;84:110-117. Epub 2018-03-31.
Assessing Potential Confounding and Misclassification Bias When Studying the Safety of the Childhood Immunization Schedule
Some parents are concerned the childhood immunization schedule could increase risk for allergic disorders, including asthma. To inform future safety studies of this speculated association, a parent survey was conducted to examine the risk of misclassification of vaccination status in electronic health record data, and to assess the potential for confounding if asthma risk factors varied by vaccination status. A survey was conducted among parents of children 19 to 35 months old at 6 medical organizations within the Vaccine Safety Datalink. Parents of children in 4 vaccination groups were surveyed: 1) no vaccines by 12 months of age and a diagnosis of parental vaccine refusal; 2) consistent vaccine limiting (≤2 vaccines per visit); 3) not consistently vaccine limiting but otherwise undervaccinated with a vaccine refusal diagnosis; and 4) fully vaccinated with no delays and no vaccine refusal. Parents were surveyed about their child’s vaccination status and whether asthma risk factors existed. Among a survey sample of 2043 parents, 1209 responded (59.2%). For receiving no vaccines, the observed agreement between parent report and electronic health record data was 94.0% (κ = 0.79); for receiving all vaccines with no delays, the observed agreement was 87.3% (κ = 0.73). Although most asthma risk factors (allergic rhinitis, eczema, food allergies, family asthma history) reported by parents did not differ significantly between children in the vaccination groups studied, several factors (aeroallergen sensitivity, breastfeeding) differed significantly between groups. Measurement and control of disease risk factors should be carefully considered in observational studies of the safety of the immunization schedule.
Authors: Daley MF; Shoup JA; Newcomer SR; Jackson ML; Groom HC; Jacobsen SJ; McLean HQ; Klein NP; Weintraub ES; McNeil MM; Glanz JM
Acad Pediatr. 2018 Sep - Oct;18(7):754-762. Epub 2018-03-28.
Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study
Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. To examine the incidence of these events in a cohort of transgender persons. Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Kaiser Permanente in Georgia and northern and southern California. 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Inability to determine which transgender members received hormones elsewhere. The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Authors: Getahun D; Hunkeler E; Silverberg MJ; Goodman M; et al.
Ann Intern Med. 2018 08 21;169(4):205-213. Epub 2018-07-10.
Cutaneous Melanoma Risk among People with HIV in the United States and Canada
Cutaneous melanoma incidence may be modestly elevated in people with HIV (PWH) vs. people without HIV. However, little is known about the relationship of immunosuppression, HIV replication, and antiretroviral therapy (ART) with melanoma risk. PWH of white race in the North American AIDS Cohort Collaboration on Research and Design were included. A standardized incidence ratio was calculated comparing risk with the white general population, standardizing by age, sex, and calendar period. Associations between melanoma incidence and current, lagged, and cumulative measures of CD4 count, HIV RNA level, and ART use were estimated with Cox regression, adjusting for established risk factors such as age and annual residential ultraviolet B (UVB) exposure. Eighty melanomas were diagnosed among 33,934 white PWH (incidence = 40.75 per 100,000 person-years). Incidence was not elevated compared with the general population [standardized incidence ratio = 1.15, 95% confidence interval (95% CI) = 0.91 to 1.43]. Higher melanoma incidence was associated with older age [adjusted hazard ratio (aHR) per decade increase = 1.50, 95% CI = 1.20 to 1.89] and higher UVB exposure (aHR for exposure ≥35 vs. <35 mW/m = 1.62, 95% CI = 0.99 to 2.65). Current, lagged, and cumulative CD4 and HIV RNA were not associated with melanoma incidence. Melanoma incidence was higher among people ART-treated for a larger proportion of time in the previous 720 days (aHR per 10% increase = 1.16, 95% CI = 1.03 to 1.30). These results suggest that HIV-induced immune dysfunction does not influence melanoma development. The association between ART and melanoma risk may be due to increased skin surveillance among PWH engaged in clinical care. Associations with age and UVB confirmed those established in the general population.
Authors: Yanik EL; Neugebauer RS; Silverberg MJ; Dubrow R; et al.
J Acquir Immune Defic Syndr. 2018 08 15;78(5):499-504.
Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-control study
The population effectiveness of human papillomavirus (HPV) catch-up vaccination, defined in the USA as first vaccination at ages 13-26 years, has not been studied extensively. We aimed to assess the risk of cervical intraepithelial neoplasia (CIN) 2, CIN3, adenocarcinoma in situ, or cancer (CIN2+ and CIN3+) by prior HPV vaccination status, age at first dose, and number of doses in women participating in a screening programme within a large integrated health-care system. We performed a nested case-control study of women enrolled in Kaiser Permanente Northern California (an integrated health-care delivery system in California, USA). Cases were women with CIN2+ or CIN3+ confirmed by histology between Jan 1, 1995, and June 30, 2014, and incidence density-selected controls were age-matched women without CIN2+ or CIN3+ at the time each case occurred. For each case, we randomly selected five controls. Cases and controls were aged 26 years or younger when the HPV quadrivalent vaccine became available in 2006. Rate ratios (RRs) from conditional logistic regression were estimated by age at time of first HPV quadrivalent vaccine dose (14-17 years, 18-20 years, and ≥21 years), and number of doses (one, two, and three or more doses) compared with no prior vaccination, with adjustment for smoking, hormonal contraceptive prescription, race or ethnicity, sexually transmitted infections, immunosuppression, parity, and number of outpatient visits. 4357 incident CIN2+ cases and 21 773 matched controls were included in the study. Of these, 1849 were incident CIN3+ cases with 9242 matched controls. The youngest age at time of first vaccination was 14 years. One or more HPV vaccine doses conferred protection against CIN2+ (RR 0·82, 95% CI 0·73-0·93) and CIN3+ (0·77, 0·64-0·94). We found the strongest protection against CIN2+ in women who had received at least three vaccine doses and had received their first dose aged 14-17 years (0·52, 0·36-0·74) or aged 18-20 years (0·65, 0·49-0·88). No significant protection was found in women aged 21 years or older at time of first dose (0·94, 0·81-1·09). Inferences were similar for CIN3+, but with stronger effects for women who received at least three vaccine doses and had received their first dose aged 14-17 years (0·27, 0·13-0·56) or aged 18-20 years (0·59, 0·36-0·97). Catch-up quadrivalent HPV vaccination with three doses was effective against CIN2+ and CIN3+ in girls and women aged 14-20 years at time of first vaccine dose but not for women aged 21 years and older at first dose. US National Cancer Institute.
Authors: Silverberg MJ; Leyden WA; Lam JO; Gregorich SE; Huchko MJ; Kulasingam S; Kuppermann M; Smith-McCune KK; Sawaya GF
Lancet Child Adolesc Health. 2018 Oct;2(10):707-714. Epub 2018-08-08.
Safety of repeated doses of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in adults and adolescents
In light of waning immunity to pertussis following receipt of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine, maintaining protection may require repeated Tdap vaccination. We evaluated the safety of repeated doses of tetanus-containing vaccine in 68 915 nonpregnant adolescents and adults in the Vaccine Safety Datalink population who had received an initial dose of Tdap. Compared with 7521 subjects who received a subsequent dose of tetanus toxoid, reduced diphtheria (Td) vaccine, the 61 394 subjects who received a subsequent dose of Tdap did not have significantly elevated risk of medical visits for seizure, cranial nerve disorders, limb swelling, pain in limb, cellulitis, paralytic syndromes, or encephalopathy/encephalitis/meningitis. These results suggest that repeated Tdap vaccination has acceptable safety relative to Tdap vaccination followed by Td vaccination.
Authors: Jackson ML; Yu O; Nelson JC; Nordin JD; Tartof SY; Klein NP; Donahue JG; Irving SA; Glanz JM; McNeil MM; Jackson LA
Pharmacoepidemiol Drug Saf. 2018 08;27(8):921-925. Epub 2018-06-03.
Risk of Spontaneous Abortion After Inadvertent Human Papillomavirus Vaccination in Pregnancy
To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink. Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12-27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models. We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
Obstet Gynecol. 2018 07;132(1):35-44.
Disparities in Initiation of Direct-Acting Antiviral Agents for Hepatitis C Virus Infection in an Insured Population
The cost of direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection may contribute to treatment disparities. However, few data exist on factors associated with DAA initiation. We conducted a retrospective cohort study of HCV-infected Kaiser Permanente Northern California members aged ≥18 during October 2014 to December 2016, using Poisson regression models to evaluate demographic, behavioral, and clinical factors associated with DAA initiation. Of 14 790 HCV-infected patients aged ≥18 (median age, 60; interquartile range, 53-64), 6148 (42%) initiated DAAs. DAA initiation was less likely among patients who were non-Hispanic black (adjusted rate ratio [aRR] = 0.7; 95% confidence interval [CI], 0.7-0.8), Hispanic (aRR = 0.8; 95% CI, 0.7-0.9), and of other minority races/ethnicities (aRR = 0.9; 95% CI, 0.8-1.0) than among non-Hispanic white people and among those with lowest compared with highest neighborhood deprivation index (ie, a marker of socioeconomic status) (aRR = 0.8; 95% CI, 0.7-0.8). Having maximum annual out-of-pocket health care costs >$3000 compared with ≤$3000 (aRR = 0.9; 95% CI, 0.8-0.9) and having Medicare (aRR = 0.8; 95% CI, 0.8-0.9) or Medicaid (aRR = 0.7; 95% CI, 0.6-0.8) compared with private health insurance were associated with a lower likelihood of DAA initiation. Behavioral factors (eg, drug abuse diagnoses, alcohol use, and smoking) were also significantly associated with a lower likelihood of DAA initiation (all P < .001). Clinical factors associated with a higher likelihood of DAA initiation were advanced liver fibrosis, HCV genotype 1, previous HCV treatment (all P < .001), and HIV infection ( P = .007). Racial/ethnic and socioeconomic disparities exist in DAA initiation. Substance use may also influence patient or provider decision making about DAA initiation. Strategies are needed to ensure equitable access to DAAs, even in insured populations.
Authors: Marcus JL; Lam JO; Quesenberry CP; Silverberg MJ; et al.
Public Health Rep. 2018 Jul/Aug;133(4):452-460. Epub 2018-05-11.
Benefits and harms of lung cancer screening in HIV-infected individuals with CD4+ ≥ 500: a simulation study
Lung cancer is the leading cause of non-AIDS-defining cancer deaths among HIV-infected individuals. Although lung cancer screening with low-dose computed tomography (LDCT) is endorsed by multiple national organizations, whether HIV-infected individuals would have similar benefit as uninfected individuals from lung cancer screening is unknown. Our objective was to determine the benefits and harms of lung cancer screening among HIV-infected individuals. We modified an existing simulation model, the Lung Cancer Policy Model, for HIV-infected patients. Veterans Aging Cohort Study, Kaiser Permanente Northern California HIV Cohort, and medical literature. HIV-infected current and former smokers. Lifetime. Population. Annual LDCT screening from ages 45, 50, or 55 until ages 72 or 77 years. Benefits assessed included lung cancer mortality reduction and life-years gained; harms assessed included numbers of LDCT examinations, false-positive results, and overdiagnosed cases. For HIV-infected patients with CD4 cell count at least 500 cells/μl and 100% antiretroviral therapy adherence, screening using the Centers for Medicare & Medicaid Services criteria (age 55-77, 30 pack-years of smoking, current smoker or quit within 15 years of screening) would reduce lung cancer mortality by 18.9%, similar to the mortality reduction of uninfected individuals. Alternative screening strategies utilizing lower screening age and/or pack-years criteria increase mortality reduction, but require more LDCT examinations. Strategies assumed 100% screening adherence. Lung cancer screening reduces mortality in HIV-infected patients with CD4 cell count at least 500 cells/μl, with a number of efficient strategies for eligibility, including the current Centers for Medicare & Medicaid Services criteria.
Authors: Kong CY; Sigel K; Criss SD; Sheehan DF; Triplette M; Silverberg MJ; Henschke CI; Justice A; Braithwaite RS; Wisnivesky J; Crothers K
AIDS. 2018 06 19;32(10):1333-1342.
Pneumococcal Conjugate Vaccine Safety in Elderly Adults
The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) were both recommended to adults aged ≥65 years. The study examines adults ≥65 years for risk of adverse events (AEs) requiring medical attention following vaccination with PCV13 as compared with vaccination with PPSV23, a long-standing vaccine with a satisfactory safety profile. The cohort study included 6 Vaccine Safety Datalink sites. The exposed person-time included follow-up time of the first PCV13 received by subjects age ≥65 years from January 1 to August 15, 2015. The comparator person-time included follow-up time after the first PPSV23 received by subjects of the same age during Janaury 1 to August 15 of each year of 2011-2015. The prespecified AEs included cardiovascular events, Bell’s palsy, Guillain-Barré syndrome, syncope, erythema multiforme, thrombocytopenia, cellulitis and infection, allergic reaction, and anaphylaxis. Inverse probability of treatment weighting-adjusted Poisson regression models was used to estimate the relative risk (RR) of each AE. A total of 313 136 doses of PCV13 and 232 591 doses of PPSV23 were included. The adjusted RRs comparing the incidence of AEs following PCV13 vs PPSV23 were all <1, except for anaphylaxis, which was insignificant with an RR of 1.32 (95% confidence interval, 0.30-5.79). Only 1 patient who received PCV13 and 4 other vaccines concomitantly was confirmed by medical chart review as having experienced anaphylaxis after vaccination. These data do not support an increased rate of adverse events following PCV13 administration in elders compared with PPSV23 and should provide reassurance regarding continued use of PCV13.
Authors: Tseng HF; Klein NP; Jacobsen SJ; et al.
Open Forum Infect Dis. 2018 Jun;5(6):ofy100. Epub 2018-05-02.
Birth outcomes following immunization of pregnant women with pandemic H1N1 influenza vaccine 2009-2010
Following the H1N1 influenza pandemic in 2009, pregnant women were recommended to receive both seasonal (TIV) and H1N1 influenza vaccines. This study presents incidence of adverse birth and pregnancy outcomes among a population of pregnant women immunized with TIV and H1N1 vaccines at Kaiser Permanente Northern California during 2009-2010. We telephone surveyed pregnant Kaiser Permanente Northern California members to assess non-medically-attended reactions following H1N1, TIV or both vaccines during 2009-2010 (n=5365) in a separate study. Here we assessed preterm birth (<37weeks), very preterm birth (<32weeks), low birth weight (<2500 g, LBW), very low birth weight (<1500g), small for gestational age, spontaneous abortions, stillbirths and congenital anomalies among this cohort by comparing incidence and 95% confidence intervals between the following immunization groups: TIV only, H1N1 only, H1N1 prior to TIV immunization, TIV prior to H1N1 and both immunizations given at the same time. Results did not vary significantly between groups. Comparing H1N1 with TIV, incidence were similar for preterm births (6.37vs 6.28/100 births), very preterm births (5.30vs 8.29/1000 births), LBW (4.19vs 2.90/100 births), very LBW (4.54vs 5.52/1000 births), small for gestational age (9.99vs 9.24/1000 births), spontaneous abortion (7.10vs 6.83/1000 pregnancies), stillbirths (7.10vs 4.57/1000 pregnancies), and congenital anomalies (2.66vs 2.43/100 births). Although constrained by small sample size, complex vaccine groups, and differential vaccine availability during 2009-2010, this study found no difference in adverse birth outcomes between H1N1 vaccine and TIV.
Authors: Eaton A; Lewis N; Fireman B; Hansen J; Baxter R; Gee J; Klein NP
Vaccine. 2018 05 03;36(19):2733-2739. Epub 2017-09-13.
Mental Health of Transgender and Gender Nonconforming Youth Compared With Their Peers
Understanding the magnitude of mental health problems, particularly life-threatening ones, experienced by transgender and/or gender nonconforming (TGNC) youth can lead to improved management of these conditions. Electronic medical records were used to identify a cohort of 588 transfeminine and 745 transmasculine children (3-9 years old) and adolescents (10-17 years old) enrolled in integrated health care systems in California and Georgia. Ten male and 10 female referent cisgender enrollees were matched to each TGNC individual on year of birth, race and/or ethnicity, study site, and membership year of the index date (first evidence of gender nonconforming status). Prevalence ratios were calculated by dividing the proportion of TGNC individuals with a specific mental health diagnosis or diagnostic category by the corresponding proportion in each reference group by transfeminine and/or transmasculine status, age group, and time period before the index date. Common diagnoses for children and adolescents were attention deficit disorders (transfeminine 15%; transmasculine 16%) and depressive disorders (transfeminine 49%; transmasculine 62%), respectively. For all diagnostic categories, prevalence was severalfold higher among TGNC youth than in matched reference groups. Prevalence ratios (95% confidence intervals [CIs]) for history of self-inflicted injury in adolescents 6 months before the index date ranged from 18 (95% CI 4.4-82) to 144 (95% CI 36-1248). The corresponding range for suicidal ideation was 25 (95% CI 14-45) to 54 (95% CI 18-218). TGNC youth may present with mental health conditions requiring immediate evaluation and implementation of clinical, social, and educational gender identity support measures.
Authors: Becerra-Culqui TA; Hunkeler EM; Silverberg MJ; Goodman M; et al.
Pediatrics. 2018 05;141(5). Epub 2018-04-16.
Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings
In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown. To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD. This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015. Recommended childhood vaccines between ages 1 month and 12 years. The proportion of children who received all of their vaccine doses according to ACIP recommendations. The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child’s younger sibling and to limit the number of vaccines administered during the younger sibling’s first year of life. Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.
Authors: Zerbo O; Fireman BH; Klein NP; et al.
JAMA Pediatr. 2018 05 01;172(5):469-475.
Recent abacavir use increases risk for Types 1 and 2 myocardial infarctions among adults with HIV
There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV. Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence. Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome. Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.
Authors: Elion RA; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of IeDEA; et al.
J Acquir Immune Defic Syndr. 2018 05 01;78(1):62-72.
Live Attenuated Influenza Vaccination Prior To Age 3 Years and Subsequent Development of Asthma: A 14-Year Follow-Up Study
Live-attenuated influenza vaccines (LAIVs) are not licensed in children younger than 2 years of age because of a wheezing safety signal that has not been fully elucidated. In 2000, the Kaiser Permanente Vaccine Study Center conducted a placebo-controlled randomized clinical trial (RCT) of LAIV in children. As many of these children were still enrolled in Kaiser Permanente in 2014, we could assess the possible long-term association between LAIV and subsequent asthma diagnosis. We identified all children who were originally enrolled into the LAIV RCT at younger than 3 years of age. We followed up subjects until disenrollment from the health plan, a first diagnosis of asthma, or through the end of the study period in 2014. Asthma was defined by a first International Classification of Diseases, 9th revision, Clinical Modification code (493.*) assigned at an outpatient or emergency department encounter. We performed a survival analysis of time to first asthma diagnosis among children receiving LAIV or placebo with a Cox proportional hazards model. We identified 1151 children in the original RCT who were 12 through 35 months of age at the time of enrollment and who had received 2 doses of LAIV or placebo. A total of 767 (66.7%) RCT participants were still Kaiser Permanente Northern California members in 2014. There was no evidence of differential dropout by treatment group. The hazard ratio for new-onset asthma for LAIV recipients compared with placebo was 1.1 (95% confidence interval: 0.88-1.41; P = 0.38). We found no evidence of increased risk of subsequent asthma diagnosis among children younger than 3 years of age who received LAIV compared with placebo.
Authors: Baxter RP; Lewis N; Fireman B; Hansen J; Klein NP; Ortiz JR
Pediatr Infect Dis J. 2018 05;37(5):383-386.
Immunogenicity and safety of the quadrivalent meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT) in splenectomized or hyposplenic children and adolescents: Results of a phase III, open, non-randomized study
Individuals with functional or anatomic asplenia are at high risk for meningococcal disease. We evaluated the immunogenicity and safety of 1 and 2 doses of the quadrivalent meningococcal serogroups A, C, W, Y tetanus toxoid-conjugate vaccine (MenACWY-TT) in this high-risk population. This phase III, open-label, controlled, non-randomized study (NCT01641042) enrolled 1-17-year-olds with impaired splenic activity (high-risk group) and age-matched healthy controls (control group). We measured immune responses to MenACWY-TT by serum bactericidal activity assays using rabbit (rSBA) and human (hSBA) complement and in terms of antibodies against polysaccharides of the 4 vaccine serogroups. We evaluated vaccine response rates (VRRs) as 4-fold increases from pre-vaccination levels or titers ≥1:32 (rSBA)/≥1:8 (hSBA). We recorded solicited and unsolicited adverse events (AEs) during 4 and 31 days post-vaccination, and serious AEs (SAEs) and new onset of chronic illnesses (NOCIs) throughout the study. The according-to-protocol cohort for immunogenicity included 40 participants per group. In both groups, the first MenACWY-TT dose induced rSBA VRRs of 92.5-100% and hSBA VRRs of 55.6-77.1% across vaccine serogroups. Following the second MenACWY-TT dose, all participants had high responses, with rSBA and hSBA VRRs of 73.0-100% across vaccine serogroups. rSBA and hSBA geometric mean titers for each serogroup increased in both groups (with different magnitudes, but ≥13.1-fold) compared with baseline levels. Polysaccharide antibody concentrations ≥2.0 μg/ml were detected in ≥84.4% of participants and were similar between groups. Incidences of solicited and unsolicited AEs were comparable between groups. We recorded SAEs in 4/43 participants in the high-risk group and 1/43 participants in the control group (none vaccine-related). No NOCIs were reported. In this descriptive study, MenACWY-TT induced similar functional and humoral immune responses and had a clinically acceptable safety profile in children and adolescents with impaired splenic activity and in healthy controls.
Authors: Klein NP; Habanec T; Kosina P; Shah NR; Kolhe D; Miller JM; Hezareh M; Van der Wielen M
Vaccine. 2018 04 19;36(17):2356-2363. Epub 2018-03-22.
Recent Intrauterine device use and the risk of precancerous cervical lesions and cervical cancer
Understanding the effect of contraceptives on the development of precancerous lesions of the cervix and cervical cancer may provide information that is valuable to women in contraceptive decision-making. The purpose of this study was to evaluate the association between recent intrauterine device (IUD) use (by type) and cervical intraepithelial neoplasia 2, 3, adenocarcinoma in situ or cancer (CIN2+ or CIN3+). Case-control study of 17,559 women age 18-49 with incident CIN2+ cases and 5:1 age-matched, incidence-density selected controls (N=87,378) who were members of Kaiser Permanente Northern California Healthcare System from 1996-2014. Recent IUD use, within 18 months prior to index, was the exposure of interest. We identified 1,657 IUD users among the cases and 7,925 IUD users among controls. After adjusting for sexually transmitted infection testing, smoking, HPV vaccination, hormonal contraceptive use, parity, race and number of outpatient healthcare system visits, IUD use was associated with an increased rate of CIN2+ [rate ratio (RR) 1.12, 95% confidence interval (1.05-1.18), p
Authors: Averbach S; Silverberg MJ; Leyden W; Smith-McCune K; Raine-Bennett T; Sawaya GF
Contraception. 2018 Apr 16.
Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children
Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.
Authors: Hansen J; Zhang L; Eaton A; Baxter R; Robertson CA; Decker MD; Greenberg DP; Bassily E; Klein NP
Vaccine. 2018 04 12;36(16):2133-2138. Epub 2018-03-14.
Multimorbidity Among Persons Living with HIV in the U.S
Age-associated conditions are increasingly common among persons living with human immunodeficiency virus (HIV) (PLWH). A longitudinal investigation of their accrual is needed given their implications on clinical care complexity. We examined trends in the co-occurrence of age-associated conditions among PLWH receiving clinical care, and differences in their prevalence by demographic subgroup. This cohort study was nested within the North American AIDS Cohort Collaboration on Research and Design. Participants from HIV outpatient clinics were antiretroviral therapy-exposed PLWH receiving clinical care (ie, ≥1 CD4 count) in the United States during 2000-2009. Multimorbidity was irreversible, defined as having ≥2: hypertension, diabetes mellitus, chronic kidney disease, hypercholesterolemia, end-stage liver disease, or non-AIDS-related cancer. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) comparing demographic subgroups were obtained by Poisson regression with robust error variance, using generalized estimating equations for repeated measures. Among 22969 adults, 79% were male, 36% were black, and the median baseline age was 40 years (interquartile range, 34-46 years). Between 2000 and 2009, multimorbidity prevalence increased from 8.2% to 22.4% (Ptrend < .001). Adjusting for age, this trend was still significant (P < .001). There was no difference by sex, but blacks were less likely than whites to have multimorbidity (aPR, 0.87; 95% CI, .77-.99). Multimorbidity was the highest among heterosexuals, relative to men who have sex with men (aPR, 1.16; 95% CI, 1.01-1.34). Hypertension and hypercholesterolemia most commonly co-occurred. Multimorbidity prevalence has increased among PLWH. Comorbidity prevention and multisubspecialty management of increasingly complex healthcare needs will be vital to ensuring that they receive needed care.
Authors: Wong C; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
Clin Infect Dis. 2018 04 03;66(8):1230-1238.
Association Between Gender Confirmation Treatments and Perceived Gender Congruence, Body Image Satisfaction, and Mental Health in a Cohort of Transgender Individuals
Transgender individuals sometimes seek gender confirmation treatments (GCT), including hormone therapy (HT) and/or surgical change of the chest and genitalia (“top” and “bottom” gender confirmation surgeries). These treatments may ameliorate distress resulting from the incongruence between one’s physical appearance and gender identity. The aim was to examine the degree to which individuals’ body-gender congruence, body image satisfaction, depression, and anxiety differed by GCT groups in cohorts of transmasculine (TM) and transfeminine (TF) individuals. The Study of Transition, Outcomes, and Gender is a cohort study of transgender individuals recruited from 3 health plans located in Georgia, Northern California, and Southern California; cohort members were recruited to complete a survey between 2015-2017. Participants were asked about: history of GCT; body-gender congruence; body image satisfaction; depression; and anxiety. Participants were categorized as having received: (1) no GCT to date; (2) HT only; (3) top surgery; (4) partial bottom surgery; and (5) definitive bottom surgery. Outcomes of interest included body-gender congruence, body image satisfaction, depression, and anxiety. Of the 2,136 individuals invited to participate, 697 subjects (33%) completed the survey, including 347 TM and 350 TF individuals. The proportion of participants with low body-gender congruence scores was significantly higher in the “no treatment” group (prevalence ratio [PR] = 3.96, 95% CI 2.72-5.75) compared to the definitive bottom surgery group. The PR for depression comparing participants who reported no treatment relative to those who had definitive surgery was 1.94 (95% CI 1.42-2.66); the corresponding PR for anxiety was 4.33 (95% CI 1.83-10.54). Withholding or delaying GCT until depression or anxiety have been treated may not be the optimal treatment course given the benefits of reduced levels of distress after undergoing these interventions. Strengths include the well-defined sampling frame, which allowed correcting for non-response, a sample with approximately equal numbers of TF and TM participants, and the ability to combine data on HT and gender confirmation surgeries. Limitations include the cross-sectional design and the fact that participants may not be representative of the transgender population in the United States. Body-gender congruence and body image satisfaction were higher, and depression and anxiety were lower among individuals who had more extensive GCT compared to those who received less treatment or no treatment at all. Owen-Smith AA, Gerth J, Sineath RC, et al. Association Between Gender Confirmation Treatments and Perceived Gender Congruence, Body Image Satisfaction and Mental Health in a Cohort Of Transgender Individuals. J Sex Med 2018;15:591-600.
Authors: Owen-Smith AA; Hunkeler E; Silverberg MJ; Goodman M; et al.
J Sex Med. 2018 Apr;15(4):591-600. Epub 2018-02-17.
Meningococcal conjugate vaccine safety surveillance in the Vaccine Safety Datalink using a tree-temporal scan data mining method
The objective of our study was to conduct a data mining analysis to identify potential adverse events (AEs) following MENACWY-D using the tree-temporal scan statistic in the Vaccine Safety Datalink population and demonstrate the feasibility of this method in a large distributed safety data setting. Traditional pharmacovigilance techniques used in vaccine safety are generally geared to detecting AEs based on pre-defined sets of conditions or diagnoses. Using a newly developed tree-temporal scan statistic data mining method, we performed a pilot study to evaluate the safety profile of the meningococcal conjugate vaccine Menactra® (MenACWY-D), screening thousands of potential AE diagnoses and diagnosis groupings. The study cohort included enrolled participants in the Vaccine Safety Datalink aged 11 to 18 years who had received MenACWY-D vaccination(s) between 2005 and 2014. The tree-temporal scan statistic was employed to identify statistical associations (signals) of AEs following MENACWY-D at a 0.05 level of significance, adjusted for multiple testing. We detected signals for 2 groups of outcomes: diseases of the skin and subcutaneous tissue, fever, and urticaria. Both groups are known AEs following MENACWY-D vaccination. We also identified a statistical signal for pleurisy, but further examination suggested it was likely a false signal. No new MENACWY-D safety concerns were raised. As a pilot study, we demonstrated that the tree-temporal scan statistic data mining method can be successfully applied to screen broadly for a wide range of vaccine-AE associations within a large health care data network.
Authors: Li R; Weintraub E; McNeil MM; Kulldorff M; Lewis EM; Nelson J; Xu S; Qian L; Klein NP; Destefano F
Pharmacoepidemiol Drug Saf. 2018 04;27(4):391-397. Epub 2018-02-15.
Association Between Estimated Cumulative Vaccine Antigen Exposure Through the First 23 Months of Life and Non-Vaccine-Targeted Infections From 24 Through 47 Months of Age
Some parents are concerned that multiple vaccines in early childhood could weaken their child’s immune system. Biological data suggest that increased vaccine antigen exposure could increase the risk for infections not targeted by vaccines. To examine estimated cumulative vaccine antigen exposure through the first 23 months of life in children with and without non-vaccine-targeted infections from 24 through 47 months of age. A nested case-control study was conducted in 6 US health care organizations participating in the Vaccine Safety Datalink. Cases were identified by International Classification of Diseases codes for infectious diseases in the emergency department and inpatient medical settings and then validated by medical record review. Cases of non-vaccine-targeted infection were matched to controls by age, sex, health care organization site, and chronic disease status. Participants were children ages 24 through 47 months, born between January 1, 2003, and September 31, 2013, followed up until December 31, 2015. Cumulative vaccine antigen exposure, estimated by summing the number of antigens in each vaccine dose received from birth through age 23 months. Non-vaccine-targeted infections, including upper and lower respiratory infections and gastrointestinal infections, from 24 through 47 months of age, and the association between these infections and estimated cumulative vaccine exposure from birth through 23 months. Conditional logistic regression was used to estimate matched odds ratios representing the odds of non-vaccine-targeted infections for every 30-unit increase in estimated cumulative number of antigens received. Among the 944 patients (193 cases and 751 controls), the mean (SD) age was 32.5 (6.3) months, 422 (45%) were female, and 61 (7%) had a complex chronic condition. Through the first 23 months, the estimated mean (SD) cumulative vaccine antigen exposure was 240.6 (48.3) for cases and 242.9 (51.1) for controls. The between-group difference for estimated cumulative antigen exposure was -2.3 (95% CI, -10.1 to 5.4; P = .55). Among children with vs without non-vaccine-targeted infections from 24 through 47 months of age, the matched odds ratio for estimated cumulative antigen exposure through age 23 months was not significant (matched odds ratio, 0.94; 95% CI, 0.84 to 1.07). Among children from 24 through 47 months of age with emergency department and inpatient visits for infectious diseases not targeted by vaccines, compared with children without such visits, there was no significant difference in estimated cumulative vaccine antigen exposure through the first 23 months of life.
Authors: Glanz JM; Zerbo O; et al.
JAMA. 2018 03 06;319(9):906-913.
Infant Hospitalizations and Mortality After Maternal Vaccination
The Advisory Committee on Immunization Practices currently recommends pregnant women receive influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines. There are limited studies of the long-term safety in infants for vaccines administered during pregnancy. We evaluate whether maternal receipt of influenza and Tdap vaccines increases the risk of infant hospitalization or death in the first 6 months of life. We included singleton, live birth pregnancies in the Vaccine Safety Datalink between 2004 and 2014. Outcomes were infant hospitalizations and mortality in the first 6 months of life. We performed a case-control study matching case patients and controls 1:1 and used conditional logistic regression to estimate odds ratios for maternal exposure to influenza and/or Tdap vaccines in pregnancy. There were 413 034 live births in our population. Of these, 25 222 infants had hospitalizations and 157 infants died in the first 6 months of life. We found no association between infant hospitalization and maternal influenza (adjusted odds ratio: 1.00; 95% confidence interval [CI]: 0.96-1.04) or Tdap (adjusted odds ratio: 0.94; 95% CI: 0.88-1.01) vaccinations. We found no association between infant mortality and maternal influenza (adjusted odds ratio: 0.96; 95% CI: 0.54-1.69) or Tdap (adjusted odds ratio: 0.44; 95% CI: 0.17-1.13) vaccinations. We found no association between vaccination during pregnancy and risk of infant hospitalization or death in the first 6 months of life. These findings support the safety of current recommendations for influenza and Tdap vaccination during pregnancy.
Authors: Sukumaran L; Klein NP; Weintraub ES; et al.
Pediatrics. 2018 03;141(3). Epub 2018-02-20.
Cancer burden attributable to cigarette smoking among HIV-infected people in North America
With combination-antiretroviral therapy, HIV-infected individuals live longer with an elevated burden of cancer. Given the high prevalence of smoking among HIV-infected populations, we examined the risk of incident cancers attributable to ever smoking cigarettes. Observational cohort of HIV-infected participants with 270 136 person-years of follow-up in the North American AIDS Cohort Collaboration on Research and Design consortium. Among 52 441 participants, 2306 were diagnosed with cancer during 2000-2015. Estimated hazard ratios and population-attributable fractions (PAF) associated with ever cigarette smoking for all cancers combined, smoking-related cancers, and cancers that were not attributed to smoking. People with cancer were more frequently ever smokers (79%) compared with people without cancer (73%). Adjusting for demographic and clinical factors, cigarette smoking was associated with increased risk of cancer overall [hazard ratios = 1.33 (95% confidence interval: 1.18-1.49)]; smoking-related cancers [hazard ratios = 2.31 (1.80-2.98)]; lung cancer [hazard ratios = 17.80 (5.60-56.63)]; but not nonsmoking-related cancers [hazard ratios = 1.12 (0.98-1.28)]. Adjusted PAFs associated with ever cigarette smoking were as follows: all cancers combined, PAF = 19% (95% confidence interval: 13-25%); smoking-related cancers, PAF = 50% (39-59%); lung cancer, PAF = 94% (82-98%); and nonsmoking-related cancers, PAF = 9% (1-16%). Among HIV-infected persons, approximately one-fifth of all incident cancer, including half of smoking-related cancer, and 94% of lung cancer diagnoses could potentially be prevented by eliminating cigarette smoking. Cigarette smoking could contribute to some cancers that were classified as nonsmoking-related cancers in this report. Enhanced smoking cessation efforts targeted to HIV-infected individuals are needed.
Authors: Altekruse SF; Silverberg MJ; Engels EA; et al.
AIDS. 2018 02 20;32(4):513-521.
Postlicensure Safety Surveillance of Congenital Anomaly and Miscarriage Among Pregnancies Exposed to Quadrivalent Human Papillomavirus Vaccine
Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.
Authors: Sy LS; Klein NP; Jacobsen SJ; et al.
Hum Vaccin Immunother. 2018 02 01;14(2):412-419. Epub 2017-12-14.
Human Immunodeficiency Virus (HIV)- and Non-HIV-Associated Immunosuppression and Risk of Cervical Neoplasia
To estimate the risk of cervical intraepithelial neoplasia grade 2, 2-3, 3, adenocarcinoma in situ, or cancer (CIN 2 or worse) among women with human immunodeficiency virus (HIV)- and non-HIV-associated immunosuppression. We performed a case-control study of 20,146 women with incident CIN 2 or worse and 5:1 age-matched, incidence-density selected women in a control group (n=100,144) enrolled in an integrated health care system from 1996 to 2014. Adjusted rate ratios (RRs) from conditional logistic regression were obtained for HIV status (stratified by CD4 T-cells), solid organ transplant history, and immunosuppressive medication use. Risk of CIN 2 or worse was increased among women with HIV (n=36 women in the case group and 79 women in the control group; adjusted RR 2.0, 95% CI 1.3-3.0) compared with those without HIV and in solid organ transplant recipients (n=51 women in the case group and 68 women in the control group; RR 3.3, 95% CI 2.3-4.8) compared with women without a prior transplant. The highest risks were among women with HIV and less than 200 CD4 T-cells/microliter (n=9 women in the case group and eight women in the control group; RR 5.6, 95% CI 2.1-14.7) compared with those without HIV and in solid organ transplant recipients prescribed three or greater immunosuppressive medication classes (n=32 women in the case group and 33 women in the control group; RR 4.1, 95% CI 2.5-6.8) compared with women without a prior transplant and zero medication classes. No increased risks were observed for women with HIV and 500 or greater CD4 T-cells/microliter (n=9 women in the case group and 43 women in the control group; RR 0.8, 95% CI 0.4-1.7) compared with those without HIV or women without prior solid organ transplantation prescribed two or fewer immunosuppressive medication classes (n=1,262 women in the case group and 6,100 women in the control group; RR 0.95, 95% CI 0.89-1.01) compared with women without and a prior transplant and zero medication classes. Risk of CIN 2 or worse is increased in women with a prior solid organ transplant or who have HIV and CD4 cells/microliter less than 500 but not in women with HIV and higher CD4 levels or in women without a prior solid organ transplant but who are prescribed only one or two immunosuppressive medication classes.
Authors: Silverberg MJ; Leyden WA; Chi A; Gregorich S; Huchko MJ; Kulasingam S; Kuppermann M; Seto A; Smith-McCune KK; Sawaya GF
Obstet Gynecol. 2018 Jan;131(1):47-55.
Long-Term Effectiveness of the Live Zoster Vaccine in Preventing Shingles: A Cohort Study
A live attenuated zoster vaccine was licensed in the United States in 2006 for prevention of shingles in persons aged 60 years or older; the indication was extended in 2011 to cover those aged 50-59 years. We assessed vaccine effectiveness (VE) against shingles for 8 years after immunization at Kaiser Permanente Northern California. VE was estimated by Cox regression with a calendar timeline that was stratified by birth year. We adjusted for demographics and time-varying covariates, including comorbidities and immune compromise. From 2007 to 2014, 1.4 million people entered the study when they became age eligible for vaccination; 392,677 (29%) received the zoster vaccine. During 5.8 million person-years of follow-up, 48,889 cases of shingles were observed, including 5,766 among vaccinees. VE was 49.1% (95% confidence interval (CI): 47.5, 50.6) across all follow-up. VE was 67.5% (95% CI: 65.4, 69.5) during the first year after vaccination, waned to 47.2% (95% CI: 44.1, 50.1) during the second year after vaccination, and then waned more gradually through year 8, when VE was 31.8% (95% CI: 15.1, 45.2). Unexpectedly, VE in persons vaccinated when they were aged 80 years or older was similar to VE in younger vaccinees, and VE in persons vaccinated when immune compromised was similar to VE in persons vaccinated when immune competent.
Authors: Baxter R; Bartlett J; Fireman B; Marks M; Hansen J; Lewis E; Aukes L; Chen Y; Klein NP; Saddier P
Am J Epidemiol. 2018 01 01;187(1):161-169.
The safety of live attenuated influenza vaccine in children and adolescents 2 through 17years of age: A Vaccine Safety Datalink study
To evaluate the safety of live attenuated influenza vaccine (LAIV) in children 2 through 17 years of age. The study was conducted in 6 large integrated health care organizations participating in the Vaccine Safety Datalink (VSD). Trivalent LAIV safety was assessed in children who received LAIV between September 1, 2003 and March 31, 2013. Eighteen pre-specified adverse event groups were studied, including allergic, autoimmune, neurologic, respiratory, and infectious conditions. Incident rate ratios (IRRs) were calculated for each adverse event, using self-controlled case series analyses. For adverse events with a statistically significant increase in risk, or an IRR > 2.0 regardless of statistical significance, manual medical record review was performed to confirm case status. During the study period, 396 173 children received 590 018 doses of LAIV. For 13 adverse event groups, there was no significant increased risk of adverse events following LAIV. Five adverse event groups (anaphylaxis, syncope, Stevens-Johnson syndrome, adverse effect of drug, and respiratory failure) met criteria for manual medical record review. After review to confirm cases, 2 adverse event groups remained significantly associated with LAIV: anaphylaxis and syncope. One confirmed case of anaphylaxis was observed following LAIV, a rate of 1.7 per million LAIV doses. Five confirmed cases of syncope were observed, a rate of 8.5 per million doses. In a study of trivalent LAIV safety in a large cohort of children, few serious adverse events were detected. Anaphylaxis and syncope occurred following LAIV, although rarely. These data provide reassurance regarding continued LAIV use.
Authors: Daley MF; Klein NP; Weintraub E; et al.
Pharmacoepidemiol Drug Saf. 2018 01;27(1):59-68. Epub 2017-11-17.
Cohort profile: Study of Transition, Outcomes and Gender (STRONG) to assess health status of transgender people
The Study of Transition, Outcomes and Gender (STRONG) was initiated to assess the health status of transgender people in general and following gender-affirming treatments at Kaiser Permanente health plans in Georgia, Northern California and Southern California. The objectives of this communication are to describe methods of cohort ascertainment and data collection and to characterise the study population. A stepwise methodology involving computerised searches of electronic medical records and free-text validation of eligibility and gender identity was used to identify a cohort of 6456 members with first evidence of transgender status (index date) between 2006 and 2014. The cohort included 3475 (54%) transfeminine (TF), 2892 (45%) transmasculine (TM) and 89 (1%) members whose natal sex and gender identity remained undetermined from the records. The cohort was matched to 127 608 enrollees with no transgender evidence (63 825 women and 63 783 men) on year of birth, race/ethnicity, study site and membership year of the index date. Cohort follow-up extends through the end of 2016. About 58% of TF and 52% of TM cohort members received hormonal therapy at Kaiser Permanente. Chest surgery was more common among TM participants (12% vs 0.3%). The proportions of transgender participants who underwent genital reconstruction surgeries were similar (4%-5%) in the two transgender groups. Results indicate that there are sufficient numbers of events in the TF and TM cohorts to further examine mental health status, cardiovascular events, diabetes, HIV and most common cancers. STRONG is well positioned to fill existing knowledge gaps through comparisons of transgender and reference populations and through analyses of health status before and after gender affirmation treatment. Analyses will include incidence of cardiovascular disease, mental health, HIV and diabetes, as well as changes in laboratory-based endpoints (eg, polycythemia and bone density), overall and in relation to gender affirmation therapy.
Authors: Quinn VP; Hunkeler E; Silverberg MJ; Goodman M; et al.
BMJ Open. 2017 12 27;7(12):e018121. Epub 2017-12-27.
Rates and risk factors associated with hospitalization for pneumonia with ICU admission among adults
Pneumonia poses a significant burden to the U.S. health-care system. However, there are few data focusing on severe pneumonia, particularly cases of pneumonia associated with specialized care in intensive care units (ICU). We used administrative and electronic medical record data from six integrated health care systems to estimate rates of pneumonia hospitalizations with ICU admissions among adults during 2006 through 2010. Pneumonia hospitalization was defined as either a primary discharge diagnosis of pneumonia or a primary discharge diagnosis of sepsis or respiratory failure with a secondary diagnosis of pneumonia in administrative data. ICU admissions were collected from internal electronic medical records from each system. Comorbidities were identified by ICD-9-CM codes coded during the current pneumonia hospitalization, as well as during medical visits that occurred during the year prior to the date of admission. We identified 119,537 adult hospitalizations meeting our definition for pneumonia. Approximately 19% of adult pneumonia hospitalizations had an ICU admission. The rate of pneumonia hospitalizations requiring ICU admission during the study period was 76 per 100,000 population/year; rates increased for each age-group with the highest rates among adults aged ≥85 years. Having a co-morbidity approximately doubled the risk of ICU admission in all age-groups. Our study indicates a significant burden of pneumonia hospitalizations with an ICU admission among adults in our cohort during 2006 through 2010, especially older age-groups and persons with underlying medical conditions. These findings reinforce current strategies aimed to prevent pneumonia among adults.
Authors: Storms AD; Chen J; Jackson LA; Nordin JD; Naleway AL; Glanz JM; Jacobsen SJ; Weintraub ES; Klein NP; Gargiullo PM; Fry AM
BMC Pulm Med. 2017 Dec 16;17(1):208. Epub 2017-12-16.
Congenital microcephaly: Case definition & guidelines for data collection, analysis, and presentation of safety data after maternal immunisation
Authors: DeSilva M; Oleske JM; Brighton Collaboration Congenital Microcephaly Working Group; et al.
Vaccine. 2017 12 04;35(48 Pt A):6472-6482.
Respiratory distress in the neonate: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data
Authors: Sweet LR; Klein NP; Brighton Collaboration Respiratory Distress in the Neonate Working Group; et al.
Vaccine. 2017 12 04;35(48 Pt A):6506-6517.
Patterns of childhood immunization and all-cause mortality
Evidence supports the safety of the recommended childhood immunization schedule as a whole. However, additional research is warranted as parents’ refusing or delaying vaccinations has increased in recent years. All-cause mortality has been identified as a priority outcome to study in the context of the recommended immunization schedule. We included children born January 1, 2004 through December 31, 2009, enrolled in the Vaccine Safety Datalink (VSD) from birth through 18 months of age. We examined vaccination patterns during the first 18 months of life among 8 vaccines, and identified deaths occurring between 19 and 48 months of age. We excluded children with complex chronic conditions, contraindications to vaccination, and deaths due to injuries, congenital anomalies, or diseases with onset prior to 19 months of age. We calculated mortality rates among children with different patterns of immunization, and incidence rate ratios (IRR) using the Cox proportional hazards model for children vaccinated according to the schedule versus undervaccinated children, adjusting for outpatient healthcare utilization, influenza vaccination, sex, and VSD site. Among 312,388 children in the study, 199,661 (64%) were vaccinated according to the schedule, and 112,727 (36%) were delayed or not vaccinated for at least one vaccine dose. Of 18 deaths eligible for analysis, 11 occurred in children following the schedule (2.28 per 100,000 person-years), and seven occurred in undervaccinated children (2.57 per 100,000 person-years). Mortality rates among children following the schedule were not significantly different from those of undervaccinated children when excluding deaths with unknown causes (IRR = 1.29, 95% CI = 0.33-4.99), as well as when including deaths with unknown causes (IRR = 0.84, 95% CI = 0.32-2.99). Although there were few deaths, our results do not indicate a difference in risk of all-cause mortality among fully vaccinated versus undervaccinated children. Our findings support the safety of the currently recommended immunization schedule with regard to all-cause mortality.
Authors: McCarthy NL; Sukumaran L; Newcomer S; Glanz J; Daley MF; McClure D; Klein NP; Irving S; Jackson ML; Lewin B; Weintraub E
Vaccine. 2017 12 04;35(48 Pt B):6643-6648. Epub 2017-10-20.
Use of acellular pertussis vaccines in the United States: can we do better?
Despite robust vaccination schedules and high vaccination rates, many countries, including the U.S., have seen large pertussis outbreaks with a shift in recent years in the distribution of disease burden towards adolescents and young adults. Areas covered: This perspective covers problems related to the increased incidence of pertussis among adolescents. Because the Tdap vaccine only protects against pertussis for 1-2 years after vaccination, we propose a new strategy which aims to optimize the benefit of Tdap in adolescents. Expert commentary: Current pertussis vaccination schedules are based on age and have not been effective at protecting adolescents and teenagers from pertussis outbreaks. An alternative to the current practice would be to take advantage of the cyclical nature of pertussis outbreaks. Rather than immunizing children and adolescent solely based on age regardless of risk of pertussis at that moment, perhaps we should consider a ‘timed’ Tdap. The goal would be to administer Tdap to susceptible adolescents and young adults during periods when there is a greater risk of being exposed to pertussis. This approach would optimize the use of an effective, but short-lived vaccine by maximizing protection at the time of increased risk.
Authors: Klein NP; Zerbo O
Expert Rev Vaccines. 2017 12;16(12):1175-1179. Epub 2017-10-20.
Redefining HIV Preexposure Prophylaxis Failures
Authors: Marcus JL; Hurley LB; Nguyen DP; Silverberg MJ; Volk JE
Clin Infect Dis. 2017 10 30;65(10):1768-1769.
Risk of venous thromboembolism following influenza vaccination in adults aged 50years and older in the Vaccine Safety Datalink
Influenza-like illness and inflammation are known risk factors for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have characterized the risk of VTE following influenza vaccination. We examined VTE risk after vaccination in adults 50years old and older within the Vaccine Safety Datalink (VSD). We used the self-controlled case series method to determine the risk of VTE among age-eligible adults who received influenza vaccine (with or without pandemic H1N1) and experienced a VTE during the months of September through December in 2007 through 2012. Presumptive VTE cases were identified among VSD participants using diagnostic codes, diagnostic tests, and oral anticoagulant prescription. Potential cases were validated by medical record review. The VTE incidence rate ratio was calculated among confirmed cases for the risk window 1 to 10days after vaccination relative to all other person-time from September through December. Of the 1,488 presumptive cases identified, 508 were reviewed, of which 492 (97%) were confirmed cases of VTE. The analysis included 396 incident, confirmed cases. Overall, there was no increased risk of VTE in the 1 to 10days after influenza vaccination (IRR=0.89, 95% CI 0.69-1.17) compared to the control period. Results were similar when all person-time was censored before vaccination. A post hoc analysis showed an increased risk among current tobacco smokers (IRR=2.57, 95% CI 1.06-6.23). No clustering of VTE was observed in the 1-42days after vaccination. Overall, there was no evidence that inactivated influenza vaccine was associated with VTE in adults ≥50years old. An increased risk was found among current smokers in a post hoc analysis. These findings are consistent with previous research and support the safety of annual vaccination in this population.
Authors: Vickers ER; McClure DL; Naleway AL; Jacobsen SJ; Klein NP; Glanz JM; Weintraub ES; Belongia EA
Vaccine. 2017 Oct 13;35(43):5872-5877. Epub 2017-09-06.
Latent tuberculous infection testing among HIV-infected persons in clinical care, United States, 2010-2012.
SETTING: Current guidelines recommend latent tuberculous infection (LTBI) testing at the time of human immunodeficiency virus (HIV) diagnosis and annually thereafter for persons at high risk of LTBI. OBJECTIVES: To estimate LTBI testing prevalence and describe the characteristics of HIV-infected persons who would benefit from annual LTBI testing. DESIGN: We estimated the proportions of LTBI testing among a nationally representative sample of HIV-infected adults in care between 2010 and 2012, and compared the patient characteristics of those with a positive LTBI test result to those with a negative result using chi2 tests. RESULTS: Among 2772 patients, 68.8% had been tested for LTBI at least once since HIV diagnosis, and 39.4% had been tested during the previous 12 months. Among patients tested at least once, 6.9% tested positive, 80.7% tested negative, and 12.4% had an indeterminate or undocumented result. Patients with a positive test were significantly more likely to be foreign-born, have lower educational attainment, and a household income at or below the federal poverty level. CONCLUSIONS: More than 30% of HIV-infected patients had never been tested for LTBI. Providers should test all patients for LTBI at the time of HIV diagnosis. The patient characteristics associated with a positive LTBI test result may guide provider decisions about annual testing.
Authors: Reaves EJ; Shah NS; France AM; Morris SB; Kammerer S; Skarbinski J; Bradley H
Int J Tuberc Lung Dis. 2017 Oct 1;21(10):1118-1126. doi: 10.5588/ijtld.17.0041.
Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12
Inactivated influenza vaccine is recommended in any stage of pregnancy, but evidence of safety in early pregnancy is limited, including for vaccines containing A/H1N1pdm2009 (pH1N1) antigen. We sought to determine if receipt of vaccine containing pH1N1 was associated with spontaneous abortion (SAB). We conducted a case-control study over two influenza seasons (2010-11, 2011-12) in the Vaccine Safety Datalink. Cases had SAB and controls had live births or stillbirths and were matched on site, date of last menstrual period, and age. Of 919 potential cases identified using diagnosis codes, 485 were eligible and confirmed by medical record review. Exposure was defined as vaccination with inactivated influenza vaccine before the SAB date; the primary exposure window was the 1-28days before the SAB. The overall adjusted odds ratio (aOR) was 2.0 (95% CI, 1.1-3.6) for vaccine receipt in the 28-day exposure window; there was no association in other exposure windows. In season-specific analyses, the aOR in the 1-28days was 3.7 (95% CI 1.4-9.4) in 2010-11 and 1.4 (95% CI 0.6-3.3) in 2011-12. The association was modified by influenza vaccination in the prior season (post hoc analysis). Among women who received pH1N1-containing vaccine in the previous influenza season, the aOR in the 1-28days was 7.7 (95% CI 2.2-27.3); the aOR was 1.3 (95% CI 0.7-2.7) among women not vaccinated in the previous season. This effect modification was observed in each season. SAB was associated with influenza vaccination in the preceding 28days. The association was significant only among women vaccinated in the previous influenza season with pH1N1-containing vaccine. This study does not and cannot establish a causal relationship between repeated influenza vaccination and SAB, but further research is warranted.
Authors: Donahue JG; Klein NP; Belongia EA; et al.
Vaccine. 2017 Sep 25;35(40):5314-5322.
Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine
Menactra� vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell’s palsy, seizures, neuritis, Guillain-Barr� syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.
Authors: Hansen J; Zhang L; Klein NP; Robertson CA; Decker MD; Greenberg DP; Bassily E; Baxter R
Vaccine. 2017 Sep 20.
Maternal and Infant Outcomes After Human Papillomavirus Vaccination in the Periconceptional Period or During Pregnancy
To evaluate whether quadrivalent human papillomavirus vaccine (4vHPV) administered during the periconceptional period or during pregnancy was associated with increased risks for adverse obstetric events, adverse birth outcomes, or selected major structural birth defects. We conducted a retrospective, observational cohort study using administrative and health care data from the Vaccine Safety Datalink. Insured women 13-27 years old with singleton pregnancies and a live birth from January 1, 2007, through September 1, 2013, who received 4vHPV during the periconceptional period (2 weeks before to 2 weeks after their last menstrual period), during pregnancy, or during both periods combined were compared with women who had a live birth during the same time period and received 4vHPV 4-18 months before their last menstrual period. We examined risks of gestational diabetes, hypertensive disorders of pregnancy, chorioamnionitis, preterm birth, small-for-gestational-age birth, and selected major structural birth defects in offspring. We estimated relative risks associated with receipt of 4vHPV during the periconceptional period, during pregnancy, and both exposure periods combined using a generalized linear model with Poisson distribution including a propensity score that included relevant maternal demographic and pregnancy characteristics. Of 92,579 potentially eligible pregnant women, 720 received 4vHPV during the periconceptional period, 638 received 4vHPV during pregnancy, and 8,196 received 4vHPV during the comparison period. Administration of 4vHPV during pregnancy was not associated with increased risk of adverse obstetric events, birth outcomes. Preterm birth occurred in 7.9% of pregnancies with vaccine exposures during pregnancy compared with 7.6% of pregnancies with vaccination in the comparison period (adjusted relative risk 0.97, 95% CI 0.72-1.3). Major structural birth defects were diagnosed in 2.0% of pregnancies with vaccine exposure during pregnancy compared with 1.8% of pregnancies with vaccine exposure during the comparison period (adjusted prevalence ratio 1.0, 95% CI 0.52-1.9). Results were similar for 4vHPV exposure during the periconceptional period. Quadrivalent HPV vaccine inadvertently administered in pregnancy or during the periconceptional period was not associated with adverse pregnancy or birth outcomes.
Authors: Lipkind HS; Klein NP; Kharbanda EO; et al.
Obstet Gynecol. 2017 Sep;130(3):599-608.
Association of Multiple Primary Skin Cancers With Human Immunodeficiency Virus Infection, CD4 Count, and Viral Load
Persons with human immunodeficiency virus (HIV) have a 2.8-fold higher risk than HIV-uninfected persons of nonmelanoma skin cancer (NMSC), defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Individuals with a prior NMSC history are at increased risk for subsequent NMSC, but the magnitude of risk and its relation to HIV disease-related factors, including CD4 count and viral load (VL), are unknown. To better understand how laboratory markers currently used to evaluate HIV disease progression may be associated with subsequent NMSC risk. This cohort study analyzed 455 HIV-infected and 1945 HIV-uninfected patients, all of them members of the Kaiser Permanente Northern California (KPNC) health care plan, diagnosed with at least 1 NMSC from 1996-2008 to determine risk of subsequent NMSCs in relation to CD4 count and VL. All participants were white, non-Hispanic persons 18 years or older who had had at least 1 NMSC during the 1996-2008 period. Participants entered the cohort at their first NMSC diagnosis and were observed through 2008. Incidence rates were calculated and adjusted hazard ratios were estimated using extended Cox regression models with recent CD4 count and VL analyzed as time-changing covariates. Measured CD4 count, VL, and subsequent NMSC (BCC and SCC). The cohort comprised 455 HIV-infected participants (13 [3%] women) and 1952 HIV-uninfected participants (154 [8%] women). Median duration of observation was 4.6 years, and 16.5% (n = 390) either died (n = 35) or lost KPNC membership status (n = 355) without having a subsequent primary NMSC. Compared with HIV-uninfected persons, HIV-infected individuals were slightly younger (mean age, 52.5 vs 55.5 years), more likely men (97% vs 92%), more likely to have smoked (57% vs 45%), and less likely to be overweight/obese (50% vs 61%). The small observed differences by HIV status in matching characteristics (ie, age and sex) resulted from the restriction of the original cohort to those with at least 1 NMSC. Compared with uninfected individuals, those with HIV infection with a recent biomarker of more severe immune deficiency (CD4 count <200 cells/mL) had a 44% increased risk of subsequent NMSC overall and a 222% increase risk of SCC in particular, suggesting that subsequent SCC risk is associated with immune dysfunction. HIV-infected persons compared with HIV-uninfected persons were are at higher risk for subsequent new SCC but not BCC, with a dose-response relationship between risk and lower CD4 counts and higher VLs. Subsequent new primary SCCs had a strong association with lower CD4 and higher VL among HIV-infected persons, suggesting that immune dysfunction might contribute to increased SCC risk. Clinical implications include targeted monitoring for SCC among HIV-infected individuals, particularly those with low CD4 counts or high VLs.
Authors: Asgari MM; Ray GT; Quesenberry CP; Katz KA; Silverberg MJ
JAMA Dermatol. 2017 Sep 01;153(9):892-896.
Febrile Seizure Risk after Vaccination in Children One to Five Months of Age
The risk of febrile seizure is temporarily increased for a few days after the administration of certain vaccines in children aged six to 23 months. Our objective was to determine the febrile seizure risk following vaccination in children aged one to five months, when six different vaccines are typically administered. We identified emergency department visits and inpatient admissions with International Classification of Diseases, Ninth Revision, febrile seizure codes among children enrolled in nine Vaccine Safety Datalink participating health care organizations from 2006 through 2011. Febrile seizures were confirmed by medical record abstraction. We used the self-controlled risk-interval method to compare the incidence of febrile seizure during postvaccination days 0 to 1 (risk interval) versus days 14 to 20 (control interval). We identified 15 febrile seizure cases that occurred after 585,342 vaccination visits. The case patients were aged three to five months. The patients had received a median of four (range two to six) vaccines simultaneously. The incidence rate ratio of febrile seizure after vaccination was 23 (95% confidence interval 5.13 to 100.8), and the attributable risk was 3.92 (95% confidence interval 1.68 to 6.17) febrile seizure cases per 100,000 persons vaccinated. Vaccination in children aged three to five months was associated with a large relative risk of febrile seizure on the day of and the day after vaccination, but the risk was small in absolute terms. Postvaccination febrile seizure should not be a concern for the vast majority of children receiving vaccines, but clinicians might take this risk into consideration when evaluating and treating children susceptible to seizures precipitated by fever.
Authors: Duffy J; Hambidge SJ; Jackson LA; Kharbanda EO; Klein NP; Naleway A; Omer SB; Weintraub E; Vaccine Safety Datalink
Pediatr Neurol. 2017 Aug 23.
Cancer-Attributable Mortality Among People With Treated Human Immunodeficiency Virus Infection in North America
Cancer remains an important cause of morbidity and mortality in people with human immunodeficiency virus (PWHIV) on effective antiretroviral therapy (ART). Estimates of cancer-attributable mortality can inform public health efforts. We evaluated 46956 PWHIV receiving ART in North American HIV cohorts (1995-2009). Using information on incident cancers and deaths, we calculated population-attributable fractions (PAFs), estimating the proportion of deaths due to cancer. Calculations were based on proportional hazards models adjusted for age, sex, race, HIV risk group, calendar year, cohort, CD4 count, and viral load. There were 1997 incident cancers and 8956 deaths during 267145 person-years of follow-up, and 11.9% of decedents had a prior cancer. An estimated 9.8% of deaths were attributable to cancer (cancer-attributable mortality rate 327 per 100000 person-years). PAFs were 2.6% for AIDS-defining cancers (ADCs, including non-Hodgkin lymphoma, 2.0% of deaths) and 7.1% for non-AIDS-defining cancers (NADCs: lung cancer, 2.3%; liver cancer, 0.9%). PAFs for NADCs were higher in males and increased strongly with age, reaching 12.5% in PWHIV aged 55+ years. Mortality rates attributable to ADCs and NADCs were highest for PWHIV with CD4 counts <100 cells/mm3. PAFs for NADCs increased during 1995-2009, reaching 10.1% in 2006-2009. Approximately 10% of deaths in PWHIV prescribed ART during 1995-2009 were attributable to cancer, but this fraction increased over time. A large proportion of cancer-attributable deaths were associated with non-Hodgkin lymphoma, lung cancer, and liver cancer. Deaths due to NADCs will likely grow in importance as AIDS mortality declines and PWHIV age.
Authors: Engels EA; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; et al.
Clin Infect Dis. 2017 Aug 15;65(4):636-643.
A Flow-Based Model of the HIV Care Continuum in the United States
Understanding the flow of patients through the continuum of HIV care is critical to determine how best to intervene so that the proportion of HIV-infected persons who are on antiretroviral treatment and virally suppressed is as large as possible. Using immunological and virological data from the Centers for Disease Control and Prevention and the North American AIDS Cohort Collaboration on Research and Design from 2009 to 2012, we estimated the distribution of time spent in and dropout probability from each stage in the continuum of HIV care. We used these estimates to develop a queueing model for the expected number of patients found in each stage of the cascade. HIV-infected individuals spend an average of about 3.1 months after HIV diagnosis before being linked to care, or dropping out of that stage of the continuum with a probability of 8%. Those who link to care wait an additional 3.7 months on average before getting their second set of laboratory results (indicating engagement in care) or dropping out of care with probability of almost 6%. Those engaged in care spent an average of almost 1 year before achieving viral suppression on antiretroviral therapy or dropping out with average probability 13%. For patients who achieved viral suppression, the average time suppressed on antiretroviral therapy was an average of 4.5 years. Interventions should be targeted to more rapidly identifying newly infected individuals, and increasing the fraction of those engaged in care that achieves viral suppression.
Authors: Gonsalves GS; Silverberg MJ; Kaplan EH; et al.
J Acquir Immune Defic Syndr. 2017 Aug 15;75(5):548-553.
Increased Risk of Myocardial Infarction in HIV-Infected Individuals in North America Compared to the General Population
Previous studies of cardiovascular disease (CVD) among HIV-infected individuals have been limited by the inability to validate and differentiate atherosclerotic type 1 myocardial infarctions (T1MIs) from other events. We sought to define the incidence of T1MIs and risk attributable to traditional and HIV-specific factors among participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and compare adjusted incidence rates (IRs) to the general population Atherosclerosis Risk in Communities (ARIC) cohort. We ascertained and adjudicated incident MIs among individuals enrolled in 7 NA-ACCORD cohorts between 1995 and 2014. We calculated IRs, adjusted incidence rate ratios (aIRRs), and 95% confidence intervals of risk factors for T1MI using Poisson regression. We compared aIRRs of T1MIs in NA-ACCORD with those from ARIC. Among 29,169 HIV-infected individuals, the IR for T1MIs was 2.57 (2.30 to 2.86) per 1000 person-years, and the aIRR was significantly higher compared with participants in ARIC [1.30 (1.09 to 1.56)]. In multivariable analysis restricted to HIV-infected individuals and including traditional CVD risk factors, the rate of T1MI increased with decreasing CD4 count [≥500 cells/μL: ref; 350-499 cells/μL: aIRR = 1.32 (0.98 to 1.77); 200-349 cells/μL: aIRR = 1.37 (1.01 to 1.86); 100-199 cells/μL: aIRR = 1.60 (1.09 to 2.34); <100 cells/μL: aIRR = 2.19 (1.44 to 3.33)]. Risk associated with detectable HIV RNA [<400 copies/mL: ref; ≥400 copies/mL: aIRR = 1.36 (1.06 to 1.75)] was significantly increased only when CD4 was excluded. The higher incidence of T1MI in HIV-infected individuals and increased risk associated with lower CD4 count and detectable HIV RNA suggest that early suppressive antiretroviral treatment and aggressive management of traditional CVD risk factors are necessary to maximally reduce MI risk.
Authors: Drozd DR; Silverberg MJ; Crane HM; et al.
J Acquir Immune Defic Syndr. 2017 Aug 15;75(5):568-576.
First Trimester Influenza Vaccination and Risks for Major Structural Birth Defects in Offspring
To examine risks for major structural birth defects in infants after first trimester inactivated influenza vaccine (IIV) exposures. In this observational study, we used electronic health data from 7 Vaccine Safety Datalink sites to examine risks for selected major structural defects in infants after maternal IIV exposure. Vaccine exposures for women with continuous insurance enrollment through pregnancy who delivered singleton live births between 2004 and 2013 were identified from standardized files. Infants with continuous insurance enrollment were followed to 1 year of age. We excluded mother-infant pairs with other exposures that potentially increased their background risk for birth defects. Selected cardiac, orofacial or respiratory, neurologic, ophthalmologic or otologic, gastrointestinal, genitourinary and muscular or limb defects were identified from diagnostic codes in infant medical records using validated algorithms. Propensity score adjusted generalized estimating equations were used to estimate prevalence ratios (PRs). We identified 52 856 infants with maternal first trimester IIV exposure and 373 088 infants whose mothers were unexposed to IIV during first trimester. Prevalence (per 100 live births) for selected major structural birth defects was 1.6 among first trimester IIV exposed versus 1.5 among unexposed mothers. The adjusted PR was 1.02 (95% CI 0.94-1.10). Organ system-specific PRs were similar to the overall PR. First trimester maternal IIV exposure was not associated with an increased risk for selected major structural birth defects in this large cohort of singleton live births.
Authors: Kharbanda EO; Klein NP; Vaccine Safety Datalink; et al.
J Pediatr. 2017 Aug;187:234-239.e4. Epub 2017-05-24.
Prevalence of Drug-Resistant Minority Variants in Untreated HIV-1-Infected Individuals With and Those Without Transmitted Drug Resistance Detected by Sanger Sequencing
Minority variant human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations are associated with an increased risk of virological failure during treatment with NNRTI-containing regimens. To determine whether individuals to whom variants with isolated NNRTI-associated drug resistance were transmitted are at increased risk of virological failure during treatment with a non-NNRTI-containing regimen, we identified minority variant resistance mutations in 33 individuals with isolated NNRTI-associated transmitted drug resistance and 49 matched controls. We found similar proportions of overall and nucleoside reverse transcriptase inhibitor-associated minority variant resistance mutations in both groups, suggesting that isolated NNRTI-associated transmitted drug resistance may not be a risk factor for virological failure during treatment with a non-NNRTI-containing regimen.
Authors: Clutter DS; Silverberg MJ; Shafer RW; et al.
J Infect Dis. 2017 Aug 01;216(3):387-391.
Cohort study of cancer risk among insured transgender people
Authors: Silverberg MJ; Hunkeler E; Goodman M; et al.
Ann Epidemiol. 2017 08;27(8):499-501. Epub 2017-07-22.
Risk Perception, Sexual Behaviors, and PrEP Adherence Among Substance-Using Men Who Have Sex with Men: a Qualitative Study
The antiretroviral drug combination emtricitabine and tenofovir disoproxil fumarate (TDF/FTC) taken as pre-exposure prophylaxis (PrEP) is effective in preventing HIV infection, yet it also requires adherence and potentially decreases condom use. This study sought to examine these issues among a key population at risk of HIV infection, substance-using men who have sex with men (MSM). We conducted semi-structured interviews with an ethnically diverse sample of 30 young (aged 20-35) MSM prescribed PrEP within a large integrated healthcare system in San Francisco, who had reported recent drug use or hazardous drinking and one or more missed doses of PrEP. We explored participants’ risk perception and sexual risk behavior, drug and alcohol use, and PrEP adherence in the context of substance use. Interviews were transcribed and coded using a directed content analysis approach to identify key categories and commonalities, and differences across participants. Salient subcategories included positive psychological effects of being on PrEP (e.g., decreased anxiety, feelings of empowerment), social effects (e.g., reduced HIV stigma), and reduction in overall perceptions of HIV risk. While overall reported use of condoms went down and many reported a brief period of increased condomless sex following PrEP initiation, others continued condom use with most of their sexual partners. Contextual factors influencing their decision to engage in condomless sex included how well they knew the partner and whether the partner was on PrEP or HIV antiretroviral treatment. Factors associated with poor adherence included disruptions in daily routine and use of alcohol and methamphetamine. PrEP-prescribing clinicians should support their patients in making informed decisions about condom use and identifying strategies to maximize adherence in the context of substance use.
Authors: Storholm ED; Volk JE; Marcus JL; Silverberg MJ; Satre DD
Prev Sci. 2017 Aug;18(6):737-747.
Associations of CD4+ T-cell count, HIV-1 RNA viral load, and antiretroviral therapy with Kaposi sarcoma risk among HIV-infected persons in the United States and Canada
Kaposi sarcoma (KS) remains common among HIV-infected persons. To better understand KS etiology and to help target prevention efforts, we comprehensively examined a variety of CD4 T-cell count and HIV-1 RNA viral load (VL) measures, as well as antiretroviral therapy (ART) use, to determine independent predictors of KS risk. North American AIDS Cohort Collaboration on Research and Design. We followed HIV-infected persons during 1996-2009 from 18 cohorts. We used time-updated Cox regression to model relationships between KS risk and recent, lagged, trajectory, and cumulative CD4 count or VL measures, as well as ART use. We used Akaike’s information criterion and global P values to derive a final model. In separate models, the relationship between each measure and KS risk was highly significant (P < 0.0001). Our final mutually adjusted model included recent CD4 count [hazard ratio (HR) for <50 vs. ≥500 cells/μL = 12.4; 95% confidence interval (CI): 6.5 to 23.8], recent VL (HR for ≥100,000 vs. ≤500 copies/mL = 3.8; 95% CI: 2.0 to 7.3), and cumulative (time-weighted mean) VL (HR for ≥100,000 vs. ≤500 copies/mL = 2.5; 95% CI: 1.0 to 5.9). Each P-trend was <0.0001. After adjusting for these measures, we did not detect an independent association between ART use and KS risk. Our results suggested a multifactorial etiology for KS, with early and late phases of development. The cumulative VL effect suggested that controlling HIV replication promptly after HIV diagnosis is important for KS prevention. We observed no evidence for direct anti-KS activity of ART, independent of CD4 count and VL.
Authors: Dubrow R; Neugebauer RS; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; et al.
J Acquir Immune Defic Syndr. 2017 Aug 01;75(4):382-390.
Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors
New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load <400 copies/mL, and CD4+ count ≥500 cells/μL, the 9-year cumulative incidence of ESRD was higher than that of their HIV-negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV-positive individuals with no comorbidities and well-controlled disease may be considered low-risk kidney donor candidates.
Authors: Muzaale AD; Silverberg MJ; Segev DL; et al.
Am J Transplant. 2017 Jul;17(7):1823-1832. Epub 2017-05-12.
Maternal Tdap vaccination and risk of infant morbidity
An increased risk of diagnosed chorioamnionitis in women vaccinated with Tdap during pregnancy was previously detected at two Vaccine Safety Datalink (VSD) sites. The clinical significance of this finding related to infant outcomes remains uncertain. Retrospective cohort study of singleton live births born to women who were continuously insured from 6months prior to their last menstrual period through 6weeks postpartum, with ≥1 outpatient visit during pregnancy from January 1, 2010 to November 15, 2013 at seven integrated United States health care systems part of the VSD. We re-evaluated the association between maternal Tdap and chorioamnionitis and evaluated whether specific infant morbidities differ among infants born to mothers who did and did not receive Tdap during pregnancy. We focused on 2 Tdap exposure windows: the recommended 27-36weeks gestation or anytime during pregnancy. We identified inpatient diagnostic codes for transient tachypnea of the newborn (TTN), neonatal sepsis, neonatal pneumonia, respiratory distress syndrome (RDS), and newborn convulsions associated with an infant’s first hospitalization. A generalized linear model with Poisson distribution and log-link was used to estimate propensity score adjusted rate ratios (ARR) with 95% confidence intervals (CI). The analyses included 197,564 pregnancies. Chorioamnionitis was recorded in 6.4% of women who received Tdap vaccination any time during pregnancy and 5.2% of women who did not (ARR [95% CI]: 1.23 [1.17, 1.28]). Compared with unvaccinated women, there were no significant increased risks (ARR [95% CI]) for TTN (1.04 [0.98, 1.11]), neonatal sepsis (1.06 [0.91, 1.23]), neonatal pneumonia (0.94 [0.72, 1.22]), RDS (0.91 [0.66, 1.26]), or newborn convulsions (1.16 [0.87, 1.53]) in infants born to Tdap-vaccinated women. Despite an observed association between maternal Tdap vaccination and maternal chorioamnionitis, we did not find increased risk for clinically significant infant outcomes associated with maternal chorioamnionitis.
Authors: DeSilva M; Klein NP; Kharbanda EO; et al.
Vaccine. 2017 06 22;35(29):3655-3660. Epub 2017-05-25.
Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants
Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines’ antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.
Authors: Klein NP; Roy-Ghanta S; et al.
Vaccine. 2017 06 16;35(28):3564-3574. Epub 2017-05-20.
Waning protection following 5 doses of a 3-component diphtheria, tetanus, and acellular pertussis vaccine
The effectiveness of diphtheria, tetanus, and acellular pertussis (DTaP) vaccines wanes substantially after the 5thdose given at ages 4-6years, but has not been described following 5 doses of the same type of DTaP vaccine. We investigated waning effectiveness against pertussis in California over nearly 10years, which included large pertussis outbreaks, following 5 doses of GSK DTaP vaccines (DTaP3). We conducted a case-control study (NCT02447978) of children who received 5 doses of DTaP at Kaiser Permanente Northern California from 01/2006 through 03/2015. We compared time since the 5thdose in confirmed pertussis polymerase chain reaction (PCR)-positive cases with pertussis PCR-negative controls. We used logistic regression adjusted for calendar time, age, sex, race, and service area to estimate the effect of time since the 5thDTaP dose on the odds of pertussis. Our primary analysis evaluated waning after 5 doses of DTaP3. We also examined waning after 5 doses of any type of DTaP vaccines. Our primary analysis compared 340 pertussis cases diagnosed at ages 4-12years with 3841 controls. The any DTaP analysis compared 462 pertussis cases with 5649 controls. The majority of all DTaP doses in the study population were DTaP3(86.8%). Children who were more remote from their 5thdose were less protected than were children whose 5thdose was more recent; the adjusted odds of pertussis increased by 1.27 per year (95% CI 1.10, 1.46) after 5 doses of DTaP3and by 1.30 per year (95% CI 1.15, 1.46) after any 5 DTaP vaccines doses. Waning protection after DTaP3was similar to that following 5 doses of any type of DTaP vaccines. This finding is not unexpected as most of the DTaP vaccines administered were DTaP3.Following 5 doses of DTaP3vaccines, protection from pertussis waned 27% per year on average. NCT number: NCT02447978.
Authors: Klein NP; Bartlett J; Fireman B; Aukes L; Buck PO; Krishnarajah G; Baxter R
Vaccine. 2017 06 08;35(26):3395-3400. Epub 2017-05-12.
No association between influenza vaccination during pregnancy and adverse birth outcomes
Pregnant women are recommended to receive inactivated influenza vaccination anytime during pregnancy. Studies have investigated the impact of influenza vaccination during pregnancy on birth outcomes and results on preterm birth have been inconsistent. We conducted a retrospective cohort study among children born at a gestational age≥24weeks from January 1, 2010 to December 31, 2015 at Kaiser Permanente Northern California facilities (KPNC). We evaluated the association between maternal influenza vaccination during pregnancy and risk of preterm birth, small and large for gestational age, admission to the neonatal intensive care unit (NICU), respiratory distress syndrome, low birth weight, and low Apgar score. We ascertained the dates of maternal influenza vaccination, conception, and delivery, as well as birth outcomes from KPNC inpatient and outpatient databases. Conditional multivariate Cox regression and logistic regression analyses were used to determine the association between maternal vaccination during pregnancy and risk of each birth outcome. The study included 145,869 children. Maternal influenza vaccination during pregnancy was not associated with risk of small or large for gestational age births, preterm birth, need for mechanical ventilation at birth, respiratory distress syndrome, admission to the NICU, low birth weight, or low Apgar score. However, when we did not control for immortal time bias, the risk of preterm birth (odds ratio [OR]=0.69, 95% confidence interval [CI] 0.66-0.72) was lower among infants of vaccinated mothers. We found no association between maternal influenza vaccination during pregnancy and adverse birth outcomes. When investigating preterm birth outcome in association with vaccination during pregnancy, immortal time bias should be taken into account in the analysis.
Authors: Zerbo O; Modaressi S; Chan B; Goddard K; Lewis N; Bok K; Fireman B; Klein NP; Baxter R
Vaccine. 2017 May 31;35(24):3186-3190. Epub 2017-05-05.
Asthma exacerbations among asthmatic children receiving live attenuated versus inactivated influenza vaccines
To investigate whether there is a difference in the risk of asthma exacerbations between children with pre-existing asthma who receive live attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (IIV). We identified IIV and LAIV immunizations occurring between July 1, 2007 and March 31, 2014 among Kaiser Permanente Northern California members aged 2 to <18years with a history of asthma, and subsequent asthma exacerbations seen in the inpatient or Emergency Department (ED) setting. We calculated the ratio of the odds (OR) of an exacerbation being in the risk interval (1-14days) versus the comparison interval (29-42days) following immunization, separately for LAIV and IIV, and then examined whether the OR differed between children receiving LAIV and those receiving IIV ("difference-in-differences"). Among 387,633 immunizations, 85% were IIV and 15% were LAIV. Children getting LAIV vs. IIV were less likely to have "current or recent, persistent" asthma (25% vs. 47%), and more likely to have "remote history" of asthma (47% vs. 25%). Among IIV-vaccinated asthmatic children, the OR of an inpatient/ED asthma exacerbation was 0.97 (95% CI: 0.82-1.15). Among LAIV-vaccinated asthmatic children the OR was 0.38 (95% CI: 0.17-0.90). In the difference-in-differences analysis, the odds of asthma exacerbation following LAIV were less than IIV (Ratio of ORs: 0.40, CI: 0.17-0.95, p value: 0.04). Among children ≥2years old with asthma, we found no increased risk of asthma exacerbation following LAIV or IIV, and a decreased risk following LAIV compared to IIV.
Authors: Ray GT; Lewis N; Goddard K; Ross P; Duffy J; DeStefano F; Baxter R; Klein NP
Vaccine. 2017 05 09;35(20):2668-2675. Epub 2017-04-09.
Effectiveness of Vaccination During Pregnancy to Prevent Infant Pertussis
Vaccination against pertussis during pregnancy is recommended to protect newborns, yet there is limited information about the effectiveness of maternal tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine before the first infant dose of diphtheria, tetanus and acellular pertussis (DTaP) vaccine and during the first year of life in infants who have received DTaP. In a retrospective cohort study of infants born at Kaiser Permanente Northern California from 2010 to 2015, we estimated the effectiveness of maternal pertussis vaccination for protecting newborns against pertussis in the first 2 months of life and in the first year of life accounting for each infant DTaP dose. Among 148 981 newborns, the vaccine effectiveness of maternal Tdap was 91.4% (95% confidence interval [CI], 19.5 to 99.1) during the first 2 months of life and 69.0% (95% CI, 43.6 to 82.9) during the entire first year of life. The vaccine effectiveness was 87.9% (95% CI, 41.4 to 97.5) before infants had any DTaP vaccine doses, 81.4% (95% CI, 42.5 to 94.0) between doses 1 and 2, 6.4% (95% CI, -165.1 to 66.9) between doses 2 and 3, and 65.9% (95% CI, 4.5 to 87.8) after infants had 3 DTaP doses. Maternal Tdap vaccination was highly protective against infant pertussis, especially in the first 2 months of life. Even after infant DTaP dosing, there was evidence of additional protection from maternal Tdap vaccination for the first year of life. This study strongly supports the United States’ current recommendation to administer Tdap during each pregnancy.
Authors: Baxter R; Bartlett J; Fireman B; Lewis E; Klein NP
Pediatrics. 2017 May;139(5). Epub 2017-04-03.
Immunodeficiency, AIDS-related pneumonia, and risk of lung cancer among HIV-infected individuals
The objective is to clarify the role of immunodeficiency and pneumonia in elevated lung cancer risk among HIV-infected individuals. Cohort study of HIV-infected and HIV-uninfected adults in a large integrated healthcare system in California during 1996-2011. We used Poisson models to obtain rate ratios for lung cancer associated with HIV infection, overall and stratified by recent CD4 cells/μl (HIV-uninfected as reference group), with χ tests for trends across CD4 strata. Fully adjusted models included demographics, cancer risk factors (smoking, drug/alcohol abuse, overweight/obesity), and prior pneumonia. Among 24 768 HIV-infected and 257 600 HIV-uninfected individuals, the lung cancer rate per 100 000 person-years was 66 (n = 80 events) for HIV-infected and 33 (n = 506 events) for HIV-uninfected individuals [rate ratio 2.0, 95% confidence interval (CI): 1.7-2.2]. Overall, HIV-infected individuals were at increased risk of lung cancer after adjustment for demographics and cancer risk factors (rate ratio 1.4, 95% CI: 1.1-1.7), but not after additional adjustment for pneumonia (rate ratio 1.2, 95% CI: 0.9-1.6). Lower CD4 cell counts were associated with higher risk of lung cancer in unadjusted and demographics-adjusted models (P < 0.001 for all), but this trend did not remain after adjustment for cancer risk factors and pneumonia. Compared with HIV-uninfected individuals, HIV-infected individuals with CD4 less than 200 cells/μl were not at increased risk of lung cancer in fully adjusted models. The increased lung cancer risk among HIV patients is attributable to differences in demographics, risk factors such as smoking, and history of pneumonia. Immunodeficiency does not appear to have an independent effect on lung cancer risk.
Authors: Marcus JL; Leyden WA; Chao CR; Horberg MA; Klein DB; Quesenberry CP; Towner WJ; Silverberg MJ
AIDS. 2017 Apr 24;31(7):989-993.
Assessing misclassification of vaccination status: Implications for studies of the safety of the childhood immunization schedule
To address public concern about the safety of the childhood immunization schedule, the Institute of Medicine recommended observational studies comparing adverse health outcomes of fully vaccinated children to children under-vaccinated due to parental choice. Misclassification of vaccination status could bias such studies. To assess risk of misclassification of vaccination status within the Vaccine Safety Datalink (VSD). A retrospective cohort study was conducted in three phases. In phase 1, electronic health record (EHR) data were used to identify patterns of under-vaccination during the first 24months of life potentially due to parental choice. In phase 2, a random sample of records of under-vaccinated children was manually reviewed. In phase 3, a separate sample of parents were surveyed to assess whether EHR data accurately reflected their child’s vaccination status. Phases 1 and 2 were conducted at 6 VSD sites, phase 3 at 1 site. The study cohort included 361,901 children born 2004 through 2012. By 24months of age, 198,249 (54.8%) were fully vaccinated with no delays, 84,698 (23.4%) experienced delays but were fully vaccinated by 24months of age, 4865 (1.3%) received no vaccines, 3789 (1.0%) delayed starting vaccination until ≥4months of age, 4781 (1.3%) had consistent vaccine-limiting (≤2 vaccines per visit), and the remaining 65,519 (18.1%) were missing vaccine series or doses. When a diagnosis code for vaccine refusal was present in EHR data, encounter notes confirmed vaccine refusal as the reason for under-vaccination for nearly 100% of sampled records. Parent surveys confirmed these findings. Parents of under-vaccinated children were more likely to report visiting an alternative medical provider than parents of fully vaccinated children. Specific groups of children, under-vaccinated due to parental choice, can be identified with relatively low likelihood of misclassification of vaccination status using EHR-based vaccine data and diagnosis codes.
Authors: Daley MF; Glanz JM; Newcomer SR; Jackson ML; Groom HC; Lugg MM; McLean HQ; Klein NP; Weintraub ES; McNeil MM
Vaccine. 2017 Apr 04;35(15):1873-1878. Epub 2017-03-09.
Identifying birth defects in automated data sources in the Vaccine Safety Datalink
The Vaccine Safety Datalink (VSD), a collaboration between the Centers for Disease Control and Prevention and several large healthcare organizations, aims to monitor safety of vaccines administered in the USA. We present definitions and prevalence estimates for major structural birth defects to be used in studies of maternal vaccine safety. In this observational study, we created and refined algorithms for identifying major structural birth defects from electronic healthcare data, conducted formal chart reviews for severe cardiac defects, and conducted limited chart validation for other defects. We estimated prevalence for selected defects by VSD site and birth year and compared these estimates to those in a US and European surveillance system. We developed algorithms to enumerate >50 major structural birth defects from standardized administrative and healthcare data based on utilization patterns and expert opinion, applying criteria for number, timing, and setting of diagnoses. Our birth cohort included 497 894 infants across seven sites. The period prevalence for all selected major birth defects in the VSD from 2004 to 2013 was 1.7 per 100 live births. Cardiac defects were most common (65.4 per 10 000 live births), with one-fourth classified as severe, requiring emergent intervention. For most major structural birth defects, prevalence estimates were stable over time and across sites and similar to those reported in other population-based surveillance systems. Our algorithms can efficiently identify many major structural birth defects in large healthcare datasets and can be used in studies evaluating the safety of vaccines administered to pregnant women. Copyright © 2017 John Wiley & Sons, Ltd.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
Pharmacoepidemiol Drug Saf. 2017 Apr;26(4):412-420. Epub 2017-01-04.
Risk factors and familial clustering for fever 7-10days after the first dose of measles vaccines
Seven to ten days after a first dose of a measles-containing vaccine (MCV; i.e., MMR or MMRV), children have elevated fever risk which can be associated with febrile seizures. This study investigated individual and familial factors associated with fever 7-10days after MCV. Retrospective cohort study among children who were <36months of age at receipt of MCV in six sites of the Vaccine Safety Datalink from 1/1/2000 to 12/31/2012. We evaluated medically-attended clinic or emergency department visits with a code for fever 7-10days after any MCV ("MCV- associated"). We evaluated factors associated with MCV-associated fever using χ2 and multivariable logistic regression analyses. Among 946,806 children vaccinated with MCV, we identified 7480 (0.8%) MCV-associated fever visits. Compared with children without fever after MCV, children with MCV-associated fever were more likely to have received MMRV than MMR (OR 1.3 95% CI 1.2, 1.5), have had medically attended fever both following previous vaccines (OR 1.3 95% CI 1.1, 1.6) and at any other previous time (OR 1.7 95% CI 1.6, 1.8), have had at least 1 prior seizure (OR 2.2 95% CI 1.7, 2.7), and have had >3 medical visits within the 6months before MCV (OR 1.7 95% CI 1.6, 1.8). In families with multiple MCV-immunized children, after adjusting for healthcare seeking behavior care for fever, those whose siblings had MCV-associated fever were more likely to also have MCV-associated fever (OR 3.5 95% CI 2.5, 4.8). Children who received MMRV vaccine or who had prior medically-attended fevers and seizures during the first year of life had increased risk of fever after a first dose of measles vaccine. After adjusting for familial propensity to seek care, MCV-associated fever still clustered within families, suggesting a possible genetic basis for susceptibility to developing fever due to measles vaccines.
Authors: Klein NP; Lewis E; McDonald J; Fireman B; Naleway A; Glanz J; Jackson LA; Donahue JG; Jacobsen SJ; Weintraub E; Baxter R
Vaccine. 2017 Mar 14;35(12):1615-1621. Epub 2017-02-21.
Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial
Children under 3 years of age may benefit from a double-dose of inactivated quadrivalent influenza vaccine (IIV4) instead of the standard-dose. We compared the only United States-licensed standard-dose IIV4 (0.25 mL, 7.5 µg hemagglutinin per influenza strain) versus double-dose IIV4 manufactured by a different process (0.5 mL, 15 µg per strain) in a phase III, randomized, observer-blind trial in children 6-35 months of age (NCT02242643). The primary objective was to demonstrate immunogenic noninferiority of the double-dose for all vaccine strains 28 days after last vaccination. Immunogenic superiority of the double-dose was evaluated post hoc. Immunogenicity was assessed in the per-protocol cohort (N = 2041), and safety was assessed in the intent-to-treat cohort (N = 2424). Immunogenic noninferiority of double-dose versus standard-dose IIV4 was demonstrated in terms of geometric mean titer (GMT) ratio and seroconversion rate difference. Superior immunogenicity against both vaccine B strains was observed with double-dose IIV4 in children 6-17 months of age (GMT ratio = 1.89, 95% confidence interval [CI] = 1.64-2.17, B/Yamagata; GMT ratio = 2.13, 95% CI = 1.82-2.50, B/Victoria) and in unprimed children of any age (GMT ratio = 1.85, 95% CI = 1.59-2.13, B/Yamagata; GMT ratio = 2.04, 95% CI = 1.79-2.33, B/Victoria). Safety and reactogenicity, including fever, were similar despite the higher antigen content and volume of the double-dose IIV4. There were no attributable serious adverse events. Double-dose IIV4 may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults.
Authors: Jain VK; Klein NP; Innis BL; et al.
J Pediatric Infect Dis Soc. 2017 Mar 01;6(1):9-19.
First Occurrence of Diabetes, Chronic Kidney Disease, and Hypertension Among North American HIV-Infected Adults, 2000-2013
There remains concern regarding the occurrence of noncommunicable diseases (NCDs) among individuals aging with human immunodeficiency virus (HIV), but few studies have described whether disparities between demographic subgroups are present among individuals on antiretroviral therapy (ART) with access to care. We assessed the first documented occurrence of type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and treated hypertension (HTN) by age, sex, and race within the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). HIV-infected adults (≥18 years) who initiated ART were observed for first NCD occurrence between 1 January 2000 and 31 December 2013. Cumulative incidences as of age 70 were estimated accounting for the competing risk of death; Poisson regression was used to compare rates of NCD occurrence by demographic subgroup. We included >50000 persons with >250000 person-years of follow-up. Median follow-up was 4.7 (interquartile range, 2.4–8.1) years. Rates of first occurrence (per 100 person-years) were 1.2 for DM, 0.6 for CKD, and 2.6 for HTN. Relative to non-black women, the cumulative incidences were increased in black women (68% vs 51% for HTN, 52% vs 41% for DM, and 38% vs 35% for CKD; all P < .001); this disparity was also found among men (73% vs 60% for HTN, 44% vs 34% for DM, and 30% vs 25% for CKD; all P < .001). Racial disparities in the occurrence of DM, CKD, and HTN emphasize the need for prevention and treatment options for these HIV populations receiving care in North America.
Authors: Wong C; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
Clin Infect Dis. 2017 02 15;64(4):459-467.
HIV Infection, Immune Suppression and Age at Diagnosis of Non-AIDS-Defining Cancers
It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis. We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count. After adjusting for population differences, younger ages at diagnosis (P < .05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS-defining event was associated with a younger age at myeloma diagnosis (difference = 4; P = .01), and CD4 count <200 cells/µL (vs ≥500) was associated with a younger age at lung cancer diagnosis (difference = 4; P = .006). Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH.
Authors: Shiels MS; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA); et al.
Clin Infect Dis. 2017 02 15;64(4):468-475.
Human papillomavirus vaccination and subsequent cervical cancer screening in a large integrated healthcare system
Human papillomavirus vaccination may result in lowered intention to be screened for cervical cancer, potentially leading to gaps in screening coverage and avoidable cervical cancer diagnoses. The purpose of this study was to examine the association between human papillomavirus vaccination and subsequent cervical cancer screening initiation and adherence to recommended screening intervals to detect gaps in screening coverage and inform future prevention efforts. A retrospective cohort study was conducted in 2 distinct cohorts of female members of Kaiser Permanente Southern California, which is a large integrated healthcare delivery system. Papanicolaou screening initiation was evaluated in women who reached 21 years from 2010-2013. Adherence to recommended screening intervals was evaluated in women who were 25-30 years old in 2010. All women were observed to the end of 2013 for the evaluation of their screening behaviors. History of human papillomavirus vaccination and Papanicolaou screening were obtained from electronic medical records. Adherence to recommended screening intervals was measured as ≥85% vs <85% of the observed "screening up-to-date" person-time. Multivariable Cox and logistic regression models were used to examine associations between vaccination history and screening initiation and interval adherence. Demographic characteristics, gynecologic health history, healthcare use, and characteristics of women's primary care providers were included as potential confounders in the analyses. There were 27,352 and 41,328 women included in the screening initiation and screening interval adherence analyses, respectively. In comparison with unvaccinated women, adjusted hazard ratios (95% confidence intervals [CIs]) for screening initiation among women who had been vaccinated against human papillomavirus were 1.19 (95% CI, 1.11-1.28), 1.44 (95% CI, 1.34-1.53), and 1.57 (95% CI, 1.50-1.65) for 1, 2, and ≥3 doses, respectively. Adjusted odds ratios for screening interval adherence were 0.93 (95% CI, 0.83-1.04), 1.73 (95% CI, 1.52-1.97), and 2.29 (95% CI, 2.05-2.56), for 1, 2, and ≥3 doses, respectively. Women who had been vaccinated against human papillomavirus in this community-based, integrated healthcare setting were more likely to be screened for cervical cancer than were unvaccinated women. Our findings underscore the need for targeted interventions among unvaccinated women who may be disproportionally affected by cervical cancer, despite the presence of population-based screening programs.
Authors: Chao C; Silverberg MJ; Becerra TA; Corley DA; Jensen CD; Chen Q; Quinn VP
Am J Obstet Gynecol. 2017 Feb;216(2):151.e1-151.e9. Epub 2016-10-14.
Lot-to-Lot Consistency, Safety, Tolerability, and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants
This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.
Authors: Block SL; Klein NP; Lee AW; et al.
Pediatr Infect Dis J. 2017 Feb;36(2):202-208.
Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder
Maternal infections and fever during pregnancy are associated with increased risk for autism spectrum disorders (ASDs). To our knowledge, no study has investigated the association between influenza vaccination during pregnancy and ASD. To investigate the association between influenza infection and vaccination during pregnancy and ASD risk. This cohort study included 196 929 children born at Kaiser Permanente Northern California from January 1, 2000 to December 31, 2010, at a gestational age of at least 24 weeks. Data on maternal influenza infection and vaccination from conception date to delivery date, obtained from Kaiser Permanente Northern California inpatient and outpatient databases. Influenza infection was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification codes or positive influenza laboratory test results. Clinical diagnoses of ASDs identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 299.0, 299.8, or 299.9 recorded in Kaiser Permanente Northern California electronic medical records on at least 2 occasions any time from birth through June 2015. Within this cohort of 196 929 children, influenza was diagnosed in 1400 (0.7%) mothers and 45 231 (23%) received an influenza vaccination during pregnancy. The mean (SD) ages of vaccinated and unvaccinated women were 31.6 (5.2) and 30.4 (5.6) years, respectively. A total number of 3101 (1.6%) children were diagnosed with ASD. After adjusting for covariates, we found that maternal influenza infection (adjusted hazard ratio, 1.04; 95% CI, 0.68-1.58) or influenza vaccination (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.21) anytime during pregnancy was not associated with increased ASD risk. In trimester-specific analyses, first-trimester influenza vaccination was the only period associated with increased ASD risk (adjusted hazard ratio, 1.20; 95% CI, 1.04-1.39). However, this association could be due to chance (P = 0.1) if Bonferroni corrected for the multiplicity of hypotheses tested (n = 8). Maternal influenza vaccination in the second or third trimester was not associated with increased ASD risk. There was no association between maternal influenza infection anytime during pregnancy and increased ASD risk. There was a suggestion of increased ASD risk among children whose mothers received an influenza vaccination in their first trimester, but the association was not statistically significant after adjusting for multiple comparisons, indicating that the finding could be due to chance. These findings do not call for changes in vaccine policy or practice, but do suggest the need for additional studies on maternal influenza vaccination and autism.
Authors: Zerbo O; Qian Y; Yoshida C; Fireman BH; Klein NP; Croen LA
JAMA Pediatr. 2017 Jan 02;171(1):e163609. Epub 2017-01-02.
Affordable Care Act Implementation in a California Health Care System Leads to Growth in HIV-Positive Patient Enrollment and Changes in Patient Characteristics
This study examined implementation of the Affordable Care Act (ACA) in relation to HIV-positive patient enrollment in an integrated health care system; as well as changes in new enrollee characteristics, benefit structure, and health care utilization after key ACA provisions went into effect in 2014. This mixed-methods study was set in Kaiser Permanente Northern California (KPNC). Qualitative interviews with 29 KPNC leaders explored planning for ACA implementation. Quantitative analyses compared newly enrolled HIV-positive patients in KPNC between January and December 2012 (“pre-ACA,” N = 661) with newly enrolled HIV-positive patients between January and December 2014 (“post-ACA,” N = 880) on demographics; medical, psychiatric, and substance use disorder diagnoses; HIV clinical indicators; and type of health care utilization. Interviews found that ACA preparation focused on enrollment growth, staffing, competition among health plans, concern about cost sharing, and HIV pre-exposure prophylaxis (PrEP) services. Quantitative analyses found that post-ACA HIV-positive patient enrollment grew. New enrollees in 2014 were more likely than 2012 enrollees to be enrolled in high-deductible plans (P < 0.01) or through Medicaid (P < 0.01), and marginally more likely to have better HIV viral control (P < 0.10). They also were more likely to be diagnosed with asthma (P < 0.01) or substance use disorders (P < 0.05) and to have used primary care health services in the 6 months postenrollment (P < 0.05) than the pre-ACA cohort. As anticipated by KPNC interviewees, ACA implementation was followed by HIV-positive patient enrollment growth and changing benefit structures and patient characteristics. Although HIV viral control improved, comorbid diagnosis findings reinforced the importance of coordinated health care.
Authors: Satre DD; Altschuler A; Parthasarathy S; Silverberg MJ; Volberding P; Campbell CI
J Acquir Immune Defic Syndr. 2016 Dec 15;73(5):e76-e82.
Preexposure Prophylaxis for HIV Prevention in a Large Integrated Health Care System: Adherence, Renal Safety, and Discontinuation
Placebo-controlled and open-label studies have demonstrated the safety and efficacy of daily oral preexposure prophylaxis (PrEP) in preventing HIV infection, but data are limited on real-world PrEP use. We conducted a cohort study from July 2012 through June 2015 of Kaiser Permanente Northern California members initiating PrEP. We assessed pharmacy refill adherence and discontinuation, decreases in estimated glomerular filtration rate (eGFR), and sexually transmitted infection (STI)/HIV incidence. Overall, 972 individuals initiated PrEP, accumulating 850 person-years of PrEP use. Mean adherence was 92% overall. Black race/ethnicity [adjusted risk ratio (aRR) 3.0; 95% confidence interval: 1.7 to 5.1, P < 0.001], higher copayments (aRR 2.0; 1.2 to 3.3, P = 0.005), and smoking (aRR 1.6; 1.1 to 2.3, P = 0.025) were associated with <80% adherence. PrEP was discontinued by 219 (22.5%); female sex (aRR 2.6; 1.5 to 4.6, P < 0.001) and drug/alcohol abuse (aRR 1.8; 1.3 to 2.6, P = 0.002) were associated with discontinuation. Among 909 with follow-up creatinine testing, 141 (15.5%) had an eGFR <70 mL·min·1.73 m and 5 (0.6%) stopped PrEP because of low eGFR. Quarterly STI positivity was high and increased over time for rectal chlamydia (P < 0.001) and urethral gonorrhea (P = 0.012). No HIV seroconversions occurred during PrEP use; however, 2 occurred in individuals who discontinued PrEP after losing insurance coverage. PrEP adherence was high in clinical practice, consistent with the lack of HIV seroconversions during PrEP use. Discontinuation because of renal toxicity was rare. STI screening every 6 months, as recommended by current guidelines, may be inadequate. Strategies are needed to increase PrEP access during gaps in insurance coverage.
Authors: Marcus JL; Hurley LB; Hare CB; Nguyen DP; Phengrasamy T; Silverberg MJ; Stoltey JE; Volk JE
J Acquir Immune Defic Syndr. 2016 Dec 15;73(5):540-546.
First occurrence of diabetes, chronic kidney disease, and hypertension among North American HIV-infected adults, 2000-2013
There remains concern regarding the occurrence of non-communicable diseases (NCDs) among individuals aging with HIV but few studies have described whether disparities between demographic subgroups are present among individuals on antiretroviral therapy (ART) with access to care. We assessed the first documented occurrence of type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and treated hypertension (HTN) by age, sex, and race within the North American AIDS Cohort Collaboration on Research and Design. HIV-infected adults (?18 years) who initiated ART were observed for first NCD occurrence between 1 January 2000 – 31 December 2013. Cumulative incidences as of age 70 were estimated accounting for the competing risk of death; Poisson regression was used to compare rates of NCD occurrence by demographic subgroup. We included >50,000 persons with >250,000 person-years (PY) of follow-up. Median follow-up was 4.7 years (interquartile range (IQR): 2.4-8.1). Rates of first occurrence (per 100 PY) were: 1.2 for DM, 0.6 for CKD, and 2.6 for HTN. Relative to non-black women, the cumulative incidences were increased in black women (68% vs. 51% for HTN, 52% vs. 41% for DM, and 38% vs. 35% for CKD; all p<0.001); this disparity was also found among men (73% vs. 60% for HTN, 44% vs. 34% for DM, and 30% vs. 25% for CKD; all p<0.001). Racial disparities in the occurrence of DM, CKD, and HTN emphasize the need for prevention and treatment options for these HIV populations receiving care in North America.
Authors: Wong C; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
Clin Infect Dis. 2016 Dec 10.
Acute demyelinating events following vaccines – a case centered analysis
Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM. We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine. Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5-28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5-28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2-471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, -.04 to 1.16) cases per million doses. We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.
Authors: Baxter R; Lewis E; Goddard K; Fireman B; Bakshi N; DeStefano F; Gee J; Tseng HF; Naleway AL; Klein NP
Clin Infect Dis. 2016 Dec 01;63(11):1456-1462. Epub 2016-09-01.
Kaiser Permanente Northern California pregnancy database: Description and proof of concept study
We describe the establishment of a dynamic database linking mothers to newborns with the goal of studying vaccine safety in both pregnant women and their children and provide results of a study utilizing this database as a proof of concept. All Kaiser Permanente Northern California (KPNC) live births and their mothers were eligible for inclusion in the pregnancy database. We used the medical record number (MRN), a unique identifier, to retrieve information about events that occurred during the pregnancy and at delivery and linked this same MRN to newborns for post-partum follow up. We conducted a retrospective cohort study to evaluate the association between receipt of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy and fever 0-3days after the first dose of diphtheria tetanus and acellular pertussis (DTaP) vaccine in the infant. The study included infants who were born at ⩾37weeks gestation from January 1, 2009 – October 1, 2015 and who received their first DTaP vaccine between 6 and 10weeks of age. We utilized diagnostic codes from inpatient, emergency department, outpatient clinics, and telephone calls. We identified fever using ICD 9 code 780.6, recorded temperature ⩾101 degree Fahrenheit, or parental report. The database contained the starting and ending date of each pregnancy and basic demographic characteristics of mothers and infants. There were 859,699 women and 873,753 children in the database as of January 2016. The proof of concept study included 148,699 infants. In a multivariable logistic regression analysis, Tdap vaccination during pregnancy was not associated with infant fever 0-3daysafter first dose of DTaP (adjusted odds ratio=0.92, 95% CI 0.82-1.04). The KPNC pregnancy database can be used for studies investigating exposure during pregnancy and outcomes in mothers and/or infants, particularly monitoring vaccine safety and effectiveness.
Authors: Zerbo O; Chan B; Goddard K; Lewis N; Bok K; Klein NP; Baxter R
Vaccine. 2016 11 04;34(46):5519-5523. Epub 2016-10-07.
Racial and Ethnic Differences in Substance Use Diagnoses, Comorbid Psychiatric Disorders, and Treatment Initiation among HIV-Positive and HIV-Negative Women in an Integrated Health Plan
Access to substance use disorder (SUD) treatment is a critical issue for women with HIV. This study examined differences in SUD diagnoses, comorbid psychiatric diagnoses, and predictors of SUD treatment initiation among a diverse sample of HIV-positive women (n = 228) and a demographically similar cohort of HIV-negative women (n = 693). Diagnoses and service utilization data were obtained from electronic health records of members of a large integrated healthcare system in Northern California. HIV-positive women were less likely to initiate SUD treatment. Significant racial/ethnic differences were found among both HIV-positive and HIV-negative women with respect to SUD diagnosis type and diagnosis of comorbid psychiatric disorders. Among the HIV-negative women, rates of SUD treatment initiation were lower for black women than for white or Latina women. Multivariable logistic regression models showed that alcohol, cannabis, and opiate diagnoses were predictive of SUD treatment initiation for both cohorts, while amphetamine diagnoses, comorbid depressive disorder, and being white or Latina were predictive of SUD treatment initiation for HIV-negative, but not HIV-positive, women. Findings suggest that clinicians need to be aware of differences in substances of abuse, comorbid psychiatric disorders, and to consider the demographic and social factors that may contribute to differences in SUD treatment initiation among HIV-positive and HIV-negative women.
Authors: Storholm ED; Silverberg MJ; Satre DD
J Psychoactive Drugs. 2016 Nov-Dec;48(5):377-383. Epub 2016-10-21.
Risk of End-Stage Liver Disease in HIV-Viral Hepatitis Coinfected Persons in North America From the Early to Modern Antiretroviral Therapy Eras
Human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis B (HBV) and C (HCV) viruses are at increased risk of end-stage liver disease (ESLD). Whether modern antiretroviral therapy has reduced ESLD risk is unknown. Twelve clinical cohorts in the United States and Canada participating in the North American AIDS Cohort Collaboration on Research and Design validated ESLD events from 1996 to 2010. ESLD incidence rates and rate ratios according to hepatitis status adjusted for age, sex, race, cohort, time-updated CD4 cell count and HIV RNA were estimated in calendar periods corresponding to major changes in antiretroviral therapy: early (1996-2000), middle (2001-2005), and modern (2006-2010) eras. Among 34 119 HIV-infected adults followed for 129 818 person-years, 380 incident ESLD outcomes occurred. ESLD incidence (per 1000 person-years) was highest in triply infected (11.57) followed by HBV- (8.72) and HCV- (6.10) coinfected vs 1.27 in HIV-monoinfected patients. Adjusted incidence rate ratios (95% confidence intervals) comparing the modern to the early antiretroviral era were 0.95 (.61-1.47) for HCV, 0.95 (.40-2.26) for HBV, and 1.52 (.46-5.02) for triply infected patients. Use of antiretrovirals dually activity against HBV increased over time. However, in the modern era, 35% of HBV-coinfected patients were not receiving tenofovir. There was little use of HCV therapy. Despite increasing use of antiretrovirals, no clear reduction in ESLD risk was observed over 15 years. Treatment with direct-acting antivirals for HCV and wider use of tenofovir-based regimens for HBV should be prioritized for coinfected patients.
Authors: Klein MB; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA; et al.
Clin Infect Dis. 2016 Nov 01;63(9):1160-1167. Epub 2016-08-09.
Higher Time-updated Body Mass Index: Association with Improved CD4+ Cell Recovery on HIV Treatment
Prior studies found overweight or obese HIV-infected individuals had greater early CD4 cell recovery on antiretroviral therapy (ART), but the results have been inconsistent. We assessed the longitudinal relationship between body mass index (BMI) and CD4 cell recovery on ART in a large, multisite cohort to identify potential physiologic links between adiposity and CD4 cell expansion. We modeled the relationship of time-updated BMI with CD4 count in patients starting ART from 17 North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohorts. The primary analysis used a linear mixed effects model incorporating up to 13 years of data per patient and adjusted for age, sex, race, ART regimen, baseline CD4 count and other covariates. Sensitivity analyses limited the cohort to patients with sustained viral suppression or censored at virologic failure. Fourteen thousand eighty-four HIV-infected individuals initiating ART contributed data between 1998 and 2010. Time-updated BMI was significantly associated with CD4 cell recovery over time (P < 0.001). After 5 years of ART, the mean CD4 count at a BMI of 30 kg/m was 22% higher than at a BMI of 22 kg/m (606 vs. 498 cells per microliter) and 34% higher at a BMI of 40 kg/m (665 vs. 498 cells per microliter). Results were similar in the sensitivity analyses. Higher BMI is associated with long-term advantages in immune recovery on ART. Although it is unclear if this impacts health outcomes, including balancing the negative health effects of obesity, elucidating the underlying mechanism could identify therapies for patients with suboptimal immune reconstitution.
Authors: Koethe JR; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
J Acquir Immune Defic Syndr. 2016 Oct 01;73(2):197-204.
Invasive Pneumococcal Disease Among HIV-Infected and HIV-Uninfected Adults in a Large Integrated Healthcare System
It is unclear whether HIV-infected individuals remain at higher risk of invasive pneumococcal disease (IPD) compared with HIV-uninfected individuals. We conducted a cohort study of HIV-infected and demographically matched HIV-uninfected adults within Kaiser Permanente Northern California during the period 1996-2011. We used Poisson models to obtain rate ratios (RRs) for incident IPD associated with HIV infection and other risk factors. Among 13,079 HIV-infected and 137,643 HIV-uninfected adults, the IPD rate per 100,000 person-years was 160 (n = 109 events) for HIV-infected and 8 (n = 75 events) for HIV-uninfected subjects, with an adjusted RR of 13.0 [95% confidence interval (CI): 9.1-18.7]. For HIV-infected individuals, IPD incidence per 100,000 person-years decreased by 71% during study follow-up, from 305 in 1996-1999 to 88 in 2010-2011 (p < 0.001), with an adjusted RR of 6.6 (95% CI: 2.7-16.1) compared with HIV-uninfected subjects in 2010-2011. Risk factors for IPD among HIV-infected individuals included black compared with white race/ethnicity, smoking, cancer, and higher HIV RNA levels. The 23-valent pneumococcal polysaccharide vaccination was not associated with a reduced risk of IPD in HIV-infected or HIV-uninfected individuals. Among HIV-infected IPD cases, the most common serotype was 19A (33%), and 59% of serotypes were covered by the 13-valent pneumococcal conjugate vaccine (PCV13). Despite a dramatic decline in IPD incidence for HIV-infected adults since 1996, IPD rates were nearly sevenfold higher compared with HIV-uninfected adults in recent years, even after adjustment for risk factors. Timely antiretroviral therapy initiation, risk reduction strategies, and recent guidelines recommending PCV13 use may further reduce IPD incidence among HIV patients.
Authors: Marcus JL; Baxter R; Leyden WA; Muthulingam D; Yee A; Horberg MA; Klein DB; Towner WJ; Chao CR; Quesenberry CP; Silverberg MJ
AIDS Patient Care STDS. 2016 Oct;30(10):463-470.
Disparities in Uptake of HIV Preexposure Prophylaxis in a Large Integrated Health Care System
Authors: Marcus JL; Hurley LB; Hare CB; Silverberg MJ; Volk JE
Am J Public Health. 2016 10;106(10):e2-3.
Incidence of AIDS-Defining Opportunistic Infections in a Multicohort Analysis of HIV-infected Persons in the United States and Canada, 2000-2010
There are few recent data on the rates of AIDS-defining opportunistic infections (OIs) among human immunodeficiency virus (HIV)-infected patients in care in the United States and Canada. We studied HIV-infected participants in 16 cohorts in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) during 2000-2010. After excluding 16 737 (21%) with any AIDS-defining clinical events documented before NA-ACCORD enrollment, we analyzed incident OIs among the remaining 63 541 persons, most of whom received antiretroviral therapy during the observation. We calculated incidence rates per 100 person-years of observation (hereafter, “person-years”) with 95% confidence intervals (CIs) for the first occurrence of any OI and select individual OIs during 2000-2003, 2004-2007, and 2008-2010. A total of 63 541 persons contributed 261 573 person-years, of whom 5836 (9%) developed at least 1 OI. The incidence rate of any first OI decreased over the 3 observation periods, with 3.0 cases, 2.4 cases, and 1.5 cases per 100 person-years of observation during 2000-2003, 2004-2007, and 2008-2010, respectively (Ptrend<.001); the rates of most individual OIs decreased as well. During 2008-2010, the leading OIs included Pneumocystis jiroveci pneumonia, esophageal candidiasis, and disseminated Mycobacterium avium complex or Mycobacterium kansasii infection. For HIV-infected persons in care during 2000-2010, rates of first OI were relatively low and generally declined over this time.
Authors: Buchacz K; Goedert JJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA; et al.
J Infect Dis. 2016 Sep 15;214(6):862-72. Epub 2016-04-18.
Narrowing the gap in life expectancy between HIV-infected and HIV-uninfected individuals with access to care
It is unknown if a survival gap remains between HIV-infected and HIV-uninfected individuals with access to care. We conducted a cohort study within Kaiser Permanente California during 1996-2011, using abridged life tables to estimate the expected years of life remaining (“life expectancy”) at age 20. Among 24,768 HIV-infected and 257,600 HIV-uninfected individuals, there were 2229 and 4970 deaths, with mortality rates of 1827 and 326 per 100,000 person-years, respectively. In 1996-1997, life expectancies at age 20 for HIV-infected and HIV-uninfected individuals were 19.1 and 63.4 years, respectively, corresponding with a gap of 44.3 years (95% confidence interval: 38.4 to 50.2). Life expectancy at age 20 for HIV-infected individuals increased to 47.1 years in 2008 and 53.1 years by 2011, narrowing the gap to 11.8 years (8.9-14.8 years) in 2011. In 2008-2011, life expectancies at age 20 for HIV-infected individuals ranged from a low of 45.8 years for blacks and 46.0 years for those with a history of injection drug use to a high of 52.2 years for Hispanics. HIV-infected individuals who initiated antiretroviral therapy with CD4 ?500 cells per microliter had a life expectancy at age 20 of 54.5 years in 2008-2011, narrowing the gap relative to HIV-uninfected individuals to 7.9 years (5.1-10.6 years). For these HIV-infected individuals, the gap narrowed further in subgroups with no history of hepatitis B or C infection, smoking, drug/alcohol abuse, or any of these risk factors. Even with early treatment and access to care, an 8-year gap in life expectancy remains for HIV-infected compared with HIV-uninfected individuals.
Authors: Marcus JL; Chao CR; Leyden WA; Xu L; Quesenberry CP; Klein DB; Towner WJ; Horberg MA; Silverberg MJ
J Acquir Immune Defic Syndr. 2016 Sep 01;73(1):39-46.
Preexposure Prophylaxis and Patient Centeredness: A Call for Holistically Protecting and Promoting the Health of Gay Men
Preexposure prophylaxis has transformed HIV prevention, becoming widespread in communities of gay and bisexual men in the developed world in a short time. There is a broad concern that preexposure prophylaxis will discourage condom use among gay men (i.e., "risk compensation"). This commentary argues for broadening the focus on gay men’s health beyond sexual health to address the holistic health and well-being of gay men. Gay men may benefit from being offered candid, nonjudgmental health promotion/HIV prevention messages not requiring condom use for anal sex. Lessons can be drawn from the family planning movement, which has undergone a similar shift in focus. The principle of patient centeredness supports such a shift in gay men’s health toward the goal of providing men with the knowledge to evaluate various prevention approaches according to the specifics of their life circumstances and health needs. Bringing more nuance to discussions of sexual risk and sexual pleasure could facilitate more universally healthy attitudes regarding sex among gay men, in turn enabling healthier decisions more compatible with men’s own values and preferences.
Authors: Snowden JM; Rodriguez MI; Jackson SD; Marcus JL
Am J Mens Health. 2016 Sep;10(5):353-8. Epub 2016-07-07.
Risk of underlying chronic medical conditions for invasive pneumococcal disease in adults
In the United States, the 13-valent pneumococcal conjugate vaccine is recommended in persons ⩾65years of age, and persons ⩽65years of age with immunocompromising (IC) conditions. For invasive pneumococcal disease (IPD) prevention in those ⩽65 with non-IC medical conditions, the 23-valent polysaccharide vaccine is recommended. This group is at higher risk of IPD than the general population, but the level of risk is not well-quantified. We estimated IPD risk by individual underlying medical conditions, and by total number of conditions, for persons ⩾18years of age. We calculated the relative risks (RR) of various medical conditions, comparing the incident IPD cases to the general study population, and used Poisson regression models to estimate an IPD RR, adjusting for other conditions. We also examined IPD incidence by number of conditions diagnosed in each calendar year, using a risk-stacking model. Underlying medical conditions with the highest adjusted RR for IPD were chronic liver disease (RR 2.1, 95% CI 1.5-2.8) and chronic obstructive pulmonary disease (COPD; RR 2.1, 95% CI 1.8-2.5). IPD risk increased with increasing number of medical conditions: adjusted RR, 2.2 (95% CI 1.9-2.5) 1 condition, 2.9 (2.5-3.5) for 2 conditions, and 5.2 (4.4-6.1) for 3 conditions. For persons with a single, non-IC medical condition, IPD risk was twice that for the general KPNC population. Persons with multiple, non-IC chronic conditions exhibited increased IPD risk with each additional condition. Such information may inform discussions on recommendations for adult pneumococcal immunization and prevention.
Authors: Baxter R; Yee A; Aukes L; Snow V; Fireman B; Atkinson B; Klein NP
Vaccine. 2016 Aug 05;34(36):4293-7. Epub 2016-07-07.
Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies
Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009-2010 (40% of participants received the MIV). We found potential biases in the vaccine-birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases.
Authors: Vazquez-Benitez G; Klein NP; Nordin JD; et al.
Am J Epidemiol. 2016 Aug 01;184(3):176-86. Epub 2016-07-22.
Safety of DTaP-IPV/Hib vaccine administered routinely to infants and toddlers
The combination DTaP-IPV/Hib vaccine was licensed in the United States in 2008 for children ages 6weeks through 4years with doses administered at 2, 4, 6, and 15-18months of age. The aim of this study was to assess the safety of DTaP-IPV/Hib vaccine routinely administered as part of clinical care to infants at Kaiser Permanente Northern California. This was an observational, retrospective study that included all 2-month-old infants vaccinated with either DTaP-IPV/Hib or another DTaP-containing vaccine. We monitored all subjects for non-elective hospitalizations, emergency department visits and selected outpatient outcomes (seizures, Guillain-Barré Syndrome, encephalopathy, encephalitis, alteration of consciousness, meningitis, hypersensitivity reactions, immune thrombocytopenic purpura, hemolytic anemia, type 1 diabetes, and Kawasaki disease) beginning with their first dose through 6months after a 4th dose or until 24months of age. We calculated incidence rate ratios (IRRs) in the primary analysis by comparing rates of outcomes during the post-vaccination risk interval with rates during a comparison interval more remote from vaccination. Secondary analyses compared outcomes after DTaP-IPV/Hib with those after other DTaP-containing vaccines. We reviewed the medical records of selected outcomes. From October 1, 2008 through July 31, 2010, 14,042 subjects received a first dose of DTaP-IPV/Hib, 13,194 received 2 doses, 12,548 received 3 doses and 6702 received 4 doses. Overall, there were 166 comparisons with significantly elevated IRRs and 165 comparisons with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs in both the primary and secondary analyses did not suggest any relationship with DTaP-IPV/Hib. This study did not detect any safety concerns following DTaP-IPV/Hib and provides reassurance that DTaP-IPV/Hib administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier: NCT00804284.
Authors: Hansen J; Timbol J; Lewis N; Pool V; Decker MD; Greenberg DP; Klein NP
Vaccine. 2016 Jul 29;34(35):4172-4179. Epub 2016-06-30.
Febrile Seizure Risk After Vaccination in Children 6 to 23 Months
An increased risk of febrile seizure (FS) was identified with concomitant administration of trivalent inactivated influenza vaccine (IIV3) and pneumococcal conjugate vaccine (PCV) 13-valent during the 2010-2011 influenza season. Our objective was to determine whether concomitant administration of IIV3 with other vaccines affects the FS risk. We examined the risk of FS 0 to 1 day postvaccination for all routinely recommended vaccines among children aged 6 through 23 months during a period encompassing 5 influenza seasons (2006-2007 through 2010-2011). We used a population-based self-controlled risk interval analysis with a control interval of 14 to 20 days postvaccination. We used multivariable regression to control for receipt of concomitant vaccines and test for interaction between vaccines. Only PCV 7-valent had an independent FS risk (incidence rate ratio [IRR], 1.98; 95% confidence interval [CI], 1.00 to 3.91). IIV3 had no independent risk (IRR, 0.46; 95% CI, 0.21 to 1.02), but risk was increased when IIV3 was given with either PCV (IRR, 3.50; 95% CI, 1.13 to 10.85) or a diphtheria-tetanus-acellular-pertussis (DTaP)-containing vaccine (IRR, 3.50; 95% CI, 1.52 to 8.07). The maximum estimated absolute excess risk due to concomitant administration of IIV3, PCV, and DTaP-containing vaccines compared with administration on separate days was 30 FS per 100 000 persons vaccinated. The administration of IIV3 on the same day as either PCV or a DTaP-containing vaccine was associated with a greater risk of FS than when IIV3 was given on a separate day. The absolute risk of postvaccination FS with these vaccine combinations was small.
Authors: Duffy J; Klein NP; Vaccine Safety Datalink; et al.
Pediatrics. 2016 Jul;138(1). Epub 2016-06-06.
Demographic, Insurance, and Health Characteristics of Newly Enrolled HIV-Positive Patients After Implementation of the Affordable Care Act in California
To examine changes in HIV-positive patient enrollment in a large health care delivery system before and after key Affordable Care Act (ACA) provisions went into effect in 2014. Analyses compared HIV-positive patients newly enrolled in Kaiser Permanente Northern California between January and June 2012 (n?=?339) to those newly enrolled between January and June 2014 through the California insurance exchange or via other mechanisms (n?=?549). After the ACA, the HIV-positive patient enrollment increased. These new enrollees were more likely to be male (93.6% vs 89.1%; P?=?.01), to be enrolled in high-deductible benefit plans (??$1000; 18.8% vs 5.5%; P?=?.01), and to have better HIV viral control (HIV RNA levels below limits of quantification 79.5% vs 73.6%; P?=?.05) compared with pre-ACA new enrollees. Among post-ACA new enrollees, there were more patients in the lowest and highest age groups. Post-ACA exchange enrollees (22%) were more likely to be male and to have high-deductible plans than those enrolled through other mechanisms. More men, higher deductibles, and better HIV viral control characterize newly enrolled HIV-positive patients after the ACA in California. Evolving characteristics of HIV-positive enrollees may affect HIV policy, patient care needs, and service utilization.
Authors: Satre DD; Parthasarathy S; Altschuler A; Silverberg MJ; Storholm E; Campbell CI
Am J Public Health. 2016 Jul;106(7):1211-3. Epub 2016-04-14.
Sudden-Onset Sensorineural Hearing Loss after Immunization: A Case-Centered Analysis
Case reports of sudden sensorineural hearing loss (SSHL) following vaccines have led to concerns that vaccines may rarely cause hearing loss. Because of this concern, we analyzed for an association between SSHL and vaccinations. We used a case-centered method, equivalent to a case control design using immunization dates from all matched members of the population to calculate exposure to vaccines, rather than sampling. Kaiser Permanente Northern California (KPNC), 2007 to 2013. We searched KPNC databases from 2007 to 2013 for all first-time diagnoses of SSHL. We used the date of any hearing- or ear-related visit in the 60 days prior to the first SSHL diagnosis as the onset date. Using only SSHL cases immunized in the prior 9 months, we compared the vaccine exposure in several risk intervals prior to onset with the exposure to the same vaccine during the same time period in all KPNC membership, matched to sex and age. During the study period, >20 million vaccines were administered at KPNC. In all risk intervals prior to onset of SSHL, we found no evidence of increased risk of immunization compared with matched controls. The odds ratios for vaccination 1 week prior to SSHL were 0.965 (95% confidence interval, 0.61-1.50) for trivalent inactivated influenza vaccine (TIV); 0.842 (0.39-1.62) for tetanus, reduced diphtheria, and reduced acellular pertussis; and 0.454 (0.08-1.53) for zoster vaccine. A large-scale analysis applying a case-centered method did not detect any association between SSHL and previous receipt of TIV or other vaccines.
Authors: Baxter R; Lewis N; Bohrer P; Harrington T; Aukes L; Klein NP
Otolaryngol Head Neck Surg. 2016 Jul;155(1):81-6. Epub 2016-03-29.
Case centered analysis of Optic Neuritis following vaccines
We evaluated the risk of optic neuritis (ON) after vaccines, using a case-centered analysis, comparing the time since vaccination for the patients with ON with that for all similar vaccinees in a large integrated health plan population. We did not detect any association between ON and receipt of any type of vaccine.
Authors: Baxter R; Lewis E; Fireman B; DeStefano F; Gee J; Klein NP
Clin Infect Dis. 2016 Jul 01;63(1):79-81. Epub 2016-04-10.
Qualifications, Demographics, Satisfaction, and Future Capacity of the HIV Care Provider Workforce in the United States, 2013-2014.
BACKGROUND: The human immunodeficiency virus (HIV)-infected population in the United States is increasing by about 30 000 annually (new infections minus deaths). With improvements in diagnosis and engagement in care, additional qualified HIV care providers may be needed. METHODS: We surveyed a probability sample of 2023 US HIV care providers in 2013-2014, including those at Ryan White HIV/AIDS Program (RWHAP)-funded facilities and in private practices. We estimated future patient care capacity by comparing counts of providers entering and planning to leave practice within 5 years, and the number of patients under their care. RESULTS: Of surveyed providers, 1234 responded (adjusted response rate, 64%): 63% were white, 11% black, 11% Hispanic, and 16% other race/ethnicity; 37% were satisfied/very satisfied with salary/reimbursement, and 33% were satisfied/very satisfied with administrative time. Compared with providers in private practice, more providers at RWHAP-funded facilities were HIV specialists (71% vs 43%; P < .0001) and planned to leave HIV practice within 5 years (11% vs 4%; P = .0004). An estimated 190 more full-time equivalent providers (defined as 40 HIV clinical care hours per week) entered practice in the past 5 years than are expected to leave in the next 5 years. If these rates continue, by 2019 patient care capacity will increase by 65 000, compared with an increased requirement of at least 100 000. CONCLUSIONS: Projected workforce growth by 2019 will not accommodate the increased number of HIV-infected persons requiring care. RWHAP-funded facilities may face attrition of highly qualified providers. Dissatisfaction with salary/reimbursement and administrative burden is substantial, and black and Hispanic providers are underrepresented relative to HIV patients.
Authors: Weiser J; Beer L; West BT; Duke CC; Gremel GW; Skarbinski J
Clin Infect Dis. 2016 Oct 1;63(7):966-975. doi: 10.1093/cid/ciw442. Epub 2016 Jun 29.
Five-Year Antibody Persistence and Booster Response Following One or Two Doses of Meningococcal A, C, W, and Y Tetanus Toxoid Conjugate Vaccine in Healthy Children
We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children. In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up. At year 5, ?64.0% of 1-dose and ?74.6% of 2-dose recipients had hSBA titers ?8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers ?8. One month postvaccination, all booster dose recipients and ?78.5% of primary dose recipients exhibited hSBA titers ?8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile. With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated.
Authors: Klein NP; Baine Y; Kolhe D; Baccarini CI; Miller JM; Van der Wielen M
Pediatr Infect Dis J. 2016 06;35(6):662-72.
Response to Therapy in Antiretroviral Therapy-Na Patients with Isolated Nonnucleoside Reverse-Transcriptase Inhibitor-Associated Transmitted Drug Resistance
Nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated transmitted drug resistance (TDR) is the most common type of TDR. Few data guide the selection of antiretroviral therapy (ART) for patients with such resistance. We reviewed treatment outcomes in a cohort of HIV-1-infected patients with isolated NNRTI TDR who initiated ART between April 2002 and May 2014. In an as-treated analysis, virological failure (VF) was defined as not reaching undetectable virus levels within 24 weeks, virological rebound, or switching regimens during viremia. In an intention-to-treat analysis, failure was defined more broadly as VF, loss to follow-up, and switching during virological suppression. Of 3245 patients, 131 (4.0%) had isolated NNRTI TDR; 122 received a standard regimen comprising 2 NRTIs plus a boosted protease inhibitor (bPI; n = 54), an integrase strand transfer inhibitor (INSTI; n = 52), or an NNRTI (n = 16). The median follow-up was 100 weeks. In the as-treated analysis, VF occurred in 15% (n = 8), 2% (n = 1), and 25% (n = 4) of patients in the bPI, INSTI, and NNRTI groups, respectively. In multivariate regression, there was a trend toward a lower risk of VF with INSTIs than with bPIs (hazard ratio: 0.14; 95% confidence interval: 0.02 to 1.1; P = 0.07). In intention-to-treat multivariate regression, INSTIs had a lower risk of failure than bPIs (hazard ratio: 0.38; 95% confidence interval: 0.18 to 0.82; P = 0.01). Patients with isolated NNRTI TDR experienced low VF rates with INSTIs and bPIs. INSTIs were noninferior to bPIs in an analysis of VF but superior to bPIs when frequency of switching and loss to follow-up were also considered.
Authors: Clutter DS; Fessel WJ; Rhee SY; Hurley LB; Klein DB; Ioannidis JP; Silverberg MJ; Shafer RW
J Acquir Immune Defic Syndr. 2016 Jun 01;72(2):171-6.
Monocyte activation by interferon-alpha is associated with failure to achieve a sustained virologic response after treatment for hepatitis C virus infection
Interferon ? (IFN-?) and ribavirin can induce a sustained virologic response (SVR) in some but not all hepatitis C virus (HCV)-infected patients. The mechanism of effective treatment is unclear. One possibility is that IFN-? differentially improves the functional capacity of classic myeloid dendritic cells (mDCs) by altering expression of surface molecules or cytokines. Others have proposed that antigen-presenting cell activation could be paradoxically detrimental during HCV infection because of the production by monocytes of substances inhibitory or toxic to plasmacytoid dendritic cells. We examined responses to in vitro IFN-? treatment of peripheral blood leukocyte samples from a retrospective treatment cohort of nearly 200 HCV-seropositive patients who had undergone antiviral therapy with ribavirin and pegylated IFN. We analyzed the variable responses of antigen-presenting cell subsets to drug. We found that patients achieving SVR were no more likely to have robust mDC activation in response to IFN-? than those who did not achieve SVR. Rather, patients achieving SVR were distinguished by restrained monocyte activation in the presence of IFN-?, a factor that was second in importance only to IL28B genotype in its association with SVR. These results suggest that interindividual variability in the response of monocytes to IFN-? is an important determinant of treatment success with IFN-?-based regimens.
Authors: Hartigan-O'Connor DJ; Lin D; Ryan JC; Shvachko VA; Cozen ML; Segal MR; Terrault NA; Lanier LL; Manos MM; McCune JM
J Infect Dis. 2014 May 15;209(10):1602-12. Epub 2013-12-10.
Influenza Vaccination During Pregnancy: Influenza Seasons 2002-2012, Vaccine Safety Datalink
Pregnant women are at risk for influenza-related complications and have been recommended for vaccination by the Advisory Committee on Immunization Practices (ACIP) since 1990. Annual rates of influenza coverage of pregnant women have been consistently low. The Vaccine Safety Datalink was used to assess influenza vaccine coverage over 10 consecutive years (2002-2012); assess patterns related to changes in ACIP recommendations; identify predictors of vaccination; and compare the results with those published by national U.S. surveys. Retrospective cohort study of 721,898 pregnancies conducted in 2014. Coverage rates were assessed for all pregnancies and for live births only. Multivariate regression analysis identified predictors associated with vaccination. Coverage increased from 8.8% to 50.9% in 2002-2012. Seasonal coverage rates increased slowly following the 2004 ACIP influenza vaccine recommendation (to remove the first trimester restriction), but spiked significantly during the 2009 H1N1 influenza pandemic. Significant predictors of vaccination during pregnancy included older age; vaccination in a previous season; high-risk conditions in addition to pregnancy; pregnancy during either the 2004-2005 or 2009-2010 seasons; entering the influenza season after the first trimester of pregnancy; and a pregnancy with longer overlap with the influenza season (p<0.001 for each). Influenza vaccination coverage among pregnant women increased between the 2002-2003 and 2011-2012 seasons, although it was still below the developmental Healthy People 2020 goal of 80%. The 2004 ACIP language change positively impacted first-trimester vaccination uptake. Vaccine Safety Datalink data estimates were consistent with U.S. estimates.
Authors: Groom HC; Klein NP; Naleway AL; et al.
Am J Prev Med. 2016 Apr;50(4):480-8. Epub 2015-10-31.
Use of abacavir and risk of cardiovascular disease among HIV-infected individuals
Evidence is conflicting about the association of abacavir use and cardiovascular disease (CVD) among HIV-infected individuals. Previous studies may have been biased by the preferential initiation or continuation of abacavir in patients with renal dysfunction. We conducted a cohort study in Kaiser Permanente California during 1998-2011, following HIV-infected adults initiating antiretroviral therapy until the earliest of CVD (ie, coronary heart disease or ischemic stroke), health plan disenrollment, death, or end of study. We used inverse-probability weighting to fit marginal structural models to estimate hazard ratios (HRs) for CVD comparing regimens with and without abacavir. Propensity score models included demographics, HIV-specific factors, and CVD risk factors, including alcohol/drug use, smoking, overweight/obesity, diabetes, lipid-lowering and hypertension therapy, and renal dysfunction (ie, estimated glomerular filtration rate <60 mL·min·1.73 m). Among 8154 subjects, 178 had ?1 CVD event, with 24/704 (3.4%) in the abacavir group and 154/7450 (2.1%) in the group initiating regimens without abacavir. Abacavir users had more renal dysfunction at antiretroviral therapy initiation (7.0% vs. 3.3%, P < 0.001). Compared with patients initiating regimens without abacavir, abacavir users had a 2.2-fold higher risk of CVD in intention-to-treat analysis [HR 2.2, 95% confidence interval (CI): 1.4 to 3.5], a 2.7-fold higher risk when remaining on their initial regimens for ?1 year (HR 2.7, 95% CI: 1.5 to 5.0), and a 2.1-fold higher risk in per-protocol analysis (HR 2.1, 95% CI: 0.9 to 5.0). Abacavir was associated with an over 2-fold increased risk of CVD, which was not explained by renal dysfunction or other CVD risk factors.
Authors: Marcus JL; Neugebauer RS; Leyden WA; Chao CR; Xu L; Quesenberry CP; Klein DB; Towner WJ; Horberg MA; Silverberg MJ
J Acquir Immune Defic Syndr. 2016 Apr 1;71(4):413-9.
Risk of anaphylaxis after vaccination in children and adults
Anaphylaxis is a potentially life-threatening allergic reaction. The risk of anaphylaxis after vaccination has not been well described in adults or with newer vaccines in children. We sought to estimate the incidence of anaphylaxis after vaccines and describe the demographic and clinical characteristics of confirmed cases of anaphylaxis. Using health care data from the Vaccine Safety Datalink, we determined rates of anaphylaxis after vaccination in children and adults. We first identified all patients with a vaccination record from January 2009 through December 2011 and used diagnostic and procedure codes to identify potential anaphylaxis cases. Medical records of potential cases were reviewed. Confirmed cases met the Brighton Collaboration definition for anaphylaxis and had to be determined to be vaccine triggered. We calculated the incidence of anaphylaxis after all vaccines combined and for selected individual vaccines. We identified 33 confirmed vaccine-triggered anaphylaxis cases that occurred after 25,173,965 vaccine doses. The rate of anaphylaxis was 1.31 (95% CI, 0.90-1.84) per million vaccine doses. The incidence did not vary significantly by age, and there was a nonsignificant female predominance. Vaccine-specific rates included 1.35 (95% CI, 0.65-2.47) per million doses for inactivated trivalent influenza vaccine (10 cases, 7,434,628 doses given alone) and 1.83 (95% CI, 0.22-6.63) per million doses for inactivated monovalent influenza vaccine (2 cases, 1,090,279 doses given alone). The onset of symptoms among cases was within 30 minutes (8 cases), 30 to less than 120 minutes (8 cases), 2 to less than 4 hours (10 cases), 4 to 8 hours (2 cases), the next day (1 case), and not documented (4 cases). Anaphylaxis after vaccination is rare in all age groups. Despite its rarity, anaphylaxis is a potentially life-threatening medical emergency that vaccine providers need to be prepared to treat.
Authors: McNeil MM; Klein NP; DeStefano F; et al.
J Allergy Clin Immunol. 2016 Mar;137(3):868-78. Epub 2015-10-06.
Waning Tdap Effectiveness in Adolescents
Because the effectiveness of diphtheria-tetanus-acellular pertussis (DTaP) vaccine wanes substantially after the fifth dose at ages 4 to 6 years, there is a growing cohort of adolescents who rely on tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) for protection against pertussis. Yet despite high Tdap vaccine coverage among adolescents, California experienced large pertussis outbreaks in 2010 and 2014. We investigated Tdap vaccine effectiveness (VE) and waning within Kaiser Permanente Northern California among adolescents exclusively vaccinated with DTaP vaccines. We modeled pertussis risk in relation to Tdap vaccination status among adolescents beginning on their 10th birthday. We estimated the hazard ratio (HR) for each subsequent year after Tdap compared with unvaccinated adolescents by using Cox regression, adjusting for calendar time, age, gender, race, and facility. We calculated VE as 1 – HR. We also treated time since Tdap vaccination as a continuous variable and estimated the change in the HR per 1-year increase since vaccination. On the basis of 1207 pertussis cases, Tdap VE during the first year after vaccination was 68.8% (95% confidence interval [CI] 59.7% to 75.9%), decreasing to 8.9% (95% CI -30.6% to 36.4%) by ?4 years after vaccination. Adolescents who were more remote from Tdap were significantly more likely to test positive for pertussis than were those vaccinated more recently (HR per year 1.35, 95% CI 1.22 to 1.50). Routine Tdap did not prevent pertussis outbreaks. Among adolescents who have only received DTaP vaccines in childhood, Tdap provided moderate protection against pertussis during the first year and then waned rapidly so that litle protection remained 2-3 years after vaccination..
Authors: Klein NP; Bartlett J; Fireman B; Baxter R
Pediatrics. 2016 Mar;137(3):e20153326. Epub 2016-02-05.
Successful Implementation of HIV Preexposure Prophylaxis: Lessons Learned From Three Clinical Settings
The past 3years have marked a transition from research establishing the safety and efficacy of HIV preexposure prophylaxis (PrEP) to questions about how to optimize its implementation. Until recently, PrEP was primarily offered as part of randomized controlled trials or open-label studies. These studies highlighted the key components of PrEP delivery, including regular testing for HIV and other sexually transmitted infections (STIs), adherence and risk-reduction support, and monitoring for renal toxicity. PrEP is now increasingly provided in routine clinical settings. This review summarizes models for PrEP implementation from screening through initiation and follow-up, focusing on the strengths and weaknesses of three delivery systems: a health maintenance organization, an STI clinic, and a primary care practice. These early implementation experiences demonstrate that PrEP can be successfully delivered across a variety of settings and highlight strategies to streamline PrEP delivery in clinical practice.
Authors: Marcus JL; Volk JE; Pinder J; Liu AY; Bacon O; Hare CB; Cohen SE
Curr HIV/AIDS Rep. 2016 Feb 22.
Maternal Tdap vaccination: Coverage and acute safety outcomes in the vaccine safety datalink, 2007-2013
Since October 2012, the combined tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) has been recommended in the United States during every pregnancy. In this observational study from the Vaccine Safety Datalink, we describe receipt of Tdap during pregnancy among insured women with live births across seven health systems. Using a retrospective matched cohort, we evaluated risks for selected medically attended adverse events in pregnant women, occurring within 42 days of vaccination. Using a generalized estimating equation, we calculated adjusted incident rate ratios (AIRR). Our vaccine coverage cohort included 438,487 live births between January 1, 2007 and November 15, 2013. Across the coverage cohort, 14% received Tdap during pregnancy. By 2013, Tdap was administered during pregnancy in 41.7% of live births, primarily in the 3rd trimester. Our vaccine safety cohort included 53,885 vaccinated and 109,253 matched unvaccinated pregnant women. There was no increased risk for a composite outcome of medically attended acute adverse events within 3 days of vaccination. Similarly, across the safety cohort, over a 42 day window, incident neurologic events, thrombotic events, and new onset proteinuria did not differ by maternal receipt of Tdap. Among women receiving Tdap at 20 weeks gestation or later, as compared to their matched controls, there was no increased risk for gestational diabetes or cardiac events while venous thromboembolic events and thrombocytopenia were diagnosed within 42 days of vaccination at slightly decreased rates. Tdap coverage during pregnancy increased from 2007 through 2013, but was still below 50%. No acute maternal safety signals were detected in this large cohort.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
Vaccine. 2016 Feb 10;34(7):968-73. Epub 2016-01-04.
Absence of venous thromboembolism risk following quadrivalent human papillomavirus vaccination, Vaccine Safety Datalink, 2008-2011
To investigate concerns about a potential association between quadrivalent human papillomavirus vaccination (HPV4) and venous thromboembolism (VTE), we conducted a self-controlled case series study in adolescents and young adults 9-26 years of age in the Vaccine Safety Datalink. We identified potential VTE cases diagnosed in 2008 through 2011 who had also received at least one HPV4 dose during that period. We confirmed each presumptive diagnosis by medical record review. We calculated incidence rate ratios (IRRs) and 95% confidence intervals (CI) to estimate the risk in the 1-60 day period following HPV4 exposure and in subsets of that period. IRRs were stratified by age, gender, hormonal contraceptive use, and recent surgery or trauma. We identified 313 potential cases of VTE among HPV4 vaccinees, and 291 (93%) had sufficient medical records for review. Of these, we confirmed 156 (54%) cases. VTE was uncommon among males (n=3) and 9-12 year olds (n=4). Nearly all confirmed cases (97%) had at least one known risk factor for VTE, including hormonal contraceptive use, obesity, and hypercoagulability. Sixteen (10%) confirmed cases occurred in the 1-60 days following HPV4 exposure. The risk of VTE varied from 1.47 (95% CI: 0.47-4.64) in the 1-7 days following HPV4 exposure to 0.92 (95% CI: 0.54-1.57) in the 1-60 days following vaccination. It was not possible to calculate a stratified IRR for males due to small sample size; the other risk factors evaluated did not significantly affect the risk of VTE after HPV4 exposure. The risk of developing VTE among 9- to 26-year-olds was not elevated following HPV4 exposure. Sample size limited our ability to rigorously evaluate potential effect modifiers, such as gender, through stratified analysis.
Authors: Naleway AL; Klein NP; Vaccine Safety Datalink; et al.
Vaccine. 2016 Jan 2;34(1):167-71. Epub 2015-Nov-06.
A picture is worth a thousand words: maps of HIV indicators to inform research, programs, and policy from NA-ACCORD and CCASAnet clinical cohorts
Maps are powerful tools for visualization of differences in health indicators by geographical region, but multi-country maps of HIV indicators do not exist, perhaps due to lack of consistent data across countries. Our objective was to create maps of four HIV indicators in North, Central, and South American countries. Using data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet), we mapped median CD4 at presentation for HIV clinical care, proportion retained in HIV primary care, proportion prescribed antiretroviral therapy (ART), and the proportion with suppressed plasma HIV viral load (VL) from 2010 to 2012 for North, Central, and South America. The 15 Canadian and US clinical cohorts and 7 clinical cohorts in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru represented approximately 2-7% of persons known to be living with HIV in these countries. Study populations were selected for each indicator: median CD4 at presentation for care was estimated among 14,811 adults; retention was estimated among 87,979 adults; ART use was estimated among 84,757 adults; and suppressed VL was estimated among 51,118 adults. Only three US states and the District of Columbia had a median CD4 at presentation >350 cells/mm(3). Haiti, Mexico, and several states had >85% retention in care; lower (50-74%) retention in care was observed in the US West, South, and Mid-Atlantic, and in Argentina, Brazil, and Peru. ART use was highest (90%) in Mexico. The percentages of patients with suppressed VL in the US South and Northeast were lower than in most of Central and South America. These maps provide visualization of gaps in the quality of HIV care and allow for comparison between and within countries as well as monitoring policy and programme goals within geographical boundaries.
Authors: Althoff KN; Sierra-Madero J; North American Aids Cohort Collaboration on Research and Design (NA-ACCORD) and Caribbean, Central and South America Network for Hiv Epidemiology (CCASAnet); et al.
J Int AIDS Soc. 2016;19(1):20707. Epub 2016-04-04.
Predictive value of prostate specific antigen in a European HIV-positive cohort: does one size fit all?
It is common practice to use prostate specific antigen (PSA) ≥4.0 ng/ml as a clinical indicator for men at risk of prostate cancer (PCa), however, this is unverified in HIV+ men. We aimed to describe kinetics and predictive value of PSA for PCa in HIV+ men. A nested case control study of 21 men with PCa and 40 matched-controls within EuroSIDA was conducted. Prospectively stored plasma samples before PCa (or matched date in controls) were measured for the following markers: total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG). Conditional logistic regression models investigated associations between markers and PCa. Mixed models were used to describe kinetics. Sensitivity and specificity of using tPSA >4 ng/ml to predict PCa was calculated. Receiver operating characteristic curves were used to identify optimal cutoffs in HIV+ men for total PSA. 61 HIV+ men were included with a median 6 (IQR 2-9) years follow-up. Levels of tPSA increased by 13.7% per year (95% CI 10.3, 17.3) in cases, but was stable in controls (-0.4%; 95% CI -2.5, 1.7). Elevated PSA was associated with higher odds of PCa at first (OR for twofold higher 4.7; 95% CI 1.7, 12.9; P<0.01) and last sample (8.1; 95% CI 1.1, 58.9; P=0.04). A similar relationship was seen between fPSA and PCa. Testosterone and SHBG level were not associated with PCa. tPSA level >4 ng/ml had 99% specificity and 38% sensitivity. The optimal PSA cutoff was 1.5 ng/ml overall (specificity =84%, sensitivity =81%). PSA was highly predictive of PCa in HIV+ men; however, the commonly used PSA>4 ng/ml to indicate high PCa risk was not sensitive in our population and use of the lower cutoff of PSA>1.5 ng/ml warrants consideration.
Authors: Shepherd L; Silverberg M; EuroSIDA in EuroCOORD; et al.
Antivir Ther (Lond). 2016;21(6):529-534. Epub 2016-01-29.
Rising Obesity Prevalence and Weight Gain Among Adults Starting Antiretroviral Therapy in the United States and Canada
The proportion of overweight and obese adults in the United States and Canada has increased over the past decade, but temporal trends in body mass index (BMI) and weight gain on antiretroviral therapy (ART) among HIV-infected adults have not been well characterized. We conducted a cohort study comparing HIV-infected adults in the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD) to United States National Health and Nutrition Examination Survey (NHANES) controls matched by sex, race, and age over the period 1998 to 2010. Multivariable linear regression assessed the relationship between BMI and year of ART initiation, adjusting for sex, race, age, and baseline CD4(+) count. Temporal trends in weight on ART were assessed using a generalized least-squares model further adjusted for HIV-1 RNA and first ART regimen class. A total of 14,084 patients from 17 cohorts contributed data; 83% were male, 57% were nonwhite, and the median age was 40 years. Median BMI at ART initiation increased from 23.8 to 24.8?kg/m(2) between 1998 and 2010 in NA-ACCORD, but the percentage of those obese (BMI ?30?kg/m(2)) at ART initiation increased from 9% to 18%. After 3 years of ART, 22% of individuals with a normal BMI (18.5-24.9?kg/m(2)) at baseline had become overweight (BMI 25.0-29.9 kg/m(2)), and 18% of those overweight at baseline had become obese. HIV-infected white women had a higher BMI after 3 years of ART as compared to age-matched white women in NHANES (p?=?0.02), while no difference in BMI after 3 years of ART was observed for HIV-infected men or non-white women compared to controls. The high prevalence of obesity we observed among ART-exposed HIV-infected adults in North America may contribute to health complications in the future.
Authors: Koethe JR; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
AIDS Res Hum Retroviruses. 2016 Jan;32(1):50-8. Epub 2015-09-09.
Prevalence of non-HIV cancer risk factors in persons living with HIV/AIDS: a meta-analysis
The burden of cancer among persons living with HIV/AIDS (PLWHA) is substantial and increasing. We assessed the prevalence of modifiable cancer risk factors among adult PLWHA in Western high-income countries since 2000. Meta-analysis. We searched PubMed to identify articles published in 2011-2013 reporting prevalence of smoking, alcohol consumption, overweight/obesity, and infection with human papillomavirus (HPV), hepatitis C virus (HCV) and hepatitis B virus (HBV) among PLWHA. We conducted random effects meta-analyses of prevalence for each risk factor, including estimation of overall, sex-specific, and HIV-transmission-group-specific prevalence. We compared prevalence in PLWHA with published prevalence estimates in US adults. The meta-analysis included 113 publications. Overall summary prevalence estimates were current smoking, 54% [95% confidence interval (CI) 49-59%] versus 20-23% in US adults; cervical high-risk HPV infection, 46% (95% CI 34-58%) versus 29% in US females; oral high-risk HPV infection, 16% (95% CI 10-23%) versus 4% in US adults; anal high-risk HPV infection (men who have sex with men), 68% (95% CI 57-79%), with no comparison estimate available; chronic HCV infection, 26% (95% CI 21-30%) versus 0.9% in US adults; and HBV infection, 5% (95% CI 4-5%) versus 0.3% in US adults. Overweight/obesity prevalence (53%; 95% CI 46-59%) was below that of US adults (68%). Meta-analysis of alcohol consumption prevalence was impeded by varying assessment methods. Overall, we observed considerable study heterogeneity in prevalence estimates. Prevalence of smoking and oncogenic virus infections continues to be extraordinarily high among PLWHA, indicating a vital need for risk factor reduction efforts.
Authors: Park LS; Hernández-Ramírez RU; Silverberg MJ; Crothers K; Dubrow R
AIDS. 2016 Jan;30(2):273-91.
Laboratory Measures as Proxies for Primary Care Encounters: Implications for Quantifying Clinical Retention Among HIV-Infected Adults in North America
Because of limitations in the availability of data on primary care encounters, patient retention in human immunodeficiency virus (HIV) care is often estimated using laboratory measurement dates as proxies for clinical encounters, leading to possible outcome misclassification. This study included 83,041 HIV-infected adults from 14 clinical cohorts in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) who had ?1 HIV primary care encounters during 2000-2010, contributing 468,816 person-years of follow-up. Encounter-based retention (REB) was defined as ?2 encounters in a calendar year, ?90 days apart. Laboratory-based retention (RLB) was defined similarly, using the dates of CD4-positive cell counts or HIV-1 RNA measurements. Percentage of agreement and the ? statistic were used to characterize agreement between RLB and REB. Logistic regression with generalized estimating equations and stabilized inverse-probability-of-selection weights was used to elucidate temporal trends and the discriminatory power of RLB as a predictor of REB, accounting for age, sex, race/ethnicity, primary HIV risk factor, and cohort site as potential confounders. Both REB and RLB increased from 2000 to 2010 (from 67% to 78% and from 65% to 77%, respectively), though REB was higher than RLB throughout (P < 0.01). RLB agreed well with REB (80%-86% agreement; ? = 0.55-0.62, P < 0.01) and had a strong, imperfect ability to discriminate between persons retained and not retained in care by REB (C statistic: C = 0.81, P < 0.05). As a proxy for REB, RLB had a sensitivity and specificity of 84% and 77%, respectively, with misclassification error of 18%.
Authors: Rebeiro PF; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design; et al.
Am J Epidemiol. 2015 Dec 1;182(11):952-60. Epub 2015-11-17.
The HIV Care Cascade Measured Over Time and by Age, Sex, and Race in a Large National Integrated Care System
HIV care cascades can evaluate programmatic success over time. However, methodologies for estimating cascade stages vary, and few have evaluated differences by demographic subgroups. We examined cascade performance over time and by age, sex, and race/ethnicity in , providing HIV care in eight US states and Washington, DC. We created cascades for HIV+ members’ age ?13 for 2010-2012. We measured “linkage” (a visit/CD4 within 90 days of being diagnosed for new patients; ?1 medical visit/year if established); “retention” (?2 medical visits ?60 days apart); filled ART (filled ?3 months of combination ART); and viral suppression (HIV RNA <200 copies/mL last measured in year). The cascades were stratified by calendar year, sex, age, and race/ethnicity. We found men had statistically (p?
Authors: Horberg MA; Silverberg MJ; et al.
AIDS Patient Care STDS. 2015 Nov;29(11):582-90.
Polymorphisms In HLA Class II Genes Are Associated With Susceptibility To Staphylococcus aureus Infection In A Caucasian Population
Staphylococcus aureus (S. aureus) can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. A genomewide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45344 matched controls; 584,535 single nucleotide polymorphisms (SNP) were genotyped on a European-specific array. Coverage was increased by imputation of >25 million common SNPs using 1000 Genomes Reference panel. In addition human leukocyte antigen (HLA) serotypes were also imputed. ?Logistic regression assuming an additive genetic model revealed several imputed SNPs [e.g., SNP rs115231074: odds ratio (OR)=1.22, P=1.3 x 10(-10); rs35079132: OR=1.24, P=3.8 x 10(-8)] achieving genome-wide significance on chromosome 6 in HLA Class II region. One adjacent genotyped SNP was nearly genomewide significant (rs4321864 OR=1.13, P=8.8 x 10(-8)). These polymorphisms are located near HLA-DRA and HLA-DRB1 genes. Further logistic regression results where the most significant GWAS SNPs were conditioned on HLA-DRB1*04 serotype showed additional support for the strength of association between HLA Class II genetic variants with S. aureus infection. Our study results provide the first reported evidence of human genetic susceptibility to S. aureus infection.
Authors: DeLorenze GN; Nelson CL; Scott WK; Allen AS; Ray GT; Tsai AL; Quesenberry CP; Fowler VG
J Infect Dis. 2015 Oct 8.
Cumulative Incidence of Cancer Among Persons With HIV in North America: A Cohort Study
Cancer is increasingly common among persons with HIV. To examine calendar trends in cumulative cancer incidence and hazard rate by HIV status. Cohort study. North American AIDS Cohort Collaboration on Research and Design during 1996 to 2009. 86 620 persons with HIV and 196 987 uninfected adults. Cancer type-specific cumulative incidence by age 75 years and calendar trends in cumulative incidence and hazard rates, each by HIV status. Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; non-Hodgkin lymphoma, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%. Among persons with HIV, calendar trends in cumulative incidence and hazard rate decreased for Kaposi sarcoma and non-Hodgkin lymphoma. For anal, colorectal, and liver cancer, increasing cumulative incidence, but not hazard rate trends, were due to the decreasing mortality rate trend (-9% per year), allowing greater opportunity to be diagnosed. Despite decreasing hazard rate trends for lung cancer, Hodgkin lymphoma, and melanoma, cumulative incidence trends were not seen because of the compensating effect of the declining mortality rate. Secular trends in screening, smoking, and viral co-infections were not evaluated. Cumulative cancer incidence by age 75 years, approximating lifetime risk in persons with HIV, may have clinical utility in this population. The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation.
Authors: Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; et al.
Ann Intern Med. 2015 Oct 6;163(7):507-18.
Service Delivery and Patient Outcomes in Ryan White HIV/AIDS Program-Funded and -Nonfunded Health Care Facilities in the United States.
IMPORTANCE: Outpatient human immunodeficiency virus (HIV) health care facilities receive funding from the Ryan White HIV/AIDS Program (RWHAP) to provide medical care and essential support services that help patients remain in care and adhere to treatment. Increased access to Medicaid and private insurance for HIV-infected persons may provide coverage for medical care but not all needed support services and may not supplant the need for RWHAP funding. OBJECTIVE: To examine differences between RWHAP-funded and non-RWHAP-funded facilities and in patient outcomes between the 2 systems. DESIGN, SETTING, AND PARTICIPANTS: The study was conducted from June 1, 2009, to May 31, 2012, using data from the 2009 and 2011 cycles of the Medical Monitoring Project, a national probability sample of 8038 HIV-infected adults receiving medical care at 989 outpatient health care facilities providing HIV medical care. MAIN OUTCOMES AND MEASURES: Data were used to compare patient characteristics, service needs, and access to services at RWHAP-funded vs non-RWHAP-funded facilities. Differences in prescribed antiretroviral treatment and viral suppression were assessed. Data analysis was performed between February 2012 and June 2015. RESULTS: Overall, 34.4% of facilities received RWHAP funding and 72.8% of patients received care at RWHAP-funded facilities. With results reported as percentage (95% CI), patients attending RWHAP-funded facilities were more likely to be aged 18 to 29 years (8.5% [7.4%-9.5%] vs 5.0% [3.9%-6.2%]), female (29.2% [27.2%-31.2%] vs 20.1% [17.0%-23.1%]), black (47.5% [41.5%-53.5%] vs 25.8% [20.6%-31.0%]) or Hispanic (22.5% [16.4%-28.6%] vs 12.9% [10.6%-15.2%]), have less than a high school education (26.1% [24.0%-28.3%] vs 10.9% [8.7%-13.1%]), income at or below the poverty level (53.6% [50.3%-56.9%] vs 23.9% [19.7%-28.0%]), and lack health care coverage (25.0% [21.9%-28.1%] vs 6.1% [4.1%-8.0%]). The RWHAP-funded facilities were more likely to provide case management (76.1% [69.9%-82.2%] vs 15.4% [10.4%-20.4%]) as well as mental health (64.0% [57.0%-71.0%] vs 18.0% [14.0%-21.9%]), substance abuse (33.6% [27.0%-40.2%] vs 12.0% [8.0%-16.0%]), and other support services; patients attending RWHAP-funded facilities were more likely to receive these services. After adjusting for patient characteristics, the percentage prescribed ART antiretroviral therapy, reported as adjusted prevalence ratio (95% CI), was similar between RWHAP-funded and non-RWHAP-funded facilities (1.01 [0.99-1.03]), but among poor patients, those attending RWHAP-funded facilities were more likely to be virally suppressed (1.09 [1.02-1.16]). CONCLUSIONS AND RELEVANCE: A total of 72.8% of HIV-positive patients received care at RWHAP-funded facilities. Many had multiple social determinants of poor health and used services at RWHAP-funded facilities associated with improved outcomes. Without facilities supported by the RWHAP, these patients may have had reduced access to services elsewhere. Poor patients were more likely to achieve viral suppression if they received care at a RWHAP-funded facility.
Authors: Weiser J; Beer L; Frazier EL; Patel R; Dempsey A; Hauck H; Skarbinski J
JAMA Intern Med. 2015 Oct;175(10):1650-9. doi: 10.1001/jamainternmed.2015.4095.
Nearly Half Of US Adults Living With HIV Received Federal Disability Benefits In 2009.
The effects of HIV infection on national labor-force participation have not been rigorously evaluated. Using data from the Medical Monitoring Project and the National Health Interview Survey, we present nationally representative estimates of the receipt of disability benefits by adults living with HIV receiving care compared with the general US adult population. We found that in 2009, adults living with HIV were nine times more likely than adults in the general population to receive disability benefits. The risk of being on disability is also greater for younger and more educated adults living with HIV compared to the general population, which suggests that productivity losses can result from HIV infection. To prevent disability, early diagnosis and treatment of HIV are essential. This study offers a baseline against which to measure the impacts of recently proposed or enacted changes to Medicaid and private insurance markets, including the Affordable Care Act and proposed revisions to the Social Security Administration’s HIV Infection Listings.
Authors: Huang YL; Frazier EL; Sansom SL; Farnham PG; Shrestha RK; Hutchinson AB; Fagan JL; Viall AH; Skarbinski J
Health Aff (Millwood). 2015 Oct;34(10):1657-65. doi: 10.1377/hlthaff.2015.0249.
Body mass index and early CD4 T-cell recovery among adults initiating antiretroviral therapy in North America, 1998-2010
Adipose tissue affects several aspects of the cellular immune system, but prior epidemiological studies have differed on whether a higher body mass index (BMI) promotes CD4 T-cell recovery on antiretroviral therapy (ART). The objective of this analysis was to assess the relationship between BMI at ART initiation and early changes in CD4 T-cell count. We used the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data set to analyse the relationship between pre-treatment BMI and 12-month CD4 T-cell recovery among adults who started ART between 1998 and 2010 and maintained HIV-1 RNA levels ?30?kg/m(2) ). Pretreatment BMI was associated with 12-month CD4 T-cell change (P??30?kg/m(2) , the observed benefit was attenuated among men to a greater degree than among women, although this difference was not statistically significant. A BMI of approximately 30?kg/m(2) at ART initiation was associated with greater CD4 T-cell recovery at 12 months compared with higher or lower BMI values, suggesting that body composition may affect peripheral CD4 T-cell recovery.
Authors: Koethe JR; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
HIV Med. 2015 Oct;16(9):572-7. Epub 2015-05-11.
Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival
Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies. We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 patients with HIV-related diffuse large B-cell lymphoma (DLBCL) diagnosed in the era of combined antiretroviral therapy (1996-2007) at Kaiser Permanente California. Eighty patients with HIV-unrelated DLBCL were included for comparison. Data on patients’ clinical history were obtained from Kaiser Permanente’s electronic health records. The density of stromal CD4, CD8 and FOXP3 T cells and CD68 macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient’s clinical history or tumor characteristics were examined using Kruskal-Wallis tests or Pearson’s correlation coefficient. The effect of stromal immune infiltration on 2-year mortality was evaluated in multivariable logistic regression. Compared with HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4 and FOXP3 T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4 cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not Epstein-Barr virus infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3 T cells. A higher density of infiltrating CD8 T cell was significantly associated with reduced mortality in patients with HIV-related DLBCL (odds ratio?=?0.30 [0.09-0.97] for ?25 vs. <10%). These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.
Authors: Chao C; Xu L; Silverberg MJ; Martínez-Maza O; Chen LH; Castor B; Abrams DI; Zha HD; Haque R; Said J
AIDS. 2015 Sep 24;29(15):1943-51.
A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results
In US cervical screening, immediate colposcopy is recommended for women with HPV-positive ASC-US (equivocal) cytology. We evaluated whether partial typing by Onclarity ™ (BD) might identify HPV-positive women with low enough CIN3+ risk to permit 1-year follow-up instead. The NCI-Kaiser Permanente Northern California Persistence and Progression cohort includes a subset of 13,890 women aged 21+ with HC2 (Qiagen)-positive ASC-US at enrollment; current median follow-up is 3.0years. Using stratified random sampling, we typed 2079 archived enrollment specimens including 329 women subsequently diagnosed with CIN3+, 563 with CIN2, and 1187 with Authors: Schiffman M; Vaughan LM; Raine-Bennett TR; Castle PE; Katki HA; Gage JC; Fetterman B; Befano B; Wentzensen N Gynecol Oncol. 2015 Sep;138(3):573-8. Epub 2015-07-04.
An Overview of Quadrivalent Human Papillomavirus Vaccine Safety – 2006 to 2015
A quadrivalent human papillomavirus (HPV4) type 6/11/16/18 vaccine (GARDASIL/SILGARD®) has been licensed in many countries around the world for the prevention of cervical, vulvar, vaginal, and anal cancers and precancers, as well as external genital warts causally related to HPV types 6/11/16/18. Across 7 phase 3 clinical trials involving more than 29,000 males and females ages 9-45 years, vaccination was generally well tolerated. Because of its expected public health benefit in reducing cervical cancer and other HPV-related diseases, the vaccine has been implemented in the national vaccination programs of several countries, with over 178 million doses distributed worldwide. Extensive efforts to assess the safety of the vaccine in routine practice have been conducted over the past 9 years since licensure, including more than 15 studies in more than 1 million preadolescents, adolescents and adults from various countries. Most have been performed in the general population although there have been some in special populations (pregnant women, HIV-infected individuals and those with systemic lupus erythematosus). We present a summary of the published, postlicensure safety data from active and passive surveillance. Only syncope, and possibly skin infections were associated with vaccination in the postlicensure setting. Serious adverse events, such as adverse pregnancy outcomes, autoimmune diseases (including Guillain-Barre Syndrome and multiple sclerosis), anaphylaxis, venous thromboembolism and stroke, were extensively studied, and no increase in the incidence of these events was found compared with background rates. These results, along with the safety data from the prelicensure clinical trials, confirm that the HPV4 vaccine has a favorable safety profile. Key policy, medical and regulatory organizations around the world have independently reviewed these data and continue to recommend routine HPV vaccination.
Authors: Vichnin M; Klein NP; Kuter BJ; et al.
Pediatr Infect Dis J. 2015 Sep;34(9):983-91.
No New HIV Infections with Increasing Use of HIV Preexposure Prophylaxis in a Clinical Practice Setting
Referrals for and initiation of preexposure prophylaxis (PrEP) for HIV infection increased dramatically in a large clinical practice setting since 2012. Despite high rates of sexually transmitted infections among PrEP users and reported decreases in condom use in a subset, there were no new HIV infections in this population.
Authors: Volk JE; Marcus JL; Phengrasamy T; Blechinger D; Nguyen DP; Follansbee S; Hare CB
Clin Infect Dis. 2015 Sep 1.
Ryan White HIV/AIDS Program Assistance and HIV Treatment Outcomes.
BACKGROUND: The Ryan White HIV/AIDS Program (RWHAP) provides persons infected with human immunodeficiency virus (HIV) with services not covered by other healthcare payer types. Limited data exist to inform policy decisions about the most appropriate role for RWHAP under the Patient Protection and Affordable Care Act (ACA). METHODS: We assessed associations between RWHAP assistance and antiretroviral therapy (ART) prescription and viral suppression. We used data from the Medical Monitoring Project, a surveillance system assessing characteristics of HIV-infected adults receiving medical care in the United States. Interview and medical record data were collected in 2009-2013 from 18 095 patients. RESULTS: Nearly 41% of patients had RWHAP assistance; 15% relied solely on RWHAP assistance for HIV care. Overall, 91% were prescribed ART, and 75% were virally suppressed. Uninsured patients receiving RWHAP assistance were significantly more likely to be prescribed ART (52% vs 94%; P < .01) and virally suppressed (39% vs 77%; P < .01) than uninsured patients without RWHAP assistance. Patients with private insurance and Medicaid were 6% and 7% less likely, respectively, to be prescribed ART than those with RWHAP only (P < .01). Those with private insurance and Medicaid were 5% and 12% less likely, respectively, to be virally suppressed (P
Authors: Bradley H; Viall AH; Wortley PM; Dempsey A; Hauck H; Skarbinski J
Clin Infect Dis. 2016 Jan 1;62(1):90-98. doi: 10.1093/cid/civ708. Epub 2015 Aug 30.
Survival Among HIV-Infected and HIV-Uninfected Individuals with Common Non-AIDS-Defining Cancers
Non-AIDS-defining cancers increasingly contribute to mortality among human immunodeficiency virus (HIV)-infected individuals. However, few studies have compared cancer prognosis by HIV status with adjustment for risk factors. We conducted a cohort study of HIV-infected and HIV-uninfected adults in Kaiser Permanente California during 1996 to 2011, following subjects diagnosed with Hodgkin lymphoma or anal, prostate, colorectal, or lung cancers. We used Kaplan-Meier curves and Cox regression to assess cancer-related mortality within 5 years, comparing HIV-infected with HIV-uninfected subjects. Adjusted models included age, race/ethnicity, sex, cancer stage, cancer treatment, and smoking. Among HIV-infected and HIV-uninfected subjects, there were 68 and 51 cases of Hodgkin lymphoma, 120 and 28 of anal cancer, 150 and 2,050 of prostate cancer, 53 and 646 of colorectal cancer, and 80 and 507 of lung cancer, respectively. Five-year cancer-related survival was reduced for HIV-infected compared with HIV-uninfected subjects, reaching statistical significance for lung cancer (10% vs. 19%, P = 0.002) but not Hodgkin lymphoma (83% vs. 89%, P = 0.40) or anal (64% vs. 74%, P = 0.38), prostate (86% vs. 92%, P = 0.074), or colorectal cancers (49% vs. 58%, P = 0.55). Adjusted results were similar, with lung cancer [HR, 1.3; 95% confidence interval (CI), 1.0-1.7] and prostate cancer (HR, 2.1; 95% CI, 1.1-4.1) reaching significance. Cancer-related mortality was higher among HIV-infected compared with HIV-uninfected individuals for prostate and lung cancers, but not Hodgkin lymphoma, anal cancer, or colorectal cancer. Our findings emphasize the need for a focus on prevention, early detection, and adequate treatment of cancer among HIV-infected individuals.
Authors: Marcus JL; Chao C; Leyden WA; Xu L; Yu J; Horberg MA; Klein D; Towner WJ; Quesenberry CP; Abrams DI; Silverberg MJ
Cancer Epidemiol Biomarkers Prev. 2015 Aug;24(8):1167-73. Epub 2015-02-24.
Differentiating Sepsis From Adverse Events After Immunization in the Neonatal Intensive Care Unit: How Is a Physician to Know?
Authors: Kuzniewicz MW; Klein NP
JAMA Pediatr. 2015 Aug;169(8):718-9.
Differences in Response to Antiretroviral Therapy by Sex and Hepatitis C Infection Status
Hepatitis C virus (HCV) co-infection and biological sex may each affect response to antiretroviral therapy (ART), yet no studies have examined HIV-associated outcomes by both HCV status and sex. We conducted a cohort study of HIV-infected adults initiating ART in Kaiser Permanente California during 1996-2011. We used piecewise linear regression to assess CD4 changes by sex and HCV status over 5 years. We used Cox regression to estimate hazard ratios (HR) by sex and HCV status for HIV RNA <500 copies/mL over 1 year, and for AIDS and death over the follow-up period. Among 12,865 subjects, there were 154 HIV/HCV-co-infected women, 1000 HIV/HCV-co-infected men, 1088 HIV-mono-infected women, and 10,623 HIV-mono-infected men. CD4 increases were slower in the first year for HIV/HCV-co-infected women (75 cells/?L) and men (70 cells/?L) compared with HIV-mono-infected women (145 cells/?L) and men (120 cells/?L; p<0.001). After 5 years, women had higher CD4 than men in both HIV-mono-infected (598 vs. 562 cells/?L, p=0.003) and HIV/HCV-co-infected individuals (567 vs. 509 cells/?L, p=0.003). Regardless of sex, HIV/HCV co-infection was associated with 40% higher mortality [95% confidence interval (CI): 1.2-1.6] compared with HIV mono-infection, but was not associated with AIDS (HR 1.1, 95% CI: 0.9-1.3) or achieving HIV RNA <500 copies/mL (HR 1.0, 95% CI: 0.9-1.1). HIV/HCV-co-infected men and women have slower CD4 recovery after starting ART and have increased mortality compared with HIV-mono-infected men and women. HCV should be aggressively treated in HIV/HCV-co-infected adults, regardless of sex.
Authors: Marcus JL; Leyden WA; Chao CR; Xu L; Quesenberry CP; Tien PC; Klein DB; Towner WJ; Horberg MA; Silverberg MJ
AIDS Patient Care STDS. 2015 Jul;29(7):370-8. Epub 2015-05-18.
Contribution of Demographic and Behavioral Factors on the Changing Incidence Rates of Oropharyngeal and Oral Cavity Cancers in Northern California
It is unknown to what extent patient demographics, smoking, and alcohol use have contributed to changes in oropharyngeal and oral cavity cancer incidence rates. We performed a cohort study of Kaiser Permanente health plan members, ages 20 to 89, for years 1995-2010 (n = 2.2 million annual members). Poisson Regression models estimated calendar trends in cancer rates both adjusted for and stratified by age, sex, smoking, and alcohol abuse history. We identified 1,383 human papillomavirus (HPV)-related and 1,344 HPV-unrelated oral cavity and oropharyngeal cancer cases. With adjustment for age and sex, HPV-related cancer incidence rates increased 3.8% per year (P < 0.001) between 1995 and 2010, whereas rates for HPV-unrelated cancers decreased 2.4% per year (P < 0.001). For years 2007 to 2010, with additional adjustment for smoking and alcohol abuse, results were nonsignificant, but similar in magnitude. The increasing rates for HPV-related cancers were more prominent among nonsmokers (+14.5%) compared with smokers (-2.5%; P-interaction = 0.058). The decreased rates for HPV-unrelated sites were more prominent among those ? 60 years (-11.0%) compared with those <60 years (+16.8%; P-interaction = 0.006), among smokers (-9.7%) compared with nonsmokers (+8.4%; P-interaction = 0.055), and among those with an alcohol abuse history (-20.4%) compared with those without a history (+5.8%; P-interaction = 0.009). The observed increasing HPV-related cancer rates are most evident among nonsmokers, whereas the decreasing HPV-unrelated cancer rates are least evident among younger individuals, nonsmokers, and those without an alcohol abuse history. Continued vigilance for oropharyngeal and oral cavity cancer is warranted, including among those without traditional risk factors such as smoking and alcohol abuse.
Authors: Katzel JA; Merchant M; Chaturvedi AK; Silverberg MJ
Cancer Epidemiol Biomarkers Prev. 2015 Jun;24(6):978-84. Epub 2015-05-08.
Antiretroviral Therapy Adherence and Use of an Electronic Shared Medical Record Among People Living with HIV
Electronic shared medical records (SMR) are emerging healthcare technologies that allow patients to engage in their healthcare by communicating with providers, refilling prescriptions, scheduling appointments, and viewing portions of medical records. We conducted a pre-post cohort study of HIV-positive adults who used and did not use SMR in two integrated healthcare systems. We compared the difference in antiretroviral refill adherence between SMR users and age- and sex-frequency matched non-users from the 12-month period prior to SMR useto the 12-month period starting 6 months after initiation of SMR use. High adherence was maintained among SMR users (change = -0.11 %) but declined among non-users (change = -2.05 %; p = 0.003). Among SMR users, there was a steady improvement in adherence as monthly frequency of SMR use increased (p = 0.009). SMR use, particularly more frequent use, is associated with maintaining high adherence and non-use is associated with declines in adherence over time among patients with access to these online services.
Authors: Saberi P; Catz SL; Leyden WA; Stewart C; Ralston JD; Horberg MA; Grothaus L; Silverberg MJ
AIDS Behav. 2015 Jun;19 Suppl 2:177-85.
Declining Relative Risk for Myocardial Infarction Among HIV-Positive Compared With HIV-Negative Individuals With Access to Care
Concerns remain for an increased myocardial infarction (MI) risk among individuals infected with human immunodeficiency virus (HIV). We conducted a cohort study evaluating MI risk from 1996 to 2011 by HIV status. The adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval, .7-1.4) in 2010-2011, the most recent study period.
Authors: Klein DB; Leyden WA; Xu L; Chao CR; Horberg MA; Towner WJ; Hurley LB; Marcus JL; Quesenberry CP; Silverberg MJ
Clin Infect Dis. 2015 Apr 15;60(8):1278-80. Epub 2015-01-16.
Human immunodeficiency virus transmission at each step of the care continuum in the United States.
IMPORTANCE: Human immunodeficiency virus (HIV) transmission risk is primarily dependent on behavior (sexual and injection drug use) and HIV viral load. National goals emphasize maximizing coverage along the HIV care continuum, but the effect on HIV prevention is unknown. OBJECTIVES: To estimate the rate and number of HIV transmissions attributable to persons at each of the following 5 HIV care continuum steps: HIV infected but undiagnosed, HIV diagnosed but not retained in medical care, retained in care but not prescribed antiretroviral therapy, prescribed antiretroviral therapy but not virally suppressed, and virally suppressed. DESIGN, SETTING, AND PARTICIPANTS: A multistep, static, deterministic model that combined population denominator data from the National HIV Surveillance System with detailed clinical and behavioral data from the National HIV Behavioral Surveillance System and the Medical Monitoring Project to estimate the rate and number of transmissions along the care continuum. This analysis was conducted January 2013 to June 2014. The findings reflect the HIV-infected population in the United States in 2009. MAIN OUTCOMES AND MEASURES: Estimated rate and number of HIV transmissions. RESULTS: Of the estimated 1,148,200 persons living with HIV in 2009, there were 207,600 (18.1%) who were undiagnosed, 519,414 (45.2%) were aware of their infection but not retained in care, 47,453 (4.1%) were retained in care but not prescribed ART, 82,809 (7.2%) were prescribed ART but not virally suppressed, and 290,924 (25.3%) were virally suppressed. Persons who are HIV infected but undiagnosed (18.1% of the total HIV-infected population) and persons who are HIV diagnosed but not retained in medical care (45.2% of the population) were responsible for 91.5% (30.2% and 61.3%, respectively) of the estimated 45,000 HIV transmissions in 2009. Compared with persons who are HIV infected but undiagnosed (6.6 transmissions per 100 person-years), persons who were HIV diagnosed and not retained in medical care were 19.0% (5.3 transmissions per 100 person-years) less likely to transmit HIV, and persons who were virally suppressed were 94.0% (0.4 transmissions per 100 person-years) less likely to transmit HIV. Men, those who acquired HIV via male-to-male sexual contact, and persons 35 to 44 years old were responsible for the most HIV transmissions by sex, HIV acquisition risk category, and age group, respectively. CONCLUSIONS AND RELEVANCE: Sequential steps along the HIV care continuum were associated with reduced HIV transmission rates. Improvements in HIV diagnosis and retention in care, as well as reductions in sexual and drug use risk behavior, primarily for persons undiagnosed and not receiving antiretroviral therapy, would have a substantial effect on HIV transmission in the United States.
Authors: Skarbinski J; Rosenberg E; Paz-Bailey G; Hall HI; Rose CE; Viall AH; Fagan JL; Lansky A; Mermin JH
JAMA Intern Med. 2015 Apr;175(4):588-96. doi: 10.1001/jamainternmed.2014.8180.
The Impact of Age on Retention in Care and Viral Suppression
Retention in care is important for all HIV-infected persons and is strongly associated with initiation of antiretroviral therapy and viral suppression. However, it is unclear how retention in care and age interact to affect viral suppression. We evaluated whether the association between retention and viral suppression differed by age at entry into care. Cross-sectional analysis (2006-2010) involving 17,044 HIV-infected adults in 14 clinical cohorts across the United States and Canada. Patients contributed 1 year of data during their first full-calendar year of clinical observation. Poisson regression examined associations between retention measures [US National HIV/AIDS Strategy (NHAS), US Department of Health and Human Services (DHHS), 6-month gap, and 3-month visit constancy] and viral suppression (HIV RNA ?200 copies/mL) by age group: 18-29 years, 30-39 years, 40-49 years, 50-59 years, and 60 years or older. Overall, 89% of patients were retained in care using the NHAS measure, 74% with the DHHS indicator, 85% did not have a 6-month gap, and 62% had visits in 3-4 quarters of the year; 54% achieved viral suppression. For each retention measure, the association with viral suppression was significant for only the younger age groups (18-29 and 30-39 years): 18-29 years [adjusted prevalence ratio (APR) = 1.33, 95% confidence interval (CI): 1.03 to 1.70]; 30-39 years (APR = 1.23, 95% CI: 1.01 to 1.49); 40-49 years (APR = 1.06, 95% CI: 0.90 to 1.22); 50-59 (APR = 0.92, 95% CI: 0.75 to 1.13); ?60 years (APR = 0.99, 95% CI: 0.63 to 1.56) using the NHAS measure as a representative example. These results have important implications for improving viral control among younger adults, emphasizing the crucial role retention in care plays in supporting viral suppression in this population.
Authors: Yehia BR; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
J Acquir Immune Defic Syndr. 2015 Apr 1;68(4):413-9.
End Stage Renal Disease Among HIV-Infected Adults in North America
Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18-80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8-3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9-5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.
Authors: Abraham AG; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA); et al.
Clin Infect Dis. 2015 Mar 15;60(6):941-9. Epub 2014-11-18.
A comparative study of molecular characteristics of diffuse large B-cell lymphoma from patients with and without human immunodeficiency virus infection
HIV-related diffuse large B-cell lymphoma (DLBCL) may be biologically different from DLBCL in the general population. We compared, by HIV status, the expression and prognostic significance of selected oncogenic markers in DLBCL diagnosed at Kaiser Permanente in California, between 1996 and 2007. Eighty HIV-infected DLBCL patients were 1:1 matched to 80 HIV-uninfected DLBCL patients by age, gender, and race. Twenty-three markers in the following categories were examined using IHC: (i) cell-cycle regulators, (ii) B-cell activators, (iii) antiapoptotic proteins, and (iv) others, such as IgM. Tumor marker expression was compared across HIV infection status by Fisher exact test. For markers differentially expressed in HIV-related DLBCL, logistic regression was used to evaluate the association between tumor marker expression and 2-year overall mortality, adjusting for International Prognostic Index, cell-of-origin phenotype, and DLBCL morphologic variants. Expression of cMYC (% positive in HIV-related and -unrelated DLBCL: 64% vs. 32%), BCL6 (45% vs. 10%), PKC-?2 (61% vs. 4%), MUM1 (59% vs. 14%), and CD44 (87% vs. 56%) was significantly elevated in HIV-related DLBCLs, whereas expression of p27 (39% vs. 75%) was significantly reduced. Of these, cMYC expression was independently associated with increased 2-year mortality in HIV-infected patients [relative risk = 3.09 (0.90-10.55)] in multivariable logistic regression. These results suggest that HIV-related DLBCL pathogenesis more frequently involves cMYC and BCL6 among other factors. In particular, cMYC-mediated pathogenesis may partly explain the more aggressive clinical course of DLBCL in HIV-infected patients.
Authors: Chao C; Silverberg MJ; Xu L; Chen LH; Castor B; Martínez-Maza O; Abrams DI; Zha HD; Haque R; Said J
Clin Cancer Res. 2015 Mar 15;21(6):1429-37. Epub 2015-01-14.
Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys.
BACKGROUND: The negative health effects of cigarette smoking and HIV infection are synergistic. OBJECTIVE: To compare the prevalence of current cigarette smoking and smoking cessation between adults with HIV receiving medical care and adults in the general population. DESIGN: Nationally representative cross-sectional surveys. SETTING: United States. PATIENTS: 4217 adults with HIV who participated in the Medical Monitoring Project and 27 731 U.S. adults who participated in the National Health Interview Survey in 2009. MEASUREMENTS: The main exposure was cigarette smoking. The outcome measures were weighted prevalence of cigarette smoking and quit ratio (ratio of former smokers to the sum of former and current smokers). RESULTS: Of the estimated 419 945 adults with HIV receiving medical care, 42.4% (95% CI, 39.7% to 45.1%) were current cigarette smokers, 20.3% (CI, 18.6% to 22.1%) were former smokers, and 37.3% (CI, 34.9% to 39.6%) had never smoked. Compared with the U.S. adult population, in which an estimated 20.6% of adults smoked cigarettes in 2009, adults with HIV were nearly twice as likely to smoke (adjusted prevalence difference, 17.0 percentage points [CI, 14.0 to 20.1 percentage points]) but were less likely to quit smoking (quit ratio, 32.4% vs. 51.7%). Among adults with HIV, factors independently associated with greater smoking prevalence were older age, non-Hispanic white or non-Hispanic black race, lower educational level, poverty, homelessness, incarceration, substance use, binge alcohol use, depression, and not achieving a suppressed HIV viral load. LIMITATION: Cross-sectional design with some generalizability limitations. CONCLUSION: Adults with HIV were more likely to smoke and less likely to quit smoking than the general adult population. Tobacco screening and cessation strategies are important considerations as part of routine HIV care.
Authors: Mdodo R; Frazier EL; Dube SR; Mattson CL; Sutton MY; Brooks JT; Skarbinski J
Ann Intern Med. 2015 Mar 3;162(5):335-44. doi: 10.7326/M14-0954.
Incident Hepatitis C Virus Infections Among Users of HIV Preexposure Prophylaxis in a Clinical Practice Setting
Authors: Volk JE; Marcus JL; Phengrasamy T; Hare CB
Clin Infect Dis. 2015 Jun 1;60(11):1728-9. Epub 2015-02-18.
Safety of Measles-Containing Vaccines in 1-Year-Old Children
All measles-containing vaccines are associated with several types of adverse events, including seizure, fever, and immune thrombocytopenia purpura (ITP). Because the measles-mumps-rubella-varicella (MMRV) vaccine compared with the separate measles-mumps-rubella (MMR) and varicella (MMR + V) vaccine increases a toddler’s risk for febrile seizures, we investigated whether MMRV is riskier than MMR + V and whether either vaccine elevates the risk for additional safety outcomes. Study children were aged 12 to 23 months in the Vaccine Safety Datalink from 2000 to 2012. Nine study outcomes were investigated: 7 main outcomes (anaphylaxis, ITP, ataxia, arthritis, meningitis/encephalitis, acute disseminated encephalomyelitis, and Kawasaki disease), seizure, and fever. Comparing MMRV with MMR + V, relative risk was estimated by using stratified exact binomial tests. Secondary analyses examined post-MMRV or MMR + V risk versus comparison intervals; risk and comparison intervals were then contrasted for MMRV versus MMR+V. We evaluated 123,200 MMRV and 584,987 MMR + V doses. Comparing MMRV with MMR + V, risks for the 7 main outcomes were not significantly different. Several outcomes had few or zero postvaccination events. Comparing risk versus comparison intervals, ITP risk was higher after MMRV (odds ratio [OR]: 11.3 [95% confidence interval (CI): 1.9 to 68.2]) and MMR + V (OR: 10 [95% CI: 4.5 to 22.5]) and ataxia risk was lower after both vaccines (MMRV OR: 0.8 [95% CI: 0.5 to 1]; MMR + V OR: 0.8 [95% CI: 0.7 to 0.9]). Compared with MMR + V, MMRV increased risk of seizure and fever 7 to 10 days after vaccination. This study did not identify any new safety concerns comparing MMRV with MMR + V or after either the MMRV or the MMR + V vaccine. This study provides reassurance that these outcomes are unlikely after either vaccine.
Authors: Klein NP; Fireman B; Baxter R; et al.
Pediatrics. 2015 Feb;135(2):e321-9. Epub 2015-01-05.
Geographic Clusters in Underimmunization and Vaccine Refusal
Parental refusal and delay of childhood vaccines has increased in recent years and is believed to cluster in some communities. Such clusters could pose public health risks and barriers to achieving immunization quality benchmarks. Our aims were to (1) describe geographic clusters of underimmunization and vaccine refusal, (2) compare clusters of underimmunization with different vaccines, and (3) evaluate whether vaccine refusal clusters may pose barriers to achieving high immunization rates. We analyzed electronic health records among children born between 2000 and 2011 with membership in Kaiser Permanente Northern California. The study population included 154,424 children in 13 counties with continuous membership from birth to 36 months of age. We used spatial scan statistics to identify clusters of underimmunization (having missed 1 or more vaccines by 36 months of age) and vaccine refusal (based on International Classification of Diseases, Ninth Revision, Clinical Modification codes). We identified 5 statistically significant clusters of underimmunization among children who turned 36 months old during 2010-2012. The underimmunization rate within clusters ranged from 18% to 23%, and the rate outside them was 11%. Children in the most statistically significant cluster had 1.58 (P < .001) times the rate of underimmunization as others. Underimmunization with measles, mumps, rubella vaccine and varicella vaccines clustered in similar geographic areas. Vaccine refusal also clustered, with rates of 5.5% to 13.5% within clusters, compared with 2.6% outside them. Underimmunization and vaccine refusal cluster geographically. Spatial scan statistics may be a useful tool to identify locations with challenges to achieving high immunization rates, which deserve focused intervention.
Authors: Lieu TA; Ray GT; Klein NP; Chung C; Kulldorff M
Pediatrics. 2015 Feb;135(2):280-9. Epub 2015-01-19.
Childhood vaccines and Kawasaki disease, Vaccine Safety Datalink, 1996-2006
Kawasaki disease is a childhood vascular disorder of unknown etiology. Concerns have been raised about vaccinations being a potential risk factor for Kawasaki disease. Data from the Vaccine Safety Datalink were collected on children aged 0-6 years at seven managed care organizations across the United States. Defining exposure as one of several time periods up to 42 days after vaccination, we conducted Poisson regressions controlling for age, sex, season, and managed care organization to determine if rates of physician-diagnosed and verified Kawasaki disease were elevated following vaccination compared to rates during all unexposed periods. We also performed case-crossover analyses to control for unmeasured confounding. A total of 1,721,186 children aged 0-6 years from seven managed care organizations were followed for a combined 4,417,766 person-years. The rate of verified Kawasaki disease was significantly lower during the 1-42 days after vaccination (rate ratio=0.50, 95% CL=0.27-0.92) and 8-42 days after vaccination (rate ratio=0.45, 95% CL=0.22-0.90) compared to rates during unexposed periods. Breaking down the analysis by vaccination category did not identify a subset of vaccines which was solely responsible for this association. The case-crossover analyses revealed that children with Kawasaki disease had lower rates of vaccination in the 42 days prior to symptom onset for both physician-diagnosed Kawasaki disease (rate ratio=0.79, 95% CL=0.64-0.97) and verified Kawasaki disease (rate ratio=0.38, 95% CL=0.20-0.75). Childhood vaccinations’ studied did not increase the risk of Kawasaki disease; conversely, vaccination was associated with a transient decrease in Kawasaki disease incidence. Verifying and understanding this potential protective effect could yield clues to the underlying etiology of Kawasaki disease.
Authors: Abrams JY; Klein NP; Belay ED; et al.
Vaccine. 2015 Jan 3;33(2):382-7. Epub 2014-11-04.
Does preventing rotavirus infections through vaccination also protect against naturally-occurring intussusception over time?
Authors: Payne DC; Baggs J; Klein NP; Parashar UD
Clin Infect Dis. 2015 Jan 1;60(1):163-4. Epub 2014-09-23.
Cytology and human papillomavirus co-test results preceding incident high-grade cervical intraepithelial neoplasia
High-risk HPV (hrHPV) and cytology co-testing is utilized for primary cervical cancer screening and for enhanced follow-up of women who are hrHPV-positive, cytology negative. However, data are lacking on the utility of this method to detect pre-cancer or cancer in community-based clinical practice. This study describes cytology and hrHPV results preceding high-grade cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer (i.e., CIN2+) in an integrated health system employing routine co-testing among women aged 30 years and older. We conducted a cross-sectional analysis of adult female members of Kaiser Permanente Northern California (KPNC) with incident CIN2+ between July 2008 and June 2009. The primary outcome was the proportions of cytologic diagnoses and hrHPV co-test results preceding a diagnosis of CIN2+. Cervical cytology and hrHPV testing results were abstracted from electronic medical records. Of 1283 CIN2+ cases among adult women, 880 (68.5%) were among women aged 30 years and older and 145/880 (16.5%, 95% CI 14.1-19.1) had only normal cytology during the 12 months prior to diagnosis. Furthermore, 133/880 (15.1%, 95% 12.9-17.7) were preceded by only normal cytology and persistent hrHPV infection (at least 2 positive hrHPV tests) during the 6-36 months preceding CIN2+ diagnosis. Incident CIN2+ is frequently preceded by normal cytology and persistent hrHPV infection among women aged 30 years and older; screening strategies that employ HPV testing and cytology may improve the detection of CIN2+ compared with cytology alone.
Authors: Park IU; Wojtal N; Silverberg MJ; Bauer HM; Hurley LB; Manos MM
PLoS ONE. 2015;10(3):e0118938. Epub 2015-03-20.
Effectiveness of Telaprevir and Boceprevir Triple Therapy for Patients with Hepatitis C Virus Infection in a Large Integrated Care Setting
In 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting. We utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012. Compared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02). In the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.
Authors: Price JC; Murphy RC; Shvachko VA; Pauly MP; Manos MM
Dig Dis Sci. 2014 Dec;59(12):3043-52. Epub 2014-08-08.
Vertical transmission of hepatitis B virus
Authors: Kubo A; Shlager L; Corley DA
Ann Intern Med. 2014 Nov 18;161(10):763.
Evaluation of the association of maternal pertussis vaccination with obstetric events and birth outcomes
In 2010, due to a pertussis outbreak and neonatal deaths, the California Department of Health recommended that the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) be administered during pregnancy. Tdap is now recommended by the Advisory Committee on Immunization Practices for all pregnant women, preferably between 27 and 36 weeks’ gestation. Limited data exist on Tdap safety during pregnancy. To evaluate whether maternal Tdap vaccination during pregnancy is associated with increased risks of adverse obstetric events or adverse birth outcomes. Retrospective, observational cohort study using administrative health care databases from 2 California Vaccine Safety Datalink sites. Of 123,494 women with singleton pregnancies ending in a live birth between January 1, 2010, and November 15, 2012, 26,229 (21%) received Tdap during pregnancy and 97,265 did not. Risks of small-for-gestational-age (SGA) births (<10th percentile), chorioamnionitis, preterm birth (<37 weeks' gestation), and hypertensive disorders of pregnancy were evaluated. Relative risk (RR) estimates were adjusted for site, receipt of another vaccine during pregnancy, and propensity to receive Tdap during pregnancy. Cox regression was used for preterm delivery, and Poisson regression for other outcomes. Vaccination was not associated with increased risks of adverse birth outcomes: crude estimates for preterm delivery were 6.3% of vaccinated and 7.8% of unvaccinated women (adjusted RR, 1.03; 95% CI, 0.97-1.09); 8.4% of vaccinated and 8.3% of unvaccinated had an SGA birth (adjusted RR, 1.00; 95% CI, 0.96-1.06). Receipt of Tdap before 20 weeks was not associated with hypertensive disorder of pregnancy (adjusted RR, 1.09; 95% CI, 0.99-1.20); chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR, 1.19; 95% CI, 1.13-1.26). In this cohort of women with singleton pregnancies that ended in live birth, receipt of Tdap during pregnancy was not associated with increased risk of hypertensive disorders of pregnancy or preterm or SGA birth, although a small but statistically significant increased risk of chorioamnionitis diagnosis was observed.
Authors: Kharbanda EO; Klein NP; Nordin JD; et al.
JAMA. 2014 Nov 12;312(18):1897-904.
Incidence and risk factors of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma in HIV-infected individuals
To examine the risk and trends of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma (HNSCC) in HIV-infected individuals and assess whether immunosuppression (measured through CD4 cell count) and other risk factors impact HNSCC risk. Incident HNSCCs at HPV-related and HPV-unrelated anatomic sites were detected in HIV-infected participants from pooled data from 17 prospective studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) between 1996 and 2009. HNSCC cases were validated using chart review or cancer registry matching. Risk factors for incident HPV-related and HPV-unrelated HNSCC were explored using mixed effects Poisson regression in a full prospective analysis, and the effect of CD4 prior to cancer diagnosis was examined in a nested case control analysis. 66 HPV-related and 182 HPV-unrelated incident HNSCCs were detected among 82,375 HIV-infected participants. Standardized incidence ratios (SIRs) for both HPV-related (SIR=3.2, 95%CI=2.5-3.4) and HPV-unrelated (SIR=3.0, 95%CI=2.5-4.1) HNSCC were significantly elevated in HIV-infected individuals compared with the US general population. Between 1996 and 2009, the age-standardized HPV-related HNSCC incidence increased non-significantly from 6.8 to 11.4per 100,000 person-years (p-trend=0.31) while the age-standardized incidence of HPV-unrelated HNSCC decreased non-significantly from 41.9 to 29.3 per 100,000 person-years (p-trend=0.16). Lower CD4 cell count prior to cancer diagnosis was significantly associated with increased HPV-related and HPV-unrelated HNSCC risk. The standardized incidence of HPV-related and HPV-unrelated HNSCC are both elevated in HIV-infected individuals. Immunosuppression may have a role in the development of both HPV-related and HPV-unrelated HNSCC.
Authors: Beachler DC; Abraham AG; Silverberg MJ; Jing Y; Fakhry C; Gill MJ; Dubrow R; Kitahata MM; Klein MB; Burchell AN; Korthuis PT; Moore RD; D'Souza G; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA
Oral Oncol. 2014 Dec;50(12):1169-76. Epub 2014-10-06.
Receipt of pertussis vaccine during pregnancy across 7 Vaccine Safety Datalink Sites
In response to widespread pertussis outbreaks and infant deaths, in 2010, the California Department of Health (CDPH) and in 2011 the Advisory Committee on Immunization Practices (ACIP) advised that the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine be administered during pregnancy. The goals of this study were to describe Tdap coverage among pregnant women following these recommendations. In this observational cohort study, we utilized electronic medical record and claims data from seven Vaccine Safety Datalink sites to identify pregnancies and Tdap administrations. All Tdap doses were classified as pre-pregnancy, during pregnancy or post-pregnancy/postpartum. For pregnancies ending in a live birth, we evaluated factors associated with Tdap vaccination. Among 289,141 live births at the California VSD sites, receipt of Tdap during pregnancy increased substantially in the years 2010, 2011, and 2012, when coverage was 15.9, 30.0 and 19.5%, respectively. Among 82,398 women with live births at the Oregon, Washington, Colorado, Wisconsin and Minnesota VSD sites, receipt of Tdap during pregnancy first increased in 2012, at 16.0%. Women receiving early prenatal care and other vaccine(s) during pregnancy had higher Tdap coverage. We observed substantial increases in Tdap coverage during pregnancy following CDPH and ACIP recommendations.
Authors: Kharbanda EO; Vazquez-Benitez G; Lipkind H; Naleway AL; Klein NP; Cheetham TC; Hambidge SJ; Vellozzi C; Nordin JD
Prev Med. 2014 Oct;67:316-9. Epub 2014-06-18.
Integrating database knowledge and epidemiological design to improve the implementation of data mining methods that evaluate vaccine safety in large healthcare databases
Large healthcare databases maintained by health plans have been widely used to conduct customized protocol-based epidemiological safety studies as well as targeted routine sequential monitoring of suspected adverse events for newly licensed vaccines. These databases also offer a rich data source to discover vaccine-related adverse events not known prior to licensure using data mining methods, but they remain relatively under-utilized for this purpose. Initial safety applications of data mining methods using big healthcare data are promising, but stronger integration of database expertize, epidemiological design, and statistical analysis strategies are needed to better leverage the available information, reduce bias, and improve reporting transparency. We enumerate major methodological challenges in mining large healthcare databases for vaccine safety research, describe existing strategies that have been used to address these issues, and identify opportunities for methodological advancements that emphasize the importance of adapting techniques used in customized protocol-based vaccine safety assessments. Investment in such research methods and in the development of deeper collaborations between database safety experts and data mining methodologists has great potential to improve existing safety surveillance programs and further increase public confidence in the safety of newly licensed vaccines.
Authors: Nelson JC; Shrotreed SM; Yu O; Peterson D; Baxter R; Fireman B; Lewis N; McClure D; Weintraub E; Xu S; Jackson LA
Stat Anal Data Min. 2014 Oct;7(5):337-51.
The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety
The Vaccine Safety Datalink (VSD) is a collaborative project between the Centers for Disease Control and Prevention (CDC) and 9 health care organizations. Established in 1990, VSD is a vital resource informing policy makers and the public about the safety of vaccines used in the United States. Large linked databases are used to identify and evaluate adverse events in over 9 million individuals annually. VSD generates rapid, important safety assessments for both routine vaccinations and emergency vaccination campaigns. VSD monitors safety of seasonal influenza vaccines in near-real time, and provided essential information on the safety of influenza A (H1N1) 2009 monovalent vaccine during the recent pandemic. VSD investigators have published important studies demonstrating that childhood vaccines are not associated with autism or other developmental disabilities. VSD prioritizes evaluation of new vaccines; searches for possible unusual health events after vaccination; monitors vaccine safety in pregnant women; and has pioneered development of biostatistical research methods.
Authors: McNeil MM; Klein NP; DeStefano F; et al.
Vaccine. 2014 Sep 22;32(42):5390-8. Epub 2014-08-06.
HIV infection and incidence of ischemic stroke
To determine the association of HIV infection and immunodeficiency with incidence of ischemic stroke. Cohort study of HIV-positive and matched HIV-negative adult Kaiser Permanente Northern and Southern California (KPNC and KPSC, respectively) members during 1996-2011 (KPNC) or 2000-2011 (KPSC). We used Poisson models to obtain rate ratios for incident ischemic stroke associated with HIV infection, both overall and stratified by CD4 cell counts (cells/?l) and HIV RNA copies (copies/ml), with HIV-negative individuals as the reference group. We also obtained rate ratios for risk factors in the HIV-positive subset. Among 24,768 HIV-positive and 257,600 HIV-negative individuals, the ischemic stroke rate per 100,000 person-years was 125 (n = 151 events) for HIV-positive and 74 (n = 1128 events) for HIV-negative individuals, with an adjusted rate ratio of 1.4 [95% confidence interval (CI) 1.2-1.7). Compared with HIV-negative individuals, HIV-positive individuals with recent CD4 cell counts of 500 cells/?l at least (rate ratio 1.0, 95% CI 0.8-1.4) or recent HIV RNA less than 500 copies/ml (rate ratio 1.1, 95% CI 0.9-1.4) had no excess risk of ischemic stroke, with similar results for HIV-positive individuals with nadir CD4 cell counts of 500 cells/?l at least (rate ratio 1.4, 95% CI 0.8-2.2) or 200-499 cells/?l (rate ratio 1.2, 95% CI 0.9-1.5). Among HIV-positive individuals only, recent CD4 cell count less than 200 cells/?l (rate ratio 2.5, 95% CI 1.3-4.6) was associated with an increased risk of ischemic stroke after adjustment for recent HIV RNA and nadir CD4 cell count, whereas recent HIV RNA and nadir CD4 were not independent risk factors. Ischemic stroke incidence in HIV-positive individuals with high CD4 cell count or low HIV RNA is similar to that of HIV-negative individuals.
Authors: Marcus JL; Leyden WA; Chao CR; Chow FC; Horberg MA; Hurley LB; Klein DB; Quesenberry CP; Towner WJ; Silverberg MJ
AIDS. 2014 Aug 24;28(13):1911-9.
Prostate Cancer Incidence and Prostate-Specific Antigen Testing Among HIV-Positive and HIV-Negative Men
We investigated whether the reported lower incidence of prostate cancer in HIV-positive men is a result of confounding factors or reduced screening. We conducted a cohort study of 17,424 HIV-positive and 182,799 HIV-negative men enrolled in Kaiser Permanente (KP). Subjects were followed from the first KP enrollment after January 01, 1996 for KP Northern California (KPNC) and January 01, 2000 for KP Southern California until the earliest of prostate cancer diagnosis, loss to follow-up, or December 31, 2007. Poisson regression was used to compare cancer rates by HIV status adjusting for age, race, smoking, alcohol/drug abuse, overweight/obesity, and diabetes. For the KPNC subset, we analyzed additional available data by HIV status on testosterone deficiency, and on prostate-specific antigen (PSA) tests as a proxy for cancer screening. The prostate cancer incidence rate was 102/100,000 person-years in HIV-positive men (n = 74 cases) and 131/100,000 person-years in HIV-negative men (n = 1195 cases), with an adjusted rate ratio of 0.73 (95% confidence interval: 0.57 to 0.92; P = 0.008). The reduced risk among HIV-positive men was greater for higher-stage cancers, which are less likely to be biased by screening differences than lower-stage cancers. In the KPNC subset, more HIV-positive (90.8%) than HIV-negative men (86.2%) received a PSA test by age 55 (P < 0.001). Decreased risk for HIV-positive men remained when examined only among those with a previous PSA test, and with adjustment for testosterone deficiency (rate ratio = 0.55; 95% confidence interval: 0.39 to 0.80; P = 0.001). Prostate cancer incidence rates are lower in HIV-positive compared with HIV-negative men, which is not explained by screening differences or the risk factors evaluated.
Authors: Marcus JL; Chao CR; Leyden WA; Xu L; Klein DB; Horberg MA; Towner WJ; Quesenberry CP; Abrams DI; Van Den Eeden SK; Silverberg MJ
J Acquir Immune Defic Syndr. 2014 Aug 15;66(5):495-502.
Impact of Vaccination on the Epidemiology of Varicella: 1995-2009
When varicella vaccine was licensed in the United States in 1995, there were concerns that childhood vaccination might increase the number of adolescents susceptible to varicella and shift disease toward older age groups where it can be more severe. We conducted a series of 5 cross-sectional studies in 1994 to 1995 (prevaccine), 2000, 2003, 2006, and 2009 in Kaiser Permanente of Northern California to assess changes in varicella epidemiology in children and adolescents, as well as changes in varicella hospitalization in people of all ages. For each study, information on varicella history and varicella occurrence during the past year was obtained by telephone survey from a sample of ?8000 members 5 to 19 years old; varicella hospitalization rates were calculated for the entire membership. Between 1995 and 2009, the overall incidence of varicella in 5- to 19-year-olds decreased from 25.8 to 1.3 per 1000 person-years, a ?90% to 95% decline in the various age categories (5-9, 10-14, and 15-19 years of age). The proportion of varicella-susceptible children and adolescents also decreased in all age groups, including in 15- to 19-year-olds (from 15.6% in 1995 to 7.6% in 2009). From 1994 to 2009, age-adjusted varicella hospitalization rates in the general member population decreased from 2.13 to 0.25 per 100,000, a ?90% decline. In the 15 years after the introduction of varicella vaccine, a major reduction in varicella incidence and hospitalization was observed with no evidence of a shift in the burden of varicella to older age groups.
Authors: Baxter R; Tran TN; Ray P; Lewis E; Fireman B; Black S; Shinefield HR; Coplan PM; Saddier P
Pediatrics. 2014 Jul;134(1):24-30. Epub 2014-06-09.
Prevention of Vertical Transmission of Hepatitis B: An Observational Study
For mothers with chronic hepatitis B virus (HBV) infection, the Centers for Disease Control and Prevention recommends immunoprophylaxis to decrease perinatal transmission. However, its effectiveness and risk factors for failure have not been well-studied in community practice. To investigate the effectiveness of a contemporary immunoprophylaxis protocol. Observational study. An HBV perinatal immunoprophylaxis program within Kaiser Permanente Northern California. 4446 infants born to 3253 HBV-positive mothers between 1997 and 2010. Adherence to immunoprophylaxis, follow-up testing rates, maternal risk factors for HBV transmission, and transmission rates. The infant infection rate was 0.75 per 100 births from 1997 to 2010 (Poisson 95% CI, 0.48 to 1.10). Rates per 100 births were 3.37 (CI, 2.08 to 5.14) for e antigen-positive mothers and 0.04 (CI, 0.001 to 0.24) for e antigen-negative mothers. Among mothers with viral load testing, the lowest level associated with transmission was 6.32 × 107 IU/mL. Infection rates per 100 births were 3.61 (CI, 0.75 to 10.56) among the 83 births to mothers with viral loads of 5 × 107 IU/mL or greater and 0 among the 831 births to mothers with viral loads less than 5 × 107 IU/mL, regardless of e antigen status. Testing for HBV immunity and infection was less complete in earlier years. Viral load testing was only consistently available starting in 2007. Prenatal HBV screening followed by postnatal prophylaxis is highly effective in preventing vertical transmission of HBV. A negative e antigen status or a viral load less than 5 × 107 IU/mL (90.9% of women tested) identifies women at extremely low risk for transmission after immunoprophylaxis who are unlikely to benefit from further interventions. Kaiser Permanente Community Benefit and National Institutes of Health.
Authors: Kubo A; Shlager L; Marks AR; Lakritz D; Beaumont C; Gabellini K; Corley DA
Ann Intern Med. 2014 Jun 17;160(12):828-35.
Non-AIDS-Defining Malignancies in the HIV-Infected Population
With the advent of effective combination antiretroviral therapy, HIV infection has been transformed from a fatal disease to a chronic condition. There is renewed clinical interest in long-term morbidities, including malignancies that occur disproportionately within this population. Non-AIDS-defining cancers (NADCs) are a significant source of morbidity and mortality in the aging HIV-infected population. There are data to suggest that incidence rates are elevated among HIV-infected individuals for many cancer sites, particularly those with a confirmed or suspected infectious etiology. The complex interplay between behavioral risk factors, coexistence of viral infections, immunodeficiency and antiretroviral therapy makes it difficult to analyze why certain cancers develop more frequently in HIV-infected individuals. The challenge to clinicians caring for HIV-infected patients is to develop and implement effective means to screen, treat, and prevent NADCs in the future. This review presents data on whether NADCs are increased in the HIV-Infected population, as well as ongoing research on epidemiology, prevention and pathogenesis of this evolving aspect of the HIV epidemic.
Authors: Wang CC; Silverberg MJ; Abrams DI
Curr Infect Dis Rep. 2014 Jun;16(6):406.
Timely Versus Delayed Early Childhood Vaccination and Seizures
Little is known regarding the timing of childhood vaccination and postvaccination seizures. In a cohort of 323?247 US children from the Vaccine Safety Datalink born from 2004 to 2008, we analyzed the association between the timing of childhood vaccination and the first occurrence of seizure with a self-controlled case series analysis of the first doses of individual vaccines received in the first 2 years of life. In infants, there was no association between the timing of infant vaccination and postvaccination seizures. In the second year of life, the incident rate ratio (IRR) for seizures after receipt of the first measles-mumps-rubella vaccine (MMR) dose at 12 to 15 months was 2.65 (95% confidence interval [CI] 1.99-3.55); the IRR after an MMR dose at 16 to 23 months was 6.53 (95% CI 3.15-13.53). The IRR for seizures after receipt of the first measles-mumps-rubella-varicella vaccine (MMRV) dose at 12 to 15 months was 4.95 (95% CI 3.68-6.66); the IRR after an MMRV dose at 16 to 23 months was 9.80 (95% CI 4.35 -22.06). There is no increased risk of postvaccination seizure in infants regardless of timing of vaccination. In year 2, delaying MMR vaccine past 15 months of age results in a higher risk of seizures. The strength of the association is doubled with MMRV vaccine. These findings suggest that on-time vaccination is as safe with regard to seizures as delayed vaccination in the first year of life, and that delayed vaccination in the second year of life is associated with more postvaccination seizures than on-time vaccination.
Authors: Hambidge SJ; Klein NP; DeStefano F; et al.
Pediatrics. 2014 Jun;133(6):e1492-9.
Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine
In 2008, a diphtheria, tetanus, acellular pertussis, and inactivated poliovirus combined vaccine (DTaP-IPV) was licensed for use in children 4 through 6 years of age. While pre-licensure studies did not demonstrate significant safety concerns, the number vaccinated in these studies was not sufficient to examine the risk of uncommon but serious adverse events. To assess the risk of serious adverse events following DTaP-IPV vaccination. The study was conducted from January 2009 through September 2012 in the Vaccine Safety Datalink (VSD) project. In the VSD, electronic vaccination and encounter data are updated and aggregated weekly as part of ongoing surveillance activities. Based on previous reports and biologic plausibility, eight potential adverse events were monitored: meningitis/encephalitis; seizures; stroke; Guillain-Barré syndrome; Stevens-Johnson syndrome; anaphylaxis; serious allergic reactions other than anaphylaxis; and serious local reactions. Adverse event rates in DTaP-IPV recipients were compared to historical incidence rates in the VSD population prior to 2009. Sequential probability ratio testing was used to analyze the data on a weekly basis. During the study period, 201,116 children received DTaP-IPV vaccine. Ninety-seven percent of DTaP-IPV recipients also received other vaccines on the same day, typically measles-mumps-rubella and varicella vaccines. There was no statistically significant increased risk of any of the eight pre-specified adverse events among DTaP-IPV recipients when compared to historical incidence rates. In this safety surveillance study of more than 200,000 DTaP-IPV vaccine recipients, there was no evidence of increased risk for any of the pre-specified adverse events monitored. Continued surveillance of DTaP-IPV vaccine safety may be warranted to monitor for rare adverse events, such as Guillain-Barré syndrome.
Authors: Daley MF; Klein NP; Weintraub E; et al.
Vaccine. 2014 May 23;32(25):3019-24. Epub 2014-03-31.
Disparities in the quality of HIV care when using US Department of Health and Human Services Indicators
We estimated US Department of Health and Human Services (DHHS)-approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ?200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
Authors: Althoff KN; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
Clin Infect Dis. 2014 Apr;58(8):1185-9. Epub 2014-01-23.
Live Vaccine Use and Safety in DiGeorge Syndrome
Live vaccines are generally contraindicated in patients with DiGeorge syndrome (DGS), a congenital disorder characterized by cellular immune deficiency. Vaccine utilization and safety in this population are not well described. This study examined vaccination patterns and adverse events following live immunization (AEFLI) in these individuals. A multicenter retrospective cohort study was conducted in subjects with DGS confirmed by fluorescence in situ hybridization assay (chromosome 22q11.2 microdeletion). Live vaccine-preventable illnesses, vaccination coverage and timeliness, and AEFLIs in the 56-day window after live vaccination were examined. Bivariate and multivariable analyses assessed the impact of demographics medical history, timing of diagnostic confirmation, and preceding immune function on vaccination patterns and AEFLIs. Of 194 subjects, 77% and 75% received measles-mumps-rubella (MMR) and varicella vaccines, respectively; 58% completed recommended vaccinations by age 19 to 35 months. Adverse events occurred after 14% and 20% of MMR and varicella vaccine doses, respectively. Most events were minor, few were serious, and no deaths were reported in post-live vaccination windows. Although early diagnostic confirmation negatively affected live vaccination coverage and timeliness (P < .001), baseline CD4% did not differ between subjects who did or did not receive live vaccines by 12 to 18 months. Among varicella vaccine recipients, those with a subsequent adverse event had a lower preceding CD4% (24.8% ± 7.3%) than those without (35.5% ± 11.7%) (P < .05); no CD4% differences were observed with MMR vaccination. Fourteen unvaccinated subjects experienced live vaccine-preventable illnesses. Live vaccines were frequently given and generally well-tolerated among patients with DGS with mild-to-moderate immunosuppression.
Authors: Hofstetter AM; Jakob K; Klein NP; Dekker CL; Edwards KM; Halsey NA; Baxter R; Williams SE; Graham PL; LaRussa P
Pediatrics. 2014 Apr;133(4):e946-54. Epub 2014-03-31.
Telaprevir or boceprevir triple therapy in patients with chronic hepatitis C and varying severity of cirrhosis
Risks and benefits of protease inhibitor (PI) (telaprevir or boceprevir) triple therapy in hepatitis C virus (HCV)-infected patients with mildly decompensated cirrhosis, including those wait-listed for liver transplantation (LT), are incompletely known. To assess virological responses and safety of PI triple therapy in patients with mildly decompensated Child-Pugh (CP) CP ?6 vs. compensated (CP = 5) cirrhosis. Multicentre cohort of 160 adults with cirrhosis treated with peginterferon/ribavirin (peg-IFN/RBV) plus telaprevir (69%) or boceprevir (31%), comparing outcomes between those with CP = 5 and CP ?6. Patients, 47% with CP ?6 cirrhosis (CP range 6-10), received PI triple therapy for a targeted duration of 48 weeks. The cohort was median age 59 years, 32% female, 59% genotype 1a, 35% previous null/partial responders. Sustained virological response at 12 weeks (SVR12) was achieved by 35% of patients with CP ?6 vs. 54% of those with CP = 5 (P = 0.02). CP = 5, achievement of rapid virological response and genotype 1b/other, independently predicted SVR12. Compared to those with CP = 5, patients with CP ?6 had more peg-IFN dose reductions, eltrombopag use, transfusions and hospitalisations to manage adverse events (all P < 0.05). Overall, 67 (42%) discontinued treatment early. Nine wait-listed patients were treated for a median of 97 days (IQR 60-160) prior to liver transplantation and five achieved post-LT SVR. In the presence of mild decompensation (Child-Pugh ?6), SVR12 rates with protease inhibitor triple therapy are significantly reduced and adverse events increased. Thus, treatment with protease inhibitor triple therapy, if judged as necessary, should be undertaken with close monitoring and awareness of the significant risks.
Authors: Saxena V; Manos MM; Yee HS; Catalli L; Wayne E; Murphy RC; Shvachko VA; Pauly MP; Chua J; Monto A; Terrault NA
Aliment Pharmacol Ther. 2014 May;39(10):1213-24. Epub 2014-03-24.
Risk of Intussusception after Monovalent Rotavirus Vaccination
Although current rotavirus vaccines were not associated with an increased risk of intussusception in large trials before licensure, recent postlicensure data from international settings suggest the possibility of a small increase in risk of intussusception after monovalent rotavirus vaccination. We examined this risk in a population in the United States. Participants were infants between the ages of 4 and 34 weeks who were enrolled in six integrated health care organizations in the Vaccine Safety Datalink (VSD) project. We reviewed medical records and visits for intussusception within 7 days after monovalent rotavirus vaccination from April 2008 through March 2013. Using sequential analyses, we then compared the risk of intussusception among children receiving monovalent rotavirus vaccine with historical background rates. We further compared the risk after monovalent rotavirus vaccination with the risk in a concurrent cohort of infants who received the pentavalent rotavirus vaccine. During the study period, 207,955 doses of monovalent rotavirus vaccine (including 115,908 first doses and 92,047 second doses) were administered in the VSD population. We identified 6 cases of intussusception within 7 days after the administration of either dose of vaccine. For the two doses combined, the expected number of intussusception cases was 0.72, resulting in a significant relative risk of 8.4. For the pentavalent rotavirus vaccine, 1,301,810 doses were administered during the study period, with 8 observed intussusception cases (7.11 expected), for a nonsignificant relative risk of 1.1. The relative risk of chart-confirmed intussusception within 7 days after monovalent rotavirus vaccination, as compared with the risk after pentavalent rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The attributable risk of intussusception after the administration of two doses of monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants vaccinated. In this prospective postlicensure study of more than 200,000 doses of monovalent rotavirus vaccine, we observed a significant increase in the rate of intussusception after vaccination, a risk that must be weighed against the benefits of preventing rotavirus-associated illness. (Funded by the Centers for Disease Control and Prevention.).
Authors: Weintraub ES; Klein NP; DeStefano F; et al.
N Engl J Med. 2014 Feb 6;370(6):513-9. Epub 2014-01-14.
Vaccinations given during pregnancy, 2002-2009: a descriptive study
A number of studies have described influenza vaccination coverage during pregnancy but few publications have described rates of other vaccinations. To describe vaccination rates during pregnancy in the Vaccine Safety Datalink (VSD), with particular focus on vaccinations contraindicated during pregnancy. Pregnancies ending in 2002 through 2009 and vaccinations administered during these pregnancies were identified in the VSD. Vaccination rates per 1000 pregnancies during the study period were calculated by vaccine type, recommendation category, pregnancy year, maternal age, and trimester. Analyses were conducted in 2012-2013. In the VSD, 669,695 pregnancies and 141,389 vaccinations were identified. Trivalent inactivated influenza (TIV) was the most commonly administered vaccination (174.1 doses per 1000 pregnancies) and was most often administered during the 2nd and 3rd trimesters. The most common vaccines in the “consider if indicated” category were tetanus-diphtheria (6.1 per 1000) and hepatitis B (3.7 per 1000). Contraindicated vaccination was infrequent, and the majority of these were measles-mumps-rubella (MMR) (1.2 per 1000); varicella (1.0 per 1000); and live-attenuated influenza vaccine (LAIV) (0.3 per 1000). Both “consider if indicated” and contraindicated vaccines were more frequently administered during early pregnancy. TIV was the most commonly administered vaccine. With the exception of TIV, other vaccines were most frequently administered during early pregnancy and among younger women, suggesting that vaccination may occur when the woman and/or provider are unaware of the pregnancy. Contraindicated vaccines were infrequently administered during pregnancy; however, given that some women received contraindicated vaccines later in pregnancy, clearer recommendations and improved provider education may be needed.
Authors: Naleway AL; Klein NP; Weintraub E; et al.
Am J Prev Med. 2014 Feb;46(2):150-7.
Immunodeficiency and Risk of Myocardial Infarction Among HIV-Positive Individuals With Access to Care
We sought to clarify the association of HIV infection and immunodeficiency on myocardial infarction (MI) risk. We conducted a cohort study from 1996 to 2009 of HIV-positive (HIV) and demographically matched HIV-negative (HIV) Kaiser Permanente California health plan members. Rate ratios (RRs) were obtained from Poisson regression models comparing MI incidence rates between HIV (overall and stratified by recent and nadir CD4 count, and recent HIV RNA levels) and HIV subjects, adjusting for age, sex, calendar era, race/ethnicity, census-based socioeconomic status, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy. Among HIV subjects, we also evaluated the independent association of CD4, HIV RNA, and antiretroviral therapy (ART) use. The study population included 22,081 HIV and 230,069 HIV subjects. The crude MI incidence rate per 100,000 person-years was 283 and 165 for HIV and HIV subjects, respectively, with an adjusted RR of 1.4 [95% confidence interval (CI): 1.3 to 1.6]. Compared with HIV subjects (reference), MI rates were similar for HIV subjects with recent CD4 ?500 cells per microliter (RR = 1.18; 95% CI: 0.96 to 1.45) and those with nadir CD4 ?500 cells per microliter (RR = 0.85; 95% CI: 0.55 to 1.33). Among HIV subjects, nadir CD4 was the only HIV-specific factor associated with MIs (RR per 100 cells = 0.88; 95% CI: 0.81 to 0.96), whereas recent CD4 and HIV RNA, prior ART use, and duration of protease inhibitors and nonnucleoside reverse transcriptase inhibitors were not associated with MIs. HIV subjects with recent or nadir CD4 ?500 cells per microliter had similar MI rates compared with HIV subjects. Lower nadir CD4, in particular, seems to be independently associated with MIs. These results strengthen recommendations for earlier ART initiation.
Authors: Silverberg MJ; Leyden WA; Xu L; Horberg MA; Chao CR; Towner WJ; Hurley LB; Quesenberry CP; Klein DB
J Acquir Immune Defic Syndr. 2014 Feb 1;65(2):160-6.
Protective Association Between Rotavirus Vaccination and Childhood Seizures in the Year Following Vaccination in US Children
Rotavirus illness has been linked to childhood seizures. We investigated whether a protective association exists between receipt of rotavirus vaccine and being hospitalized or visiting the emergency department for seizures in the year after vaccination. We retrospectively analyzed a cohort of children born after 28 February 2006 (when rotavirus vaccine was licensed in the United States) and enrolled in the Vaccine Safety Datalink (VSD) through November 2009. Seizure rates from 4 to 55 weeks following last rotavirus vaccination were compared by vaccine exposure status (fully vaccinated and unvaccinated). A time-to-event analysis using a Cox proportional hazards model was performed, accounting for time-varying covariates. We calculated the relative incidence of seizure compared by vaccine exposure status during the postexposure interval. Our cohort contained VSD data on 250 601 infants, including 186 502 children fully vaccinated (74.4%) and 64 099 (25.6%) not vaccinated with rotavirus vaccine. Rates of seizures were associated with rotavirus vaccination status. After adjusting for covariates (VSD site, age at last dose, sex, and calendar month of the index date), a statistically significant protective association was observed between a full course of rotavirus vaccination vs no vaccination for both first-ever seizures (risk ratio [RR] = 0.82; 95% confidence interval [CI], .73-.91) and all seizures (RR = 0.79; 95% CI, .71-.88). A full course of rotavirus vaccination was statistically associated with an 18%-21% reduction in risk of seizure requiring hospitalization or emergency department care in the year following vaccination, compared with unvaccinated children. This reduction in childhood seizures complements the well-documented vaccine-related benefit of preventing US diarrhea hospitalizations.
Authors: Payne DC; Baggs J; Zerr DM; Klein NP; Yih K; Glanz J; Curns AT; Weintraub E; Parashar UD
Clin Infect Dis. 2014 Jan;58(2):173-7. Epub 2013-11-20.
Predictive value of prostate-specific antigen for prostate cancer: a nested case-control study in EuroSIDA
Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV- men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV- men. We aimed to describe the kinetics and predictive value of PSA in HIV+ men. Men with PCa (n=21) and up to two matched controls (n=40) with prospectively stored plasma samples before PCa (or matched date in controls) were selected. Cases and controls were matched on date of first and last sample, age, region of residence and CD4 count at first sample date. Total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG) were measured. Conditional logistic regression models investigated associations between markers and PCa. Sensitivity and specificity of using tPSA >4 µg/L to predict PCa was calculated. Mixed models were used to describe kinetics. Sixty-one men were included with a median six (IQR 2-9) years follow-up. Time between last sample and PCa was seven (4-11) months. Cases and controls were well matched at first sample, with a median age of 51 (IQR 48-57) and CD4 of 437 (243-610) cells/mm(3). Median tPSA [2.8 (IQR: 1.6-4.6) and 0.8 (0.5-1.2) µg/L] and fPSA [0.4 (0.2-0.8) and 0.3 (0.2-0.4) µg/L] levels were higher in cases than controls at first sample. Both tPSA and fPSA increased significantly over time in cases (Figure 1), to a median at last sample of 6.1 (4.7-9.5) and 0.9 (0.6-1.3) µg/L, respectively, but were stable in controls, with a median at last sample of 0.8 (0.5-1.4) and 0.2 (0.2-0.4) µg/L (Figure). Higher levels of tPSA and fPSA were associated with higher odds of PCa at first sample [OR for 2-fold higher 4.7 (CI: 1.7-12.9) and 5.4 (1.7-17.4)]. Elevated tPSA values in cases were detectable ?5 years before PCa (p<0.01). Testosterone [overall median 19.4 (IQR 15.3-23.9) nmol/L at first sample) and SHBG [50.0 (34.0-66.0) nmol/L] levels were similar in cases and controls at first and last sample (all p>0.7). The most informative predictor of PCa was tPSA (AUC=0.9), followed by fPSA (0.8). Testosterone (AUC = 0.5) and SHBG (0.5) were poor predictors of PCa. Overall, tPSA level >4 µg/L had 99% specificity and 37% sensitivity. Performance was best in the year prior to PCa (specificity: 99%, sensitivity: 88%). PSA was highly predictive of PCa in HIV+ men. Our results indicate that PSA screening in HIV+ men may be useful, and further work is needed to identify potentially age-related cut-offs to maximize sensitivity and specificity to identify those for further evaluation at early stages of PCa.
Authors: Shepherd L; Silverberg M; EuroSIDA in Eurocoord; et al.
J Int AIDS Soc. 2014;17(4 Suppl 3):19510. Epub 2014-11-02.
Strong agreement of nationally recommended retention measures from the institute of medicine and department of health and human services
We sought to quantify agreement between Institute of Medicine (IOM) and Department of Health and Human Services (DHHS) retention indicators, which have not been compared in the same population, and assess clinical retention within the largest HIV cohort collaboration in the U.S. Observational study from 2008-2010, using clinical cohort data in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Retention definitions used HIV primary care visits. The IOM retention indicator was: ?2 visits, ?90 days apart, each calendar year. This was extended to a 2-year period; retention required meeting the definition in both years. The DHHS retention indicator was: ?1 visit each semester over 2 years, each ?60 days apart. Kappa statistics detected agreement between indicators and C statistics (areas under Receiver-Operating Characteristic curves) from logistic regression analyses summarized discrimination of the IOM indicator by the DHHS indicator. Among 36,769 patients in 2008-2009 and 34,017 in 2009-2010, there were higher percentages of participants retained in care under the IOM indicator than the DHHS indicator (80% vs. 75% in 2008-2009; 78% vs. 72% in 2009-2010, respectively) (p<0.01), persisting across all demographic and clinical characteristics (p<0.01). There was high agreement between indicators overall (??=?0.83 in 2008-2009; ??=?0.79 in 2009-2010, p<0.001), and C statistics revealed a very strong ability to predict retention according to the IOM indicator based on DHHS indicator status, even within characteristic strata. Although the IOM indicator consistently reported higher retention in care compared with the DHHS indicator, there was strong agreement between IOM and DHHS retention indicators in a cohort demographically similar to persons living with HIV/AIDS in the U.S. Persons with poorer retention represent subgroups of interest for retention improvement programs nationally, particularly in light of the White House Executive Order on the HIV Care Continuum.
Authors: Rebeiro PF; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD); et al.
PLoS ONE. 2014;9(11):e111772. Epub 2014-11-06.
Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier combination antiretroviral therapy will alter this risk
To critically appraise recent published literature about factors associated with cancer risk likely to be influenced by combination antiretroviral therapy (cART) in HIV-infected individuals, and the potential of earlier cART initiation to reduce this risk. Factors leading to increased risk of non-AIDS-defining malignancies (NADMs) in particular remain poorly understood. Immunodeficiency appears to be key, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory and coagulation pathways, and cART toxicity may also contribute. By reducing HIV replication, improving immune function, and limiting chronic inflammation, cART initiation at higher CD4 cell counts may, therefore, reduce NADM risk. However, cART only partly normalizes enhanced inflammation and coagulation seen during HIV infection and conflicting laboratory and epidemiological data have been reported as to whether (and how) cART affects NADM risk. Furthermore, secondary analyses of randomized controlled trials comparing early versus delayed cART initiation were inconclusive. Continuous epidemiological surveillance is warranted to monitor trends in cancer incidence among HIV-infected individuals and to better understand the impact of earlier cART on NADM risk. The role of adjuvant anti-inflammatory or antithrombotic therapies to reduce cancer risk deserves further investigation.
Authors: Borges AH; Dubrow R; Silverberg MJ
Curr Opin HIV AIDS. 2014 Jan;9(1):34-40.
Cost of Care for HIV-Infected Patients with Co-Occurring Substance Use Disorder or Psychiatric Disease: Report from a Large, Integrated Health Plan
Background. The costs of providing care to HIV-infected (HIV+) patients with co-occurring diagnoses of substance use (SU) disorder or psychiatric disease (PD) are not well documented. It is our objective to evaluate costs in these HIV+ patients receiving care in a large health plan. Methods. We conducted a retrospective cohort study from 1995 to 2010 to compare costs of healthcare in HIV+ patients with and without co-occurring SU disorder and/or PD diagnoses. Estimates of proportional differences in costs (rate ratios) were obtained from repeated measures generalized linear regression. Models were stratified by cost category (e.g., inpatient, outpatient). Results. Mean total healthcare costs per patient per year were higher in HIV+ patients diagnosed with SU disorder or PD compared to HIV+ patients without these comorbid conditions. After controlling for confounders, total mean costs remained significantly higher in patients diagnosed with SU disorder (RR = 1.24, 95% CI = 1.18-1.31) or PD (RR = 1.19, 95% CI = 1.15-1.24). Mean outpatient care costs were significantly greater in patients with both SU disorder and PD (RR = 1.52, 95% CI = 1.41-1.64). Conclusions. Given these higher expenditures in the care of HIV+ patients with comorbid SU disorder and/or PD, greater efforts to facilitate SU disorder or PD treatment initiation and persistence could provide substantial savings.
Authors: DeLorenze GN; Tsai AL; Horberg MA; Quesenberry CP
AIDS Res Treat. 2014;2014:570546. Epub 2014-06-22.
Licensed pertussis vaccines in the United States
The United States switched from whole cell to acellular pertussis vaccines in the 1990s following global concerns with the safety of the whole cell vaccines. Despite high levels of acellular pertussis vaccine coverage, the United States and other countries are experiencing large pertussis outbreaks. The aim of this article is to describe the historical context which led to acellular pertussis vaccine development, focusing on vaccines currently licensed in the US, and to review evidence that waning protection following licensed acellular pertussis vaccines have been significant factors in the widespread reappearance of pertussis.
Authors: Klein NP
Hum Vaccin Immunother. 2014;10(9):2684-90. Epub 2014-11-06.
Effect of Age on the Risk of Fever and Seizures Following Immunization With Measles-Containing Vaccines in Children
IMPORTANCE The first dose of live attenuated measles-containing vaccines is associated with an increased risk of febrile seizures 7 to 10 days following immunization among 12- to 23-month-old children. The combination measles, mumps, rubella, and varicella vaccine is associated with a 2-fold increased risk of febrile seizures 7 to 10 days following immunization compared with the separately administered measles, mumps, and rubella and varicella vaccines. It is unknown whether the magnitude of these increased risks depends on age at immunization. OBJECTIVE To examine the potential modifying effect of age on the risk of fever and seizures following immunization with measles-containing vaccines. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 8 Vaccine Safety Datalink sites of a total of 840,348 children 12 to 23 months of age who had received a measles-containing vaccine from 2001 through 2011. EXPOSURES Any measles-containing vaccines and measles-containing vaccines by type. MAIN OUTCOMES AND MEASURES Fever and seizure events occurring during a 42-day postimmunization observation period. RESULTS In the analysis of any measles-containing vaccines, the increased risk of seizures during the 7- to 10-day risk interval, using the remainder of the observation period as the control interval, was significantly greater among older children (relative risk, 6.5; 95% CI, 5.3-8.1; attributable risk, 9.5 excess cases per 10,000 doses; 95% CI, 7.6-11.5) than among younger children (relative risk, 3.4; 95% CI, 3.0-3.9; attributable risk?=?4.0 excess cases per 10,000 doses; 95% CI, 3.4-4.6). The relative risk of postimmunization fever was significantly greater among older children than among younger children; however, its attributable risk was not. In the analysis of vaccine type, measles, mumps, rubella, and varicella vaccine was associated with a 1.4-fold increase in the risk of fever and 2-fold increase in the risk of seizures compared with measles, mumps, and rubella vaccine administered with or without varicella vaccine in both younger and older children. CONCLUSIONS AND RELEVANCE Measles-containing vaccines are associated with a lower increased risk of seizures when administered at 12 to 15 months of age. Findings of this study that focused on safety outcomes highlight the importance of timely immunization of children with the first dose of measles-containing vaccines.
Authors: Rowhani-Rahbar A; Fireman B; Klein NP; et al.
JAMA Pediatr. 2013 Dec;167(12):1111-7.
Trends in annual incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in HIV-infected and HIV-uninfected patients
We describe trends in incidence rates of methicillin-resistant Staphylococcus aureus (MRSA) in HIV-infected and HIV-uninfected patients enrolled in a large northern California Health Plan, and the ratio of MRSA to methicillin-susceptible S. aureus (MSSA) case counts. Between 1995 and 2010, 1549 MRSA infections were diagnosed in 14060 HIV-infected patients (11·0%) compared to 89546 MRSA infections in 6597396 HIV-uninfected patients (1·4%) (P = 0·00). A steady rise in MRSA infection rates began in 1995 in HIV-uninfected patients, peaking at 396·5 infections/100000 person-years in 2007. A more rapid rise in MRSA infection rates occurred in the HIV-infected group after 2000, peaking at 3592·8 infections/100000 in 2005. A declining trend in MRSA rates may have begun in 2008-2009. Comparing the ratio of MRSA to MSSA case counts, we observed that HIV-infected patients shouldered a greater burden of MRSA infection during most years of study follow-up compared to HIV-uninfected patients.
Authors: Delorenze GN; Horberg MA; Silverberg MJ; Tsai A; Quesenberry CP; Baxter R
Epidemiol Infect. 2013 Nov;141(11):2392-402. Epub 2013-02-18.
Factors that may explain observed associations between trivalent influenza vaccination and gastrointestinal illness in young children
Previously published studies reported an increased risk of gastrointestinal illness in the 14 days following trivalent influenza vaccination (TIV) in young children. While gastrointestinal illness may be a true adverse effect of TIV, other factors may influence this observed association, such as seasonal illness patterns and children being exposed to gastrointestinal pathogens at medical visits. The objective of this study was to examine factors influencing the association between TIV and gastrointestinal illness. Specifically, using data from a previous influenza vaccine safety study, we examined the association between medical encounters without TIV and gastrointestinal illness. Using electronic health record (EHR) data from 6 managed care organizations (MCOs), we identified medically attended gastrointestinal illness cases among children 24-59 months in the 2002-2006 influenza seasons. We matched each case to four controls on sex, birthdate (month/year), MCO, influenza season, and presence of a chronic condition. We then looked 1-14 days prior to the index date (gastrointestinal illness diagnosis date) to determine whether the child had a medical encounter. We excluded previous medical encounters with gastrointestinal-related diagnoses or TIV. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. We identified 2062 gastrointestinal illness cases and matched them to 8248 controls. We observed increased odds of gastrointestinal illness within 14 days after a medical encounter (odds ratio=1.9; 95% confidence interval [CI]: 1.7-2.2) among children without chronic conditions. Among children with chronic conditions, the odds ratio was 3.9 (95% CI: 2.5-6.2). We demonstrated that another exposure related to vaccination, medical visits, is also associated with increased odds for gastrointestinal illness. This study highlights challenges of interpreting results from observational vaccine safety studies when there are co-occurring exposures, and the importance of investigating confounding in EHR data, which are an essential resource for vaccine safety research.
Authors: Newcomer SR; Hambidge SJ; McClure DL; Daley MF; Klein NP; Glanz JM
Vaccine. 2013 Aug 20;31(37):3894-8. Epub 2013-07-02.
Missed Office Visits and Risk of Mortality Among HIV-Infected Subjects in a Large Healthcare System in the United States
Linkage and retention in care soon after HIV diagnosis improves clinical outcomes. Conversely, missed visits after diagnosis are associated with increased mortality in the public care setting. We analyzed mortality among newly diagnosed HIV patients >/=18 years old in a large private care setting between 01/01/1997 and 12/31/2009, comparing patients who missed visits in their first year following diagnosis (index period) with those who did not. Patients who died during the index period were excluded. Hazard ratios (HR) for association of missed visits and mortality were obtained by Cox proportional hazards regression, adjusting for patient demographics, CD4+ counts, and AIDS-defining conditions (CDC, 1993) at diagnosis. We also evaluated risk factors of missed visits by multivariable logistic regression. 2811 patients were included, of whom 65% had >/=1 missed visit, and 226 patients died during follow-up. Patients with >/=1 missed visit had a 71% increased mortality risk (HR=1.71, p=0.001) with 12% increased rate per missed visit (HR=1.12, p<0.001). Factors associated with missed visits were younger age (OR=1.69 compared to 60+ years), Black and Latino race/ethnicity (OR=1.54, 1.48 respectively, compared to Caucasians), injection drug use (OR=2.50 compared to men who have sex with men), and lower CD4+ (OR=1.43 for CD4+ 100-199 cells/muL, OR=1.39 for 50-99 cells/muL, and OR=1.63 for CD4+ <50 cells/muL, compared with CD4+ >500 cells/muL). In an insured patient population, missed visits in the first year of HIV care are common and associated with increased mortality. Early retention in HIV care is critical to improving outcomes.
Authors: Horberg MA; Hurley LB; Silverberg MJ; Klein DB; Quesenberry CP; Mugavero MJ
AIDS Patient Care STDS. 2013 Aug;27(8):442-9. Epub 2013 Jul 19.
Differences in human immunodeficiency virus care and treatment among subpopulations in the United States.
IMPORTANCE: Early diagnosis of human immunodeficiency virus (HIV) infection, prompt linkage to and sustained care, and antiretroviral therapy are associated with reduced individual morbidity, mortality, and transmission of the virus. However, levels of these indicators may differ among population groups with HIV. Disparities in care and treatment may contribute to the higher incidence rates among groups with higher prevalence of HIV. OBJECTIVE: To examine differences between groups of persons living with HIV by sex, age, race/ethnicity, and transmission category at essential steps in the continuum of care. DESIGN AND SETTING: We obtained data from the National HIV Surveillance System of the Centers for Disease Control and Prevention to determine the number of persons living with HIV who are aware and unaware of their infection using back-calculation models. We calculated the percentage of persons linked to care within 3 months of diagnosis on the basis of CD4 level and viral load test results. We estimated the percentages of persons retained in care, prescribed antiretroviral therapy, and with viral suppression using data from the Medical Monitoring Project, a surveillance system of persons receiving HIV care in select areas representative of all such persons in the United States. PARTICIPANTS: All HIV-infected persons in the United States. MAIN OUTCOMES AND MEASURES: Percentage of persons living with HIV who are aware of their infection, linked to care, retained in care, receiving antiretroviral therapy, and achieving viral suppression. RESULTS: Of the estimated 1,148,200 persons living with HIV in 2009 in the United States, 81.9% had been diagnosed, 65.8% were linked to care, 36.7% were retained in care, 32.7% were prescribed antiretroviral therapy, and 25.3% had a suppressed viral load (
Authors: Hall HI; Frazier EL; Rhodes P; Holtgrave DR; Furlow-Parmley C; Tang T; Gray KM; Cohen SM; Mermin J; Skarbinski J
JAMA Intern Med. 2013 Jul 22;173(14):1337-44. doi: 10.1001/jamainternmed.2013.6841.
The effect of hepatitis C treatment response on medical costs: a longitudinal analysis in an integrated care setting
Studies suggest that chronic hepatitis C patients who achieve sustained virologic response (SVR) have lower risks of liver-related morbidity and mortality. Given the substantial costs and complexity of hepatitis C virus (HCV) antiviral treatment, post-treatment benefits are important to understand. To determine whether health care costs and utilization for up to 5 years after treatment differed between patients who achieved SVR and those who did not. Kaiser Permanente Medical Care Program patients receiving HCV treatment with pegylated interferon and ribavirin (Peg-IFN/RBV) from 2002 to 2007 were retrospectively analyzed, excluding those with human immunodeficiency virus (HIV) or chronic hepatitis B. Health care utilization and costs for up to 5 years after treatment completion were derived from electronic records. We compared mean annual cost and overall post-treatment costs (standardized to year-2007 dollars), and yearly utilization counts between the SVR and non-SVR groups, adjusting for pretreatment costs, age, sex, baseline cirrhosis, and race using gamma and Poisson regression models. The 1,924 patients eligible for inclusion were a mean age of 50 years; 63% male; 58% white, non-Hispanic; 62% with genotype 1; and 48% who had achieved SVR. The mean duration of post-treatment time was 3 years, and patients without SVR incurred significantly higher health care costs than patients with SVR. For each post-treatment year, total adjusted costs were significantly higher in the non-SVR group than in the SVR group, with rate ratios (RRs) and 95% CIs ranging from 1.26 (95% CI, 1.13-1.40) to 1.64 (95% CI, 1.38-1.96), driven mostly by hospital and outpatient pharmacy costs. When all post-treatment years were considered collectively, the non-SVR group had significantly higher costs overall (RR=1.41; 95% CI, 1.17-1.69) and in each category of costs. The adjusted difference in yearly total mean costs was $2,648 (95% CI, 737-4,560). In post-treatment years 2-5, adjusted liver-specific laboratory test rates were 1.8 to 2.3 times higher in the non-SVR group than in the SVR group (each year, P less than 0.001). During post-treatment years 1-5, adjusted yearly liver-related hospitalization rates were up to 2.45 times higher (95% CI, 1.56-3.85), and medicine/GI clinic visit rates were up to 1.39 times higher (95% CI, 1.23-1.54) in the non-SVR group compared with the SVR group. Health care utilization and costs after HCV antiviral therapy with Peg-IFN/RBV, particularly for liver-related tests, outpatient drugs, and hospitalizations, were significantly lower for patients who achieved SVR than for those without SVR. Our observations are consistent with the potentially lower risk of severe liver disease among patients with SVR.
Authors: Manos MM; Darbinian J; Rubin J; Ray GT; Shvachko V; Denis B; Velez F; Quesenberry C
J Manag Care Pharm. 2013 Jul-Aug;19(6):438-47.
One or Two Doses of Quadrivalent Meningococcal Serogroups A, C, W-135 and Y Tetanus Toxoid Conjugate Vaccine is Immunogenic in 9-12 Month Old Children
The incidence of invasive meningococcal disease is highest in infants. A quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) was evaluated in children 9-12 months of age. We randomized infants (1:1) to receive 1 dose of MenACWY-TT at 12 months of age (ACWY-1 group) or 2 doses at 9 and 12 months (ACWY-2). We measured immunogenicity after each dose and 1 year after completing vaccination using human serum bactericidal antibody (hSBA) assays according to prespecified criteria of ? 1:8. Local and general symptoms were solicited for 8 days after vaccination. Adverse events were recorded for 6 months after the last dose. We enrolled and vaccinated 349 subjects, of whom 248 reenrolled at Year 1 for evaluation of antibody persistence. Percentages of subjects with postvaccination hSBA ? 1:8 in the ACWY-1 group were 79.5%, 94.6%, 50.8% and 56.1% and in the 2-dose group (ACWY-2) were 88.4%, 100%, 99.3% and 99.3% postdose 2 for serogroups A, C, W-135 and Y, respectively. At Year 1, 80.0-99.1% in each group had hSBA ? 1:8, except for serogroup A, for which 20.6% (ACWY-1) and 25.9% (ACWY-2) retained hSBA ?1:8. Both schedules were well-tolerated, with no observed increase in reactogenicity after the second dose. MenACWY-TT was immunogenic when administered as a single dose at 12 months of age, or as 2 doses at 9 and 12 months, and had a clinically acceptable safety profile. Good antibody persistence was observed through 12 months postvaccination after both treatment schedules for serogroups C, W-135, Y.
Authors: Klein NP; Baine Y; Bianco V; Lestrate PR; Naz A; Blatter M; Friedland LR; Miller JM
Pediatr Infect Dis J. 2013 Jul;32(7):760-7.
Lack of Association of Guillain-Barre Syndrome with Vaccinations
Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy, thought to be an autoimmune process. Although cases of GBS have been reported following a wide range of vaccines, a clear association has only been established with the 1976 H1N1 inactivated influenza vaccine. We identified hospitalized GBS cases from Kaiser Permanente Northern California (KPNC) from 1995 through 2006. The medical record of each suspected case was neurologist-reviewed according to the Brighton Collaboration GBS case definition; only confirmed cases were included in the analyses, and cases of Miller Fisher syndrome were excluded. Using a case-centered design, we compared the odds of vaccination in the 6 and 10 weeks prior to onset of GBS to the odds of vaccination during the same time intervals in all vaccinated individuals in the entire KPNC population. We confirmed 415 incident cases of GBS (including Brighton levels 1, 2, and 3) during the study period (>30 million person-years). Incidence peaked during the winter months. The odds ratio of influenza vaccination within a 6-week interval prior to GBS, compared with the prior 9 months, was 1.1 (95% confidence interval [CI], .4-3.1). The risk in the 6-week interval compared to the prior 12 months for tetanus diphtheria combination, 23-valent pneumococcal polysaccharide, and for all vaccines combined was 1.4 (95% CI, .3-4.5), 0.7 (95% CI, .1-2.9), and 1.3 (95% CI, .8-2.3), respectively. In this large retrospective study, we did not find evidence of an increased risk of GBS following vaccinations of any kind, including influenza vaccination.
Authors: Baxter R; Bakshi N; Fireman B; Lewis E; Ray P; Vellozzi C; Klein NP
Clin Infect Dis. 2013 Jul;57(2):197-204. Epub 2013-04-11.
Effectiveness of intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy on maternal and birth outcomes in Machinga district, Malawi.
BACKGROUND: Malaria during pregnancy is associated with low birth weight and increased perinatal mortality, especially among primigravidae. Despite increasing prevalence of malarial parasite resistance to sulfadoxine-pyrimethamine (SP), SP continues to be recommended for intermittent preventive treatment in pregnancy (IPTp). METHODS: Women without human immunodeficiency virus infection were enrolled upon delivery. Data on the number of SP doses received during pregnancy were recorded. The primary outcome was placental infection demonstrated by histologic analysis. Secondary outcomes included malaria parasitemia (in peripheral, placental, cord blood specimens) at delivery and composite birth outcome (small for gestational age, preterm delivery, or low birth weight). RESULTS.: Of 703 women enrolled, 22% received <2 SP doses. Receipt of >/= 2 SP doses had no impact on histologically confirmed placental infection. IPTp-SP was associated with a dose-dependent protective effect on composite birth outcome in primigravidae, with an adjusted prevalence ratio of 0.50 (95% confidence interval [CI], .30-.82), 0.30 (95% CI, .19-.48), and 0.18 (95% CI, .05-.61) for 1, 2, and >/= 3 doses, respectively, compared with 0 doses. CONCLUSIONS: IPTp-SP did not reduce the frequency of placental infection but was associated with improved birth outcomes. Few women received no SP, so the true effect of IPTp-SP may be underestimated. Malawian pregnant women should continue to receive IPTp-SP, but alternative strategies and antimalarials for preventing malaria during pregnancy should be investigated.
Authors: Gutman J; Mwandama D; Wiegand RE; Ali D; Mathanga DP; Skarbinski J
J Infect Dis. 2013 Sep;208(6):907-16. doi: 10.1093/infdis/jit276. Epub 2013 Jun 24.
Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers
OBJECTIVE: To investigate the relationship between inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)] and coagulation (D-dimer) biomarkers and cancer risk during HIV infection. DESIGN: A prospective cohort. METHODS: HIV-infected patients on continuous antiretroviral therapy (ART) in the control arms of three randomized trials (N=5023) were included in an analysis of predictors of cancer (any type, infection-related or infection-unrelated). Hazard ratios for IL-6, CRP and D-dimer levels (log2-transformed) were calculated using Cox models stratified by trial and adjusted for demographics and CD4+ cell counts and adjusted also for all biomarkers simultaneously. To assess the possibility that biomarker levels were elevated at entry due to undiagnosed cancer, analyses were repeated excluding early cancer events (i.e. diagnosed during first 2 years of follow-up). RESULTS: During approximately 24,000 person-years of follow-up (PYFU), 172 patients developed cancer (70 infection-related; 102 infection-unrelated). The risk of developing cancer was associated with higher levels (per doubling) of IL-6 (hazard ratio 1.38, P<0.001), CRP (hazard ratio 1.16, P=0.001) and D-dimer (hazard ratio 1.17, P=0.03). However, only IL-6 (hazard ratio 1.29, P=0.003) remained associated with cancer risk when all biomarkers were considered simultaneously. Results for infection-related and infection-unrelated cancers were similar to results for any cancer. Hazard ratios excluding 69 early cancer events were 1.31 (P=0.007), 1.14 (P=0.02) and 1.07 (P=0.49) for IL-6, CRP and D-dimer, respectively. CONCLUSION: Activated inflammation and coagulation pathways are associated with increased cancer risk during HIV infection. This association was stronger for IL-6 and persisted after excluding early cancer. Trials of interventions may be warranted to assess whether cancer risk can be reduced by lowering IL-6 levels in HIV-positive individuals.
Authors: Borges AH; Silverberg MJ; SILCAAT Study Groups; et al.
AIDS. 2013 Jun 1;27(9):1433-41.
Cervical Intraepithelial Neoplasia Grade 3 and Adenocarcinoma in situ: Comparison of ICD-9 Codes and Pathology Results – Kaiser Permanente, United States, 2000-2005
Cervical intraepithelial neoplasia grade 3+ (CIN3+) and adenocarcinoma in situ incidence will be an important measure of HPV vaccine impact. Integrated healthcare delivery systems, such as Kaiser Permanente, could be used to monitor CIN3+ trends; however, limited evaluations of data from healthcare delivery systems for CIN3+ surveillance exist. We compared CIN3+ diagnoses by ICD-9 code with CIN3+ diagnoses by pathology results among 121,211 females aged 11 to 30 years who were continuously enrolled from 2000 to 2005 in either Kaiser Permanente Northern California or Kaiser Permanente Northwest. We calculated sensitivity and positive predictive value of diagnosis by ICD-9 codes using pathology CIN3+ diagnosis as the gold standard. There were 1,090 women with at least one CIN3+ diagnosis by ICD-9 code 233.1 and 1,200 women with at least one CIN3+ diagnosis by pathology results. The sensitivity of the ICD-9 code for detecting a woman with at least one pathology diagnosis for CIN3+ was 62% (740/1,200); positive predictive value was 68% (740/1,090). Among women with at least one CIN3+ diagnosis by ICD-9 code, 679 (62%) had more than one visit with this code; whereas, among women with at least one CIN3+ diagnosis by pathology, 466 (39%) had more than one CIN3+ pathology result. ICD-9 codes may underestimate the number of women with at least one CIN3+ diagnosis. Pathology results, when available, may provide better estimates of CIN3+ incidence.
Authors: Surie D; Dunne EF; Naleway AL; Weinmann S; Klein NP; Baxter R; Hutchins K; Gee J; Markowitz L
Cancer Epidemiol Biomarkers Prev. 2013 Jun;22(6):1129-32. Epub 2013-04-05.
Comprehensive Assessment of Serious Adverse Events Following Immunization by Health Care Providers
Authors: Williams SE; Klein NP; et al.
J Pediatr. 2013 Jun;162(6):1276-81, 1281.e1. Epub 2013 Feb 26.
Long-term Effectiveness of Varicella Vaccine: A 14-Year, Prospective Cohort Study
BACKGROUND: Varicella vaccine was licensed in the United States in 1995 for individuals >/=12 months of age. A second dose was recommended in the United States in June 2006. Varicella incidence and vaccine effectiveness were assessed in a 14-year prospective study conducted at Kaiser Permanente Northern California. METHODS: A total of 7585 children vaccinated with varicella vaccine in their second year of life in 1995 were followed up prospectively for breakthrough varicella and herpes zoster (HZ) through 2009. A total of 2826 of these children received a second dose in 2006-2009. Incidences of varicella and HZ were estimated and compared with prevaccine era rates. RESULTS: In this cohort of vaccinated children, the average incidence of varicella was 15.9 per 1000 person-years, nine- to tenfold lower than in the prevaccine era. Vaccine effectiveness at the end of the study period was 90%, with no indication of waning over time. Most cases of varicella were mild and occurred early after vaccination. No child developed varicella after a second dose. HZ cases were mild, and rates were lower in the cohort of vaccinated children than in unvaccinated children during the prevaccine era (relative risk: 0.61 [95% confidence interval: 0.43-0.89]). CONCLUSIONS: This study confirmed that varicella vaccine is effective at preventing chicken pox, with no waning noted over a 14-year period. One dose provided excellent protection against moderate to severe disease, and most cases occurred shortly after the cohort was vaccinated. The study data also suggest that varicella vaccination may reduce the risks of HZ in vaccinated children.
Authors: Baxter R; Ray P; Tran TN; Black S; Shinefield HR; Coplan PM; Lewis E; Fireman B; Saddier P
Pediatrics. 2013 May;131(5):e1389-96. Epub 2013 Apr 1.
Invasive cervical cancer risk among HIV-infected women: A North American multi-cohort collaboration prospective study
OBJECTIVE: HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic human papillomavirus infection-the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women. METHODS: Data were obtained from HIV-infected and -uninfected female participants in the North American AIDS Cohort Collaboration on Research and Design with no history of ICC at enrollment. Participants were followed from study entry or January 1996 through ICC, loss to follow-up, or December 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios. All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction. RESULTS: A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 person-years, respectively). HIV-infected women with baseline CD4+ T-cells of >/=350, 200-349, and <200 cells per microliter had a 2.3, 3.0, and 7.7 times increase in ICC incidence, respectively, compared with HIV-uninfected women (P(trend) = 0.001). Of the 17 HIV-infected women, medical records for the 5 years before diagnosis showed that 6 had no documented screening, 5 had screening with low-grade or normal results, and 6 had high-grade results. CONCLUSIONS: This study found elevated incidence of ICC in HIV-infected compared with -uninfected women, and these rates increased with immunosuppression.
Authors: Abraham AG; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design of IeDEA; et al.
J Acquir Immune Defic Syndr. 2013 Apr 1;62(4):405-13.
Use of web-based shared medical records among patients with HIV
To compare use of 7 shared electronic medical record (SMR) features by adult HIV patients. Observational cohort study of adult HIV-positive patients in the first 36 months following implementation of the SMR at Group Health and Kaiser Permanente Northern California. Automated data from the 36 months following SMR implementation were assessed in 2 integrated delivery systems. Cox proportional hazards analysis identified factors associated with any SMR use. Most (3888/7398) patients used the SMR at least once. Users were most likely to view medical test results (49%), use secure messaging (43%), or request appointments (31%) or medication refills (30%). Initial use was associated with new prescription for antiretroviral therapy (rate ratio [RR] 1.65, P <.001), recent change to a CD4+ count of fewer than 200 cells per microliter (RR = 1.34, P <.02), new HIV RNA of 75 or more copies per milliliter (RR = 1.63, P <.001), or recent increase in non-HIV comorbidity score (RR = 1.49, P = .0001). Users were less likely to be women (RR = 0.49, P = .0001), injection drug users (RR = 0.59, P = .0001), or from lower-socioeconomic status neighborhoods (RR = 0.68, P = .0001), and were less likely to be black (RR = 0.38, P = .0001), Hispanic (RR = 0.52, P = .0001) or Asian/Pacific Islander (RR = 0.59, P = .001). SMR use was higher among HIV patients who had indicators of recent increases in healthcare needs and lower among several vulnerable populations.
Authors: Ralston JD; Silverberg MJ; Grothaus L; Leyden WA; Ross T; Stewart C; Carzasty S; Horberg M; Catz SL
Am J Manag Care. 2013 Apr;19(4):e114-24. Epub 2013-04-01.
HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer
Background The incidence of non-melanoma skin cancers (NMSCs), including basal cell (BCC) or squamous cell carcinoma (SCC), is not well documented among HIV-positive (HIV(+)) individuals. Methods We identified 6560 HIV(+) and 36 821 HIV-negative (HIV(-)) non-Hispanic white adults who were enrolled and followed up in Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records. Poisson models estimated rate ratios that compared HIV(+) (overall and stratified by recent CD4 T-cell counts and serum HIV RNA levels) with HIV(-) subjects and were adjusted for age, sex, smoking history, obesity diagnosis history, and census-based household income. Sensitivity analyses were adjusted for outpatient visits (ie, a proxy for screening). All statistical tests were two-sided. Results The NMSC incidence rate was 1426 and 766 per 100 000 person-years for HIV(+) and HIV(-) individuals, respectively, which corresponds with an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). Similarly, the adjusted rate ratio for HIV(+) vs HIV(-) subjects was 2.6 (95% CI = 2.1 to 3.2) for SCCs, and it was 2.1 (95% CI = 1.8 to 2.3) for BCCs. There was a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV(+) subjects compared with HIV(-) subjects for SCCs (P trend < .001). Adjustment for number of outpatient visits did not affect the results. Conclusion HIV(+) subjects had a twofold higher incidence rate of NMSCs compared with HIV(-) subjects. SCCs but not BCCs were associated with immunodeficiency.
Authors: Silverberg MJ; Leyden W; Warton EM; Quesenberry CP Jr; Engels EA; Asgari MM
J Natl Cancer Inst. 2013 Mar 6;105(5):350-60. Epub 2013 Jan 4.
Prevalence of HPV types in cervical specimens from an integrated healthcare delivery system: baseline assessment to measure HPV vaccine impact
PURPOSE: Two human papillomavirus (HPV) vaccines are available to prevent cervical cancer. One early measure of HPV vaccine impact would be a reduction in vaccine-related HPV types (HPV 6, 11, 16, or 18, or HPV 16, 18) in cervical samples from young women. We aimed to assess feasibility of specimen collection and baseline HPV prevalence in an integrated healthcare delivery system. METHODS: Residual cervical specimens collected during routine cervical cancer screening (2006-2008) were retained consecutively from eligible females aged 11-29 years, stratified by age group. Specimens were evaluated for 37 HPV genotypes using the Roche Linear Array assay. RESULTS: Of 10,124 specimens submitted, 10,103 (99 %) were adequate for HPV testing. Prevalence of HPV 6, 11, 16, or 18 genotype was 11.4 % overall and was the highest in the youngest age group (18.1 % in the 11-19-year-olds, 12.5 % in the 20-24-year-olds, and 7.0 % in the 25-29-year-olds). CONCLUSIONS: HPV types 6, 11, 16, or 18 prevalence could be measured over time to assess early HPV vaccine impact using residual specimens from an integrated healthcare delivery system, particularly if sampling focused on young women.
Authors: Dunne EF; Klein NP; Unger ER; et al.
Cancer Causes Control. 2013 Feb;24(2):403-7. Epub 2013 Jan 5.
Clinical Assessment of Serious Adverse Events in Children Receiving 2009 H1N1 Vaccination
BACKGROUND: Monovalent 2009 H1N1 influenza vaccines were licensed and administered in the United States during the H1N1 influenza pandemic between 2009 and 2013. METHODS: Vaccine Adverse Event Reporting System received reports of adverse events following immunization (AEFI) after H1N1 vaccination. Selected reports were referred to the Centers for Disease Control and Prevention’s Clinical Immunization Safety Assessment network for additional review. We assessed causality using modified World Health Organization criteria. RESULTS: There were 3,928 reports of AEFI in children younger than age 18 years after 2009 H1N1 vaccination received by January 31, 2010. Of these, 214 (5.4%) were classified as serious nonfatal and 109 were referred to Clinical Immunization Safety Assessment for further evaluation. Ninety-nine (91%) had sufficient initial information to begin investigation and are described here. The mean age was 8 years (range, 6 months-17 years) and 38% were female. Median number of days between vaccination and symptom onset was 2 (range, -11 days to +41 days). Receipt of inactivated, live attenuated, or unknown type of 2009 H1N1 vaccines was reported by 68, 26 and 5 cases, respectively. Serious AEFI were categorized as neurologic events in 47 cases, as hypersensitivity in 15 cases and as respiratory events in 10 cases. At the time of evaluation, recovery was described as complete (61), partial (16), no improvement (1), or unknown (21). Causality assessment yielded the following likelihood of association with 2009 H1N1 vaccination: 8 definitely; 8 probably; 21 possibly; 43 unlikely; 17 unrelated; and 2 unclassifiable. CONCLUSIONS: Most AEFI in children evaluated were not causally related to vaccine and resolved without sequelae. Detailed clinical assessment of individual serious AEFI can provide reassurance of vaccine safety.
Authors: Pahud BA; Klein NP; Edwards KM; et al.
Pediatr Infect Dis J. 2013 Feb;32(2):163-8.
Adapting Group Sequential Methods to Observational Postlicensure Vaccine Safety Surveillance: Results of a Pentavalent Combination DTaP-IPV-Hib Vaccine Safety Study
To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barre syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.
Authors: Nelson JC; Klein NP; Jackson LA; et al.
Am J Epidemiol. 2013 Jan 15;177(2):131-41. Epub 2013 Jan 4.
Kaiser Permanente Vaccine Study Center: Highlights of 2009-2012
The Kaiser Permanente Vaccine Study Center is a specialized research organization in Oakland, California. They have been an active vaccine research group for many years, and have participated in and led a multitude of vaccine studies. This article will review the last three years of research activities.
Authors: Baxter R; Klein NP
Vaccines (Basel). 2013;1(2):139-53. Epub 2013-04-25.
Physical, Social, and Psychological Consequences of Treatment for Hepatitis C : A Community-Based Evaluation of Patient-Reported Outcomes
BACKGROUND: Hepatitis C virus (HCV) antiviral therapy entails a long treatment course, as well as significant side effects that can lead to medication non-adherence and premature termination of treatment. Few large studies have comprehensively examined patient perspectives on the treatment experience, particularly the social and personal effects. OBJECTIVE: We sought to understand how a diverse group of patients’ lives were affected during HCV treatment, and to obtain suggestions about how to better support patients during treatment. METHODS: On average, 13 months after therapy we interviewed by telephone a consecutive sample of 200 patients treated for hepatitis C with ribavirin and pegylated interferon in a comprehensive, integrated health plan in the years 2008-2010. Mixed (quantitative and qualitative) survey methods were used. RESULTS: The response rate was 68.9 %. Mean age at treatment was 51 years; 63.0 % were men; and Black, Hispanic, Asian, and White non-Hispanic racial/ethnic groups were similarly represented. Patients whose treatment was managed by nurses or clinical pharmacists (vs. physicians) were more likely to report their providers as being part of their support system (83.5 % vs. 58.9 %; p < 0.001). Most patients reported flu-like symptoms (93.5 %) and psychiatric problems (84.5 %), and 42.5 % reported side effects lasted up to 6 months after treatment. Black patients reported discontinuing treatment prematurely due to side effects more often than non-Blacks (29.4 % vs. 12.1 %; p < 0.001). Physical side effects (69.5 % of patients), psychiatric issues (43.5 %), and employment (27.4 %) were ranked among the three most difficult challenges. Patients desired help in anticipating and arranging work modifications during treatment. Most patients rated peer support, nutritional guidance, and weekly provider contact by telephone as potentially helpful resources for future patients undergoing HCV treatment. CONCLUSIONS: Patient perspectives can help formulate and refine HCV treatment support programs. Effective support programs for diverse populations are crucial as the complexities and costs of HCV treatment increase. The call for greater support from peers, providers, and employers demands new systems such as patient-centered care teams.
Authors: Manos MM; Ho CK; Murphy RC; Shvachko VA
Patient. 2013;6(1):23-34.
Biologically plausible and evidence-based risk intervals in immunization safety research
In immunization safety research, individuals are considered at risk for the development of certain adverse events following immunization (AEFI) within a specific period of time referred to as the risk interval. These intervals should ideally be determined based on biologic plausibility considering features of the AEFI, presumed or known pathologic mechanism, and the vaccine. Misspecification of the length and timing of these intervals may result in introducing bias in epidemiologic and clinical studies of immunization safety. To date, little work has been done to formally assess and determine biologically plausible and evidence-based risk intervals in immunization safety research. In this report, we present a systematic process to define biologically plausible and evidence-based risk interval estimates for two specific AEFIs, febrile seizures and acute disseminated encephalomyelitis. In addition, we review methodologic issues related to the determination of risk intervals for consideration in future studies of immunization safety.
Authors: Rowhani-Rahbar A; Klein NP; Dekker CL; Edwards KM; Marchant CD; Vellozzi C; Fireman B; Sejvar JJ; Halsey NA; Baxter R; Risk Interval Working Group of the Clinical Immunization Safety Assessment Network
Vaccine. 2012 Dec 17;31(1):271-7. Epub 2012 Jul 24.
Safety of Quadrivalent Human Papillomavirus Vaccine Administered Routinely to Females
OBJECTIVE: To assess the safety of the quadrivalent human papillomavirus vaccine (HPV4) in females following routine administration. DESIGN: In a cohort of vaccinated females, we compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a comparison interval more remote from vaccination. SETTING: Kaiser Permanente in California. PARTICIPANTS: All females who received the HPV4 vaccine. MAIN EXPOSURE: One or more doses of HPV4 between August 2006 and March 2008. MAIN OUTCOME MEASURES: Outcomes were emergency department visits and hospitalizations, grouped into predefined diagnostic categories. Within diagnostic groups, we used odds ratios (ORs) to estimate whether each subject had any outcome in postvaccination risk intervals (days 1-60, days 1-14, and day 0), compared with a control interval distant in time from vaccination. RESULTS: One hundred eighty-nine thousand six hundred twenty-nine females received at least 1 dose and 44 001 received 3 HPV4 doses. Fifty categories had significantly elevated ORs during at least 1 risk interval. Medical record review revealed that most diagnoses were present before vaccination or diagnostic workups were initiated at the vaccine visit. Only skin infections during days 1 to 14 (OR, 1.8; 95% CI, 1.3-2.4) and syncope on day of vaccination (OR, 6.0; 95% CI, 3.9-9.2) were noted by an independent Safety Review Committee as likely associations with HPV4. CONCLUSIONS: The quadrivalent human papillomavirus vaccine was associated with same-day syncope and skin infections in the 2 weeks after vaccination. This study did not detect evidence of new safety concerns among females 9 to 26 years of age secondary to vaccination with HPV4.
Authors: Klein NP; Jacobsen SJ; et al.
Arch Pediatr Adolesc Med. 2012 Dec;166(12):1140-8.
Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS)
Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine. OBJECTIVE: We sought to determine if the causal relationships between the vaccine and the AEFI reported to VAERS could be assessed through expert review. DESIGN: A stratified random sample of 100 VAERS reports received in 2004 contained 13 fatal cases, 19 cases with non-fatal disabilities, 39 other serious non-fatal cases and 29 non-serious cases. Experts knowledgeable about vaccines and clinical outcomes, reviewed each VAERS report and available medical records. MAIN OUTCOME MEASURES: Modified World Health Organization criteria were used to classify the causal relationship between vaccines and AEFI as definite, probable, possible, unlikely or unrelated. Five independent reviewers evaluated each report. If they did not reach a majority agreement on causality after initial review, the report was discussed on a telephone conference to achieve agreement. RESULTS: 108 AEFIs were identified in the selected 100 VAERS reports. After initial review majority agreement was achieved for 83% of the AEFI and 17% required further discussion. In the end, only 3 (3%) of the AEFI were classified as definitely causally related to vaccine received. Of the remaining AEFI 22 (20%) were classified as probably and 22 (20%) were classified as possibly related to vaccine received; a majority (53%) were classified as either unlikely or unrelated to a vaccine received. CONCLUSIONS: Using VAERS reports and additional documentation, causality could be assessed by expert review in the majority of VAERS reports. Assessment of VAERS reports identified that causality was thought to be probable or definite in less than one quarter of reports, and these were dominated by local reactions, allergic reactions, or symptoms known to be associated with the vaccine administered.
Authors: Loughlin AM; Klein NP; Jakob K; et al.
Vaccine. 2012 Nov 26;30(50):7253-9. Epub 2012 Oct 9.
Exposure to antiretroviral therapy and risk of cancer in HIV-infected persons
OBJECTIVE:: The incidence of certain non-AIDS-defining cancers (NADC) in HIV patients has been reported to have increasedin the combination antiretroviral therapy (ART) era. Studies are needed to directly evaluate the effect of ART use on cancer risk. DESIGN:: We followed 12,872 HIV+ Kaiser Permanente members whose complete ART history was known for incident cancers between 1996-2008. METHODS:: Cancers, identified from SEER-based cancer registries, were grouped as AIDS-defining cancers (ADC), infection-related NADC or infection-unrelated NADC. We also evaluated the most common individual cancer types. Rate ratios (RR) for ART use (yes/no) and cumulativeduration of any ART, PI and NNRTI therapy were obtained from Poisson models adjusting for demographics, pre-treatment or recent CD4 count and HIV RNA levels, years known HIV-infected, prior antiretroviral use, HIV risk, smoking, alcohol/drug abuse, overweight/obesity, and calendar year. RESULTS:: The cohort experienced 32,368person-yrs (py) of ART, 21,249pyof PI therapy, and 15,643pyof NNRTI therapy. The mean follow-up duration was 4.5 years. ADC rates decrease with increased duration of ARTuse [RR/year = 0.61, 95% CI (0.56-0.66)]; the effect was similar by therapy class. ART, PI or NNRTI therapy duration was not associated with infection-related or infection-unrelated NADC [RR/yearART = 1.00 (0.91-1.11) and 0.96 (0.90-1.01), respectively], excepta higher anal cancer risk with longer PI therapy [RR/year = 1.16 (1.02-1.31)]. CONCLUSIONS:: No therapy class-specific effect was found for ADC. ART exposure was generally not associated with NADCrisk, except for long term use of PI, which might be associated with increased anal cancer risk.
Authors: Chao C; Leyden WA; Xu L; Horberg MA; Klein D; Towner WJ; Quesenberry CP Jr; Abrams DI; Silverberg MJ
AIDS. 2012 Nov 13;26(17):2223-31.
Distribution of hepatitis C virus genotypes in a diverse US integrated health care population
Hepatitis C virus (HCV) genotypes influence response to therapy, and recently approved direct-acting antivirals are genotype-specific. Genotype distribution information can help to guide antiviral development and elucidate infection patterns. HCV genotype distributions were studied in a diverse cross-section of patients in the Northern California Kaiser Permanente health plan. Associations between genotype and race/ethnicity, age, and sex were assessed with multivariate logistic regression models. The 10,256 patients studied were median age 56 years, 62% male, 55% White non-Hispanic. Overall, 70% were genotype 1, 16% genotype 2, 12% genotype 3, 1% genotype 4, <1% genotype 5, and 1% genotype 6. Blacks (OR 4.5 [3.8-5.5]) and Asians (OR 1.2 [1.0-1.4]) were more likely to have genotype 1 than 2/3 versus non-Hispanic Whites. Women less likely had genotype 1 versus 2/3 than did men (OR 0.86 [0.78-0.94]). Versus non-Hispanic Whites, Asians (OR 0.38 [0.31-0.46]) and Blacks (OR 0.73 [0.63-0.84]) were less likely genotype1a than 1b; Hispanics (OR 1.3 [1.1-1.5]) and Native Americans (OR 1.9 [1.2-2.8]) more likely had genotype 1a than 1b. Patients age >/=65 years less likely had genotype 1a than 1b versus those age 45-64 (OR 0.34 [0.29-0.41]). The predominance of genotype 1 among all groups studied reinforces the need for new therapies targeting this genotype. Racial/ethnic variations in HCV genotype and subtype distribution must be considered in formulating new agents and novel strategies to successfully treat the diversity of hepatitis C patients.
Authors: Manos MM; Shvachko VA; Murphy RC; Arduino JM; Shire NJ
J Med Virol. 2012 Nov;84(11):1744-50.
Safety of Zostavax-A cohort study in a managed care organization
BACKGROUND: Zostavax is a live, attenuated varicella-zoster virus vaccine indicated for the prevention of herpes zoster (shingles). An observational post-licensure (Phase IV) study was conducted at Kaiser Permanente Northern California (KPNC), a US managed care organization, to assess the safety of zoster vaccine in people 60 years of age or older, vaccinated in routine medical care. METHODS: We performed a cohort study, comparing rates of clinical events resulting in hospitalizations or emergency department visits in a 42-day risk time period immediately following vaccination with rates in the same cohort in a subsequent comparison time period. The study data were reviewed and interpreted by an external safety review committee of 3 independent experts. RESULTS: Approximately 29,000 people >/= 60 years of age were vaccinated with zoster vaccine from July 2006 to November 2007. Of the 386 comparisons performed for the main analysis, 4 had an increased relative risk with a nominal p-value
Authors: Baxter R; Tran TN; Hansen J; Emery M; Fireman B; Bartlett J; Lewis N; Saddier P
Vaccine. 2012 Oct 19;30(47):6636-41. Epub 2012 Sep 8.
Waning protection after fifth dose of acellular pertussis vaccine in children
BACKGROUND: In the United States, children receive five doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine before 7 years of age. The duration of protection after five doses of DTaP is unknown. METHODS: We assessed the risk of pertussis in children in California relative to the time since the fifth dose of DTaP from 2006 to 2011. This period included a large outbreak in 2010. We conducted a case-control study involving members of Kaiser Permanente Northern California who were vaccinated with DTaP at 47 to 84 months of age. We compared children with pertussis confirmed by a positive polymerase-chain-reaction (PCR) assay with two sets of controls: those who were PCR-negative for pertussis and closely matched controls from the general population of health-plan members. We used logistic regression to examine the risk of pertussis in relation to the duration of time since the fifth DTaP dose. Children who received whole-cell pertussis vaccine during infancy or who received any pertussis-containing vaccine after their fifth dose of DTaP were excluded. RESULTS: We compared 277 children, 4 to 12 years of age, who were PCR-positive for pertussis with 3318 PCR-negative controls and 6086 matched controls. PCR-positive children were more likely to have received the fifth DTaP dose earlier than PCR-negative controls (P<0.001) or matched controls (P=0.005). Comparison with PCR-negative controls yielded an odds ratio of 1.42 (95% confidence interval, 1.21 to 1.66), indicating that after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year. CONCLUSIONS: Protection against pertussis waned during the 5 years after the fifth dose of DTaP. (Funded by Kaiser Permanente).
Authors: Klein NP; Bartlett J; Rowhani-Rahbar A; Fireman B; Baxter R
N Engl J Med. 2012 Sep 13;367(11):1012-9.
HIV infection, aging, and immune function: implications for cancer risk and prevention
PURPOSE OF REVIEW: Combination antiretroviral therapy (ART) has turned HIV infection into a complex chronic disease. This article documents cancer risk among HIV-infected persons, reviews immune system effects of HIV infection in relation to cancer risk, discusses implications for cancer prevention, and suggests future research directions. RECENT FINDINGS: There has been a shift in the cancer spectrum from AIDS-defining cancers (ADC) to non-ADC, although the burden of ADC remains high. Although a high prevalence of non-HIV cancer risk factors among HIV-infected persons contributes to cancer risk, substantial evidence has accumulated in favor of an independent association between HIV-induced immunodeficiency and elevated risk of many specific cancer types, most of viral cause, although further work is needed to disentangle immunodeficiency and smoking effects for lung cancer, and immunodeficiency and hepatitis virus effects for liver cancer. Relationships between cancer risk and two other immune system hallmarks of HIV infection, chronic inflammation, and immune dysfunction/senescence, remain poorly understood. SUMMARY: Early, sustained ART is a crucial component of cancer prevention. Continued epidemiologic monitoring is needed to detect possible effects on cancer risk of specific ART classes or medications, long-term exposure to systemic inflammation or immune dysfunction, or earlier or more effective ART.
Authors: Dubrow R; Silverberg MJ; Park LS; Crothers K; Justice AC
Curr Opin Oncol. 2012 Sep;24(5):506-16.
Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma
PURPOSE: Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL) and examined the prognostic use of detecting EBV infection. EXPERIMENTAL DESIGN: HIV-related DLBCL cases diagnosed between 1996 and 2007 within Kaiser Permanente California were identified. Immunohistochemical staining was used to analyze the expression of selected markers that are cell-cycle regulators, B-cell activators, and antiapoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman correlation coefficient. The prognostic use of EBV status was examined in multivariable Cox model adjusting for International Prognostic Index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination. RESULTS: Seventy HIV-related DLBCL cases were included (31% EBV+/-). EBV+ tumor was associated with increased expression of BLIMP1 and CD30 and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [HR, 3.3; 95% confidence interval (CI), 1.6-6.6]. Area under the ROC curve showed improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)]. CONCLUSION: Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-kappaB pathway and that detecting tumor EBV status may have prognostic use in HIV-related DLBCLs.
Authors: Chao C; Silverberg MJ; Martinez-Maza O; Chi M; Abrams DI; Haque R; Zha HD; McGuire M; Xu L; Said J
Clin Cancer Res. 2012 Sep 1;18(17):4702-12. Epub 2012 Jun 18.
Algorithm to assess causality after individual adverse events following immunizations
Assessing individual reports of adverse events following immunizations (AEFI) can be challenging. Most published reviews are based on expert opinions, but the methods and logic used to arrive at these opinions are neither well described nor understood by many health care providers and scientists. We developed a standardized algorithm to assist in collecting and interpreting data, and to help assess causality after individual AEFI. Key questions that should be asked during the assessment of AEFI include: Is the diagnosis of the AEFI correct? Does clinical or laboratory evidence exist that supports possible causes for the AEFI other than the vaccine in the affected individual? Is there a known causal association between the AEFI and the vaccine? Is there strong evidence against a causal association? Is there a specific laboratory test implicating the vaccine in the pathogenesis? An algorithm can assist with addressing these questions in a standardized, transparent manner which can be tracked and reassessed if additional information becomes available. Examples in this document illustrate the process of using the algorithm to determine causality. As new epidemiologic and clinical data become available, the algorithm and guidelines will need to be modified. Feedback from users of the algorithm will be invaluable in this process. We hope that this algorithm approach can assist with educational efforts to improve the collection of key information on AEFI and provide a platform for teaching about causality assessment.
Authors: Halsey NA; Edwards KM; Dekker CL; Klein NP; Baxter R; Larussa P; Marchant C; Slade B; Vellozzi C; Causality Working Group of the Clinical Immunization Safety Assessment network
Vaccine. 2012 Aug 24;30(39):5791-8. Epub 2012 Apr 14.
Underimmunization at discharge from the neonatal intensive care unit
OBJECTIVE: The objectives of this study are to determine immunization rates at discharge from the neonatal intensive care unit (NICU) among infants 2 months of age and above and to evaluate risk factors for underimmunization. STUDY DESIGN: A retrospective cohort study was performed for infants in six NICUs in the Northern California Kaiser Permanente Medical Care Program. Immunization status at discharge was determined for all infants discharged on or after age 60 days. Logistic regression was used to identify risk factors for underimmunization at the time of discharge. RESULT: Of 668 infants discharged on or after age 60 days from the NICU, 51% were up-to-date for routine immunizations. Twenty-seven percent of infants had received no vaccines. Factors associated with higher immunization rates at discharge include history of mechanical ventilation, congenital heart disease and a diagnosis of apnea or bronchopulmonary dysplasia during the NICU stay, whereas surgery was associated with lower immunization rates. CONCLUSION: A significant proportion of infants discharged on or after 2 months of age in the NICU in this health system was unimmunized or underimmunized at discharge. Further efforts should be made to improve immunization rates prior to discharge.
Authors: Navar-Boggan AM; Halsey NA; Escobar GJ; Golden WC; Klein NP
J Perinatol. 2012 May;32(5):363-7. Epub 2011 Aug 11.
Immunogenicity and Safety of Two Tetravalent (Measles, Mumps, Rubella, Varicella) Vaccines Co-Administered with Hepatitis A and Pneumococcal Conjugate Vaccines to Children 12 14 Months of Age
BACKGROUND:: This study compared single-dose tetravalent measles, mumps, rubella, varicella (MMRV) vaccine, Priorix-Tetra, stored refrigerated (GSK+4C) or frozen (GSK 20C), with ProQuad (Merck-20C), when co-administered with hepatitis A vaccine (HAV) and 7-valent pneumococcal conjugate vaccine (PCV7). METHODS:: Multicenter, observer-blind Phase 2 study in 1783 healthy 12-14 month-olds randomized to: GSK+4C (n=705), GSK-20C (n=689) or Merck-20C (n=389), administered concomitantly with HAV (Havrix) and PCV7 (Prevnar). Seroresponse rates and antibody geometric mean concentrations/titers (GMC/GMT) were determined from ELISA and neutralization assays. Reactogenicity and safety were assessed. RESULTS:: Seroresponse rates (Day 42) were >97% for measles and rubella viruses, and >92% for mumps virus, in all groups. Non-inferiority of both GSK+4C and GSK-20C vaccines versus Merck-20C was demonstrated for seroresponse rates to measles, mumps and rubella viruses (lower 97.5% CIs above -5%, -10%, and -5%, respectively). For varicella-zoster virus (VZV), seroresponse rates were 57.1%, 69.8%, and 86.7% in the GSK+4C, GSK-20C, and Merck-20C groups, respectively. Non-inferiority was not shown for either GSK vaccine (lower 97.5% CIs <-15%). GMC ratios for anti-VZV demonstrated non-inferiority (lower 97.5% CI >/=0.5) versus Merck-20C for GSK-20C only. GMC ratios for antibodies to HAV and to PCV7 pneumococcal serotypes also met criteria for non-inferiority for both GSK groups compared with Merck-20C. GSK vaccine safety was observed comparable to Merck-20C. Localized but not generalized measles/rubella-like rash and Grade 3 fever was reported slightly more frequently with GSK vaccines, but antipyretic use was similar. The incidence of subjects experiencing at least one serious adverse event was 2.0%, 2.9% and 1.8% in the GSK+4C, GSK-20C and Merck-20C groups, respectively. CONCLUSIONS:: Non-inferiority of both GSK MMRV vaccines versus Merck-20C was demonstrated for responses to measles, mumps and rubella viruses, but was not fully demonstrated for VZV. The vaccines showed acceptable reactogenicity/safety when co-administered with HAV and PCV7.
Authors: Blatter MM; Klein NP; Innis BL; et al.
Pediatr Infect Dis J. 2012 Aug;31(8):e133-40.
Assessing the safety of influenza vaccination in specific populations: children and the elderly
Comprehensive monitoring of the safety of influenza vaccines remains a public health priority, particularly as immunization coverage increases across different age groups at the global level. In this review, the authors provide state-of-the-art knowledge on the safety of influenza immunization among children and the elderly. The authors review the safety information in each group separately for inactivated and live attenuated influenza vaccines. Adverse events of special concern including febrile seizure, narcolepsy, asthma and Guillain-Barre syndrome are covered under specific considerations. The authors discuss the current status of the field, particularly the use of new technologies for influenza vaccines and their potential safety profile.
Authors: Rowhani-Rahbar A; Klein NP; Baxter R
Expert Rev Vaccines. 2012 Aug;11(8):973-84.
The Effect of HIV Infection, Immunodeficiency and Antiretroviral Therapy on the Risk of Hepatic Dysfunction
BACKGROUND: Limited data exists regarding the effect of chronic HIV infection on the liver. We sought to characterize the hepatic risks of HIV infection, immunodeficiency, and cumulative use of antiretroviral therapy (ART). METHODS: Adult HIV infected and 10:1 age-matched and sex-matched HIV-uninfected individuals were followed for incident hepatic dysfunction or hepatic dysfunction-related death. Multivariable Poisson regression models were used to obtain incident rate ratios, adjusting for multiple hepatic risk factors including alcohol/drug abuse, hepatitis B and C, and diabetes. RESULTS: We identified 20,775 HIV-infected and 215,158 HIV-uninfected individuals. HIV-infected individuals had a significantly greater overall risk compared with HIV-uninfected individuals of both hepatic dysfunction and hepatic dysfunction-related death. The highest risk was seen in patients with low CD4 cell counts not on ART [adjusted rate ratio of hepatic dysfunction-related death 59.4; (95% confidence interval: 39.3 to 89.7), P < 0.001; hepatic dysfunction, adjusted rate ratio 15.7 (95% confidence interval: 11.4 to 21.6), P < 0.001]. In an HIV-infected only model, factors that increased risk included low CD4 cell count, high HIV RNA level, alcohol/drug abuse, hepatitis B or C coinfection, and diabetes. Longer cumulative exposure to ART did not increase risk, regardless of therapy class. CONCLUSIONS: HIV-infected individuals have a higher risk of hepatic dysfunction and hepatic dysfunction-related death compared with HIV-uninfected individuals, even with adjustment for known hepatic risk factors. Hepatic outcomes were associated with lower CD4+ T-cell counts but not with longer cumulative ART exposure. These findings provide indirect evidence supporting early use of ART to reduce the risk for hepatic-related complications.
Authors: Towner WJ; Xu L; Leyden WA; Horberg MA; Chao CR; Tang B; Klein DB; Hurley LB; Quesenberry CP Jr; Silverberg MJ
J Acquir Immune Defic Syndr. 2012 Jul 1;60(3):321-7.
An unmasking phenomenon in an observational post-licensure safety study of adolescent girls and young women
Our recent experience in a post-licensure safety study of autoimmune conditions following the quadrivalent human papillomavirus vaccine in 189,629 girls and young women ages 9-26 years led us to question the adequacy of the exclusion of Day 0 events to prevent the erroneous association of prevalent conditions with vaccination. Of the 18 confirmed cases of Graves’ disease diagnosed in days 1-60 following vaccination, only 6 cases appeared to be truly new onset. Among the remaining 12 cases, 2 cases had abnormal thyroid stimulating hormone or thyroxine labs drawn prior to or on Day 0 but had no documented pre-existing symptoms. The other 10 cases had mention of symptoms of hyperthyroidism referencing a period prior to first HPV-4 dose. This ‘unmasking’ phenomenon, due to health care visits that include vaccination and new workups of preexisting symptoms, may not be adequately controlled through the exclusion of Day 0 events.
Authors: Jacobsen SJ; Sy LS; Ackerson BK; Chao CR; Slezak JM; Cheetham TC; Takhar HS; Velicer CM; Hansen J; Klein NP
Vaccine. 2012 Jun 29;30(31):4585-7. Epub 2012 May 11.
Immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine administered concomitantly with measles, mumps, rubella, varicella vaccine in healthy toddlers
BACKGROUND: Invasive meningococcal disease can have devastating outcomes, especially in high-risk groups such as infants. As infants are recommended to receive multiple vaccines during a single office visit, this phase 3 study assessed the safety and immune response to MenACWY-CRM at alternative visits in older infants and concomitant use with measles, mumps, rubella, varicella vaccine (MMRV) at 12 months of age. METHODS: Two age groups were concurrently enrolled: 7- to 9-month-old infants who received 2 doses of MenACWY-CRM at 7-9 and 12 months and were randomized 1:1 to receive MenACWY-CRM with or without MMRV at 12 months, and 12-month-old infants who received MMRV only at 12 months. Using predefined non-inferiority criteria, immune responses to the antigens in MMRV were compared between those who did and did not receive MenACWY-CRM; immune responses to MenACWY-CRM as measured by the percentage of subjects with human serum bactericidal activity (hSBA) titers >/= 8, were compared between those who did and did not receive concomitant MMRV. Adequacy of the immune response to 2 doses of MenACWY-CRM administered at 7-9 and 12 months was also assessed. Local and systemic reactions, adverse events resulting in withdrawal or requiring medical attention and serious adverse events were monitored. RESULTS: Concomitant administration of MMRV with MenACWY-CRM did not affect the immune response to either vaccine. The 2-dose series of MenACWY-CRM induced adequate immune response to all 4 serogroups. No increased reactogenicity was observed with MenACWY-CRM+MMRV compared with MMRV alone, and there were no study-related serious adverse events. CONCLUSIONS: Concomitant administration of MenACWY-CRM with MMRV vaccinations at 12 months was well-tolerated, without safety concerns. Robust immune responses to all components of both vaccines were produced and all criteria for non-inferiority were met, supporting the use of a 2-dose regimen of MenACWY-CRM in this age group.
Authors: Klein NP; Shepard J; Bedell L; Odrljin T; Dull P
Vaccine. 2012 Jun 6;30(26):3929-36. Epub 2012 Apr 10.
Risk of Confirmed Guillain-Barre Syndrome Following Receipt of Monovalent Inactivated Influenza A (H1N1) and Seasonal Influenza Vaccines in the Vaccine Safety Datalink Project, 2009-2010
An increased risk of Guillain-Barre syndrome (GBS) following administration of the 1976 swine influenza vaccine led to a heightened focus on GBS when monovalent vaccines against a novel influenza A (H1N1) virus of swine origin were introduced in 2009. GBS cases following receipt of monovalent inactivated (MIV) and seasonal trivalent inactivated (TIV) influenza vaccines in the Vaccine Safety Datalink Project in 2009-2010 were identified in electronic data and confirmed by medical record review. Within 1-42 days following vaccination, 9 cases were confirmed in MIV recipients (1.48 million doses), and 8 cases were confirmed in TIV-only recipients who did not also receive MIV during 2009-2010 (1.72 million doses). Five cases following MIV and 1 case following TIV-only had an antecedent respiratory infection, a known GBS risk factor; furthermore, unlike TIV, MIV administration was concurrent with heightened influenza activity. In a self-controlled risk interval analysis comparing GBS onset within 1-42 days following MIV with GBS onset 43-127 days following MIV, the risk difference was 5.0 cases per million doses (95% confidence interval: 0.5, 9.5). No statistically significant increased GBS risk was found within 1-42 days following TIV-only vaccination versus 43-84 days following vaccination (risk difference = 1.1 cases per million doses, 95% confidence interval: -3.1, 5.4). Further evaluation to assess GBS risk following both vaccination and respiratory infection is warranted.
Authors: Greene SK; Fireman BH; Lee GM; et al.
Am J Epidemiol. 2012 Jun 1;175(11):1100-9. Epub 2012 May 11.
Trends and Characteristics of Culture-Confirmed Staphylococcus aureus Infections in a Large U.S. Integrated Health Care Organization
Infections due to Staphylococcus aureus present a significant health problem in the United States. Between 1990 and 2005, there was a dramatic increase in community-associated methicillin-resistant S. aureus (MRSA), but recent reports suggest that MRSA may be declining. We retrospectively identified S. aureus isolates (n = 133,450) that were obtained from patients in a large integrated health plan between 1 January 1998 and 31 December 2009. Trends over time in MRSA were analyzed, and demographic risk factors for MRSA versus methicillin-susceptible S. aureus (MSSA) were identified. The percentage of S. aureus isolates that were MRSA increased from 9% to 20% between 1998 and 2001 and from 25% to 49% between 2002 and 2005 and decreased from 49% to 43% between 2006 and 2009. The increase in MRSA was seen in blood and in other bacteriological specimens and occurred in all age and race/ethnicity groups, though it was most pronounced in persons aged 18 to <50 years and African-Americans. Hospital onset infections were the most likely to be MRSA (odds ratio [OR], 1.58; confidence interval [CI], 1.46 to 1.70, compared to community-associated cases), but the largest increase in MRSA was in community-associated infections. Isolates from African-Americans (OR, 1.73; CI, 1.64 to 1.82) and Hispanics (OR, 1.11; CI, 1.06 to 1.16) were more likely to be MRSA than those from whites. After substantial increases between 1998 and 2005 in the proportion of S. aureus isolates that were MRSA, the proportion decreased between 2006 and 2009. Hospital onset S. aureus infections are disproportionately MRSA, as are those among African-Americans.
Authors: Ray GT; Suaya JA; Baxter R
J Clin Microbiol. 2012 Jun;50(6):1950-7. Epub 2012 Mar 14.
Determination of Optimized Multidisciplinary Care Team for Maximal Antiretroviral Therapy Adherence
OBJECTIVE: We seek to determine the optimized multidisciplinary care team (MDCT) composition for antiretroviral therapy (ART) adherence. METHODS: We analyzed all new regimen starts (n = 10,801; 7071 ART naive, 3730 ART experienced) among HIV-positive patients in Kaiser Permanente California from 1996 to 2006. We measured 12-month adherence to ART (pharmacy refill methodology) and medical center-specific patient exposure to HIV/infectious disease specialist (reference group), non-HIV primary care provider, clinical pharmacist, nurse case manager, non-nurse care coordinator, dietician, social worker/benefits coordinator, health educator, and mental health worker. We used recursive partitioning to ascertain potential MDCT compositions associated with maximal mean ART adherence. We then employed mixed linear regression with clustering by provider and medical center (adjusting for ART experience, age, gender, race/ethnicity, HIV risk, hepatitis C virus coinfection, ART regimen class, and calendar year) to test which potential MDCT combination identified had statistically significant association with ART adherence. RESULTS: We found maximal increase in adherence with pharmacist plus coordinator plus primary care provider combination (8.1% ART adherence difference compared with reference; 95% confidence interval: 2.7% to 13.5%). Other MDCT teams with significantly (P < 0.05) improved adherence compared with specialist only were nurse plus social worker with primary care provider (7.5%; 5.4% to 9.7%), specialist plus mental health worker (6.5%; 2.6% to 10.4%), pharmacist plus social worker plus primary care provider (5.7%; 4.1% to 7.4%), and pharmacist plus primary care provider (3.3%; 0.8% to 5.8%). Among these MDCTs, there were no significant differences in mean adherence, odds of maximal viral control, or CD4+ changes at 12 months (except pharmacist plus primary care provider). CONCLUSIONS: Various MDCTs were associated with improved adherence, including ones that did not include the HIV specialist but included primary care plus other health professionals. These findings have application to the HIV care team design.
Authors: Horberg MA; Bartemeier Hurley L; James Towner W; Allerton MW; Ting-Ting Tang B; Catz SL; Silverberg MJ; Quesenberry CP
J Acquir Immune Defic Syndr. 2012 Jun 1;60(2):183-90.
Comparative immunogenicity and safety of different multivalent component pertussis vaccine formulations and a 5-component acellular pertussis vaccine in infants and toddlers: A randomized, controlled, open-label, multicenter study
BACKGROUND: Pentavalent and quadrivalent combination vaccine formulations from the same manufacturer (DTaP-IPV/Hib [PENTA], DTaP-IPV [QUAD]) were investigated as to whether they were sufficiently interchangeable to tailor use to local preference or availability. METHODS: A randomized, controlled, open-label, 4-armed, multicenter study in healthy, full-term infants (42-89 days of age) was conducted in 38 centers across the United States. Participants were randomized 1:1:1:1 to a control vaccine group (3 doses DTaP, IPV, and Hib and at Dose 4 DTaP and Hib) and 3 combination vaccine groups: (1) 3 doses PENTA, then Dose 4 DTaP and Hib; (2) 4 QUAD doses and Hib; (3) 4 PENTA doses. Participants (N=2167) were immunized at 2, 4, and 6 months of age, Dose 4 participants (N=1832) at 15 months of age. Immunogenicity was assessed before Doses 1 and 4 and after Doses 3 and 4. Safety was assessed 30 days after each dose and through 180 days Post-Dose 4. RESULTS: Antibody responses and geometric mean concentrations/geometric mean titers (GMCs/GMTs) elicited by each combination vaccine were noninferior (upper-bound 90% confidence interval of GMC/GMT ratios <1.5) to control vaccines except pertactin GMCs were higher after 4 control DTaP doses (157.46EU/mL) than after Dose 4 with DTaP and Hib (after a PENTA infant series) (111.70EU/mL) and after 4 PENTA doses (98.00EU/mL). Fever rates in the combination vaccine groups were noninferior (upper bound 95% CI of combination vaccine group fever rate minus control vaccine group fever rate <10%) to the control vaccine group except the rate after 4 QUAD and Hib doses (23.5%) was higher than after 4 control DTaP doses (13.9%). CONCLUSIONS: PENTA and QUAD had similar safety profiles and no clinically important differences in immunogenicity compared with separately administered control vaccines. ClinicalTrials.gov (NCT ID: NCT00255047).
Authors: Chatterjee A; O'Keefe C; Varman M; Klein NP; Luber S; Tomovici A; Noriega F
Vaccine. 2012 May 14;30(23):3360-8. Epub 2012 Apr 1.
Safety of Zoster Vaccine in Adults from a Large Managed Care Cohort: A Vaccine Safety Datalink Study
OBJECTIVES: The aim of this study was to examine a large cohort of adults who received the zoster vaccine for evidence of an increased risk of prespecified adverse events requiring medical attention. DESIGN: Two self-comparison approaches, including a case-centred approach and a self-controlled case series (SCCS) analysis were used. SETTING: Eight managed-care organizations participating in the Vaccine Safety Datalink project in the United States. SUBJECTS: A total of 193 083 adults aged 50 and older receiving a zoster vaccine from 1 January 2007 to 31 December 2008 were included. MAIN OUTCOME MEASURES: Prespecified adverse events were identified by aggregated International Classification of Diseases, Ninth Revision (ICD-9) codes in automated health plan datasets. RESULTS: The risk of allergic reaction was significantly increased within 1-7 days of vaccination [relative risk = 2.13, 95% confidence interval (CI): 1.87-2.40 by case-centred method and relative rate = 2.32, 95% CI: 1.85-2.91 by SCCS]. No increased risk was found for the following adverse event groupings: cerebrovascular events; cardiovascular events; meningitis; encephalitis; and encephalopathy; and Ramsay-Hunt syndrome and Bell’s palsy. CONCLUSIONS: The results of this study support the findings from the prelicensure clinical trials, providing reassurance that the zoster vaccine is generally safe and well-tolerated with a small increased risk of allergic reactions in 1-7 days after vaccination.
Authors: Tseng HF; Fireman B; Vaccine Safety Datalink (VSD) Team; et al.
J Intern Med. 2012 May;271(5):510-20. Epub 2011 Nov 22.
Immunization and Bell’s Palsy in Children: A Case-Centered Analysis
Bell’s palsy (BP) is an acute and idiopathic paralysis of the facial nerve, with an estimated incidence ranging from 11.5 per 100,000 person-years to 53.3 per 100,000 person-years in different populations. BP has been reported following immunization with inactivated trivalent influenza vaccine (TIV) and hepatitis B virus (HBV) vaccine. Epidemiologic studies examining this association among children are lacking. From 2001 through 2006, all children aged
Authors: Rowhani-Rahbar A; Klein NP; Lewis N; Fireman B; Ray P; Rasgon B; Black S; Klein JO; Baxter R
Am J Epidemiol. 2012 May 1;175(9):878-85. Epub 2012 Mar 12.
Measles-Containing Vaccines and Febrile Seizures in Children Age 4 to 6 Years
BACKGROUND: In the United States, children receive 2 doses of measles-mumps-rubella vaccine (MMR) and varicella vaccine (V), the first between ages 1 to 2 years and the second between ages 4 to 6 years. Among 1- to 2-year-olds, the risk of febrile seizures 7 to 10 days after MMRV is double that after separate MMR + V. Whether MMRV or MMR + V affects risk for febrile seizure risk among 4- to 6-year-olds has not been reported. METHODS: Among 4- to 6-year-old Vaccine Safety Datalink members, we identified seizures in the emergency department and hospital from 2000 to 2008 and outpatient visits for fever from 2006 to 2008 during days 7 to 10 and 0 to 42 after MMRV and MMR + V. Incorporating medical record reviews, we assessed seizure risk after MMRV and MMR + V. RESULTS: From 2006 through 2008, 86 750 children received MMRV; from 2000 through 2008, 67 438 received same-day MMR + V. Seizures were rare throughout days 0 to 42 without peaking during days 7 to 10. There was 1 febrile seizure 7 to 10 days after MMRV and 0 after MMR + V. Febrile seizure risk was 1 per 86 750 MMRV doses (95% confidence interval, 1 per 3 426 441, 1 per 15 570) and 0 per 67 438 MMR + V doses (1 per 18 282). CONCLUSIONS: This study provides reassurance that MMRV and MMR + V were not associated with increased risk of febrile seizures among 4- to 6-year-olds. We can rule out with 95% confidence a risk greater than 1 febrile seizure per 15 500 MMRV doses and 1 per 18 000 MMR + V doses.
Authors: Klein NP; Lewis E; Baxter R; Weintraub E; Glanz J; Naleway A; Jackson LA; Nordin J; Lieu T; Belongia EA; Fireman B
Pediatrics. 2012 May;129(5):809-14. Epub 2012 Apr 2.
Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America
BACKGROUND: Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends. METHODS: In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men). RESULTS: Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7-151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5-61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8-6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5-2.2). In comparison with the period 2000-2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3-.9) in 1996-1999 and 0.9 (95% CI, .6-1.2) in 2004-2007. CONCLUSIONS: Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.
Authors: Silverberg MJ; the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA; et al.
Clin Infect Dis. 2012 Apr;54(7):1026-34. Epub 2012 Jan 30.
Rowhani-Rahbar et al. Respond to ‘Immunization and Bell’s Palsy in Children’
Authors: Rowhani-Rahbar A; Fireman B; Lewis N; Ray P; Rasgon B; Klein JO; Black S; Klein NP; Baxter R
Am J Epidemiol. 2012 Mar 12.
Recurrent Guillain-Barre Syndrome Following Vaccination
BACKGROUND: Guillain-Barre syndrome (GBS) is an acute polyradiculopathy, thought to be autoimmune, which has been reported following vaccinations. The Advisory Committee on Immunization Practices recommends not administering influenza vaccine to individuals who have had a history of GBS within 6 weeks of a prior influenza vaccination if they are not at high risk of severe complications from influenza illness. METHODS: We identified GBS cases from the Kaiser Permanente Northern California databases from 1995 into 2006 using hospital discharge codes; each medical record was neurologist-reviewed and only GBS-confirmed cases were included for follow-up. We followed confirmed cases through 2008 for vaccinations and recurrent GBS. RESULTS: We identified 550 cases of GBS over 33 million person-years. Following their GBS diagnoses, 989 vaccines were given to 279 of these individuals, including 405 trivalent inactivated influenza vaccines (TIV) administered to 107 individuals with a prior diagnosis of GBS. Among the 550 total cases of GBS, 18 initially had onset within 6 weeks of TIV; of these, 2 were revaccinated with TIV without a recurrence of GBS. Only 6 individuals of 550 (1.1%) had a second (recurrent) diagnosis of GBS. Among these 6 individuals, none had any vaccine exposure at all in the 2 months prior to the second onset of GBS. CONCLUSIONS: In our population of over 3 million members, during an 11-year period, risk of GBS recurrence was low. There were no cases of recurrent GBS after influenza vaccination and none within 6 weeks after any vaccine.
Authors: Baxter R; Lewis N; Bakshi N; Vellozzi C; Klein NP; CISA Network
Clin Infect Dis. 2012 Mar;54(6):800-4. Epub 2012 Jan 19.
Risk of intussusception following administration of a pentavalent rotavirus vaccine in US infants
CONTEXT: Current rotavirus vaccines were not associated with intussusception in large prelicensure trials. However, recent postlicensure data from international settings suggest the possibility of a low-level elevated risk, primarily in the first week after the first vaccine dose. OBJECTIVE: To examine the risk of intussusception following pentavalent rotavirus vaccine (RV5) in US infants. DESIGN, SETTING, AND PATIENTS: This cohort study included infants 4 to 34 weeks of age, enrolled in the Vaccine Safety Datalink (VSD) who received RV5 from May 2006-February 2010. We calculated standardized incidence ratios (SIRs), relative risks (RRs), and 95% confidence intervals for the association between intussusception and RV5 by comparing the rates of intussusception in infants who had received RV5 with the rates of intussusception in infants who received other recommended vaccines without concomitant RV5 during the concurrent period and with the expected number of intussusception visits based on background rates assessed prior to US licensure of the RV5 (2001-2005). MAIN OUTCOME MEASURE: Intussusception occurring in the 1- to 7-day and 1- to 30-day risk windows following RV5 vaccination. RESULTS: During the study period, 786,725 total RV5 doses, which included 309,844 first doses, were administered. We did not observe a statistically significant increased risk of intussusception with RV5 for either comparison group following any dose in either the 1- to 7-day or 1- to 30-day risk window. For the 1- to 30-day window following all RV5 doses, we observed 21 cases of intussusception compared with 20.9 expected cases (SIR, 1.01; 95% CI, 0.62-1.54); following dose 1, we observed 7 cases compared with 5.7 expected cases (SIR, 1.23; 95% CI, 0.5-2.54). For the 1- to 7-day window following all RV5 doses, we observed 4 cases compared with 4.3 expected cases (SIR, 0.92; 95% CI, 0.25-2.36); for dose 1, we observed 1 case compared with 0.8 expected case (SIR, 1.21; 95% CI, 0.03-6.75). The upper 95% CI limit of the SIR (6.75) from the historical comparison translates to an upper limit for the attributable risk of 1 intussusception case per 65,287 RV5 dose-1 recipients. CONCLUSION: Among US infants aged 4 to 34 weeks who received RV5, the risk of intussusception was not increased compared with infants who did not receive the rotavirus vaccine.
Authors: Shui IM; Baggs J; Patel M; Parashar UD; Rett M; Belongia EA; Hambidge SJ; Glanz JM; Klein NP; Weintraub E
JAMA. 2012 Feb 8;307(6):598-604.
Surveillance of Autoimmune Conditions following Routine Use of Quadrivalent Human Papillomavirus Vaccine
OBJECTIVE: An observational safety study of the quadrivalent human papillomavirus vaccine (HPV4) in women was conducted. This report presents findings from autoimmune surveillance. Design. Subjects were followed for 180days after each HPV4 dose for new diagnoses of 16 prespecified autoimmune conditions. SETTING: Two managed care organizations in California. Subjects. Number of 189,629 women who received >/=1 dose of HPV4 between 08/2006 and 03/2008. OUTCOME: Potential new-onset autoimmune condition cases amongst HPV4 recipients were identified by electronic medical records. Medical records of those with >/=12-month health plan membership prior to vaccination were reviewed by clinicians to confirm the diagnosis and determine the date of disease onset. The incidence of each autoimmune condition was estimated for unvaccinated women at one study site using multiple imputations and compared with that observed in vaccinated women. Incidence rate ratios (IRR) were calculated. Findings were reviewed by an independent Safety Review Committee (SRC). RESULTS: Overall, 1014 potential new-onset cases were electronically identified; 719 were eligible for case review; 31-40% were confirmed as new onset. Of these, no cluster of disease onset in relation to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the estimated IRR was significantly elevated except Hashimoto’s disease [IRR=1.29, 95% confidence interval: 1.08-1.56]. Further investigation of temporal relationship and biological plausibility revealed no consistent evidence for a safety signal for autoimmune thyroid conditions. The SRC and the investigators identified no autoimmune safety concerns in this study. CONCLUSIONS: No autoimmune safety signal was found in women vaccinated with HPV4.
Authors: Chao C; Klein NP; Jacobsen SJ; et al.
J Intern Med. 2012 Feb;271(2):193-203. Epub 2011 Nov 15.
An open-label, randomized, multi-center study of the immunogenicity and safety of DTaP-IPV (Kinrix) co-administered with MMR vaccine with or without varicella vaccine in healthy pre-school age children
BACKGROUND: In the US, it is recommended that 4-6 year old children receive diphtheria-tetanus-acellular pertussis (DTaP), inactivated poliovirus (IPV), measles-mumps-rubella (MMR), varicella (V), and influenza vaccines. Data relating to the concomitant administration of combination DTaP-IPV vaccine (Kinrix; GlaxoSmithKline Biologicals) and influenza or V vaccines are currently limited. This study was undertaken to evaluate the immunogenicity and reactogenicity of Kinrix when co-administered with MMR (M-M-RII((R)), Merck & Co.) and Varivax (Merck & Co.) in 4-6 year old children. METHODS: Phase IIIb, open-label, non-inferiority study (NCT00871117). We randomized (1:1) healthy 4-6 year olds to receive Kinrix+MMR+V on day 0 (Group 1), or Kinrix+MMR on day 0, followed by V at month 1 (Group 2). We measured DTaP-IPV immunogenicity before and 1 month post-vaccination (prior to V vaccination in Group 2). We collected local and general solicited symptoms within 4 days after vaccination and serious adverse events (SAEs) through 6 months post-vaccination. RESULTS: We enrolled 478 subjects. One month post-vaccination, >95% of subjects in both groups had booster responses to diphtheria, tetanus and pertussis antigens and all subjects had seroprotective anti-poliovirus antibody titers. Immune responses in Group 1 were non-inferior to Group 2 for responses to DTaP-IPV antigens according to pre-specified criteria. Reporting of solicited local events at the DTaP-IPV site appeared to be similar between the two vaccine groups, as was reporting of solicited general adverse events within 4 days of vaccination; no vaccine related SAEs were reported. CONCLUSION: Concomitant administration of varicella vaccine with Kinrix and MMR did not impact the immunogenicity of diphtheria, tetanus, pertussis or poliovirus antigens. Both vaccine regimens were well tolerated. These results support the co-administration of DTaP-IPV, MMR, and V vaccines in 4-6-year-old children, providing protection against multiple diseases in a timely and efficient manner.
Authors: Klein NP; Weston WM; Kuriyakose S; Kolhe D; Howe B; Friedland LR; Van Der Meeren O
Vaccine. 2012 Jan 11;30(3):668-74. Epub 2011 Nov 4.
Lack of association between childhood immunizations and encephalitis in California, 1998-2008
OBJECTIVE: A number of new and combination vaccines have been introduced for children in the past two decades. Encephalitis cases occurring within defined time windows following administration of pertussis- or measles-containing vaccines are eligible for compensation by the Vaccine Injury Compensation Program. Due to increased parental concerns about vaccine safety and potential neurologic adverse events following immunization with new and multiple vaccines administered at the same visit, our aim was to determine whether immunizations are associated with an increased risk of encephalitis within defined risk windows. METHODS: We reviewed immunization records from 246 pediatric encephalitis cases referred to the California Encephalitis Project between July 1998 and December 2008. We included data on 110 cases who had been immunized in the year prior to the onset of encephalitis (observation period) and had complete immunization records. We used the case-centered method to test whether cases were more likely to have developed encephalitis in defined risk windows-42, 30 and 21 days after any vaccination, 3 days after pertussis-containing vaccines and 5-15 days after measles-virus containing vaccines-compared with the rest of the observation period. RESULTS: All vaccines recommended in the current immunization schedule were represented in our sample. No increased risk of encephalitis was seen following administration of pertussis-containing vaccines, measles-containing vaccines or any number of vaccines administered in a single visit (vaccine episode); the odds ratios and 95% confidence intervals for encephalitis after a vaccine episode were: 1.0 (0.6-1.8) in a 42-day risk window, 0.9 (0.5-1.6) in a 30-day risk window and 1.2 (0.7-2.2) in a 21-day risk window. CONCLUSION: No association between receipt of currently recommended immunizations and subsequent development of encephalitis was observed in this study.
Authors: Pahud BA; Rowhani-Rahbar A; Glaser C; Gavali S; Salibay CJ; Fireman B; Dekker CL
Vaccine. 2012 Jan 5;30(2):247-53. Epub 2011 Nov 12.
Prescription Long-term Opioid Use in HIV-infected Patients
OBJECTIVES: To examine changes the in use of prescription opioids for the management of chronic noncancer pain in human immunodeficiency virus (HIV)-infected patients and to identify patient characteristics associated with long-term use. METHODS: Long-term prescription opioid use (ie, 120+ days supply or 10+ prescriptions during a year) was assessed between 1997 and 2005 among 6939 HIV-infected Kaiser Permanente members and HIV-uninfected persons in the general health plan memberships. RESULTS: In 2005, 8% of HIV individuals had prevalent long-term opioid use, more than double the prevalence among HIV-uninfected individuals. However, the large increases in use from 1997 to 2005 in the general population were not observed for HIV-infected individuals. The strongest associations with prevalent use among HIV-infected individuals were female sex with a prevalence ratio (PR) of 1.8 (95% CI=1.3, 2.5); Charlson comorbidity score of 2 or more (compared with a score of 0) with a PR of 1.9 (95% CI=1.4, 2.8); injection drug use history with a PR of 1.8 (95% CI=1.3, 2.6); and substance use disorders with a PR of 1.8 (95% CI=1.3, 2.5). CD4, HIV viral load, and acquired immunodeficiency syndrome diagnoses were associated with prevalent opioid use early in the antiretroviral therapy era (1997), but not in 2005. CONCLUSIONS: Long-term opioid use for chronic pain has remained stable over time for HIV patients, whereas its use increased in the general population. The prevalence of prescribed opioids in HIV patients was highest for certain subgroups, including women, and those with a comorbidity and substance abuse history.
Authors: Silverberg MJ; Ray GT; Saunders K; Rutter CM; Campbell CI; Merrill JO; Sullivan MD; Von Korff M; Weisner C; Banta-Green CJ
Clin J Pain. 2012 Jan;28(1):39-46.
Safety and Immunogenicity of a Novel Quadrivalent Meningococcal CRM-Conjugate Vaccine Given Concomitantly With Routine Vaccinations in Infants
BACKGROUND: In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. METHODS: In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. RESULTS: Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. CONCLUSIONS: A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.
Authors: Klein NP; Reisinger KS; Johnston W; Odrljin T; Gill CJ; Bedell L; Dull P
Pediatr Infect Dis J. 2012 Jan;31(1):64-71.
Influence of provider experience on antiretroviral adherence and viral suppression
BACKGROUND AND AIM: Early in the combination antiretroviral therapy (cART) era, provider experience (as measured by panel size) was associated with improved outcomes. We explored that association and other characteristics of provider experience. METHODS: We performed a retrospective cohort analysis in Kaiser Permanente California (an integrated health care system in the United States), examining all human immunodeficiency virus seropositive (HIV+) patients initiating a first cART regimen (antiretroviral therapy [ART]-naive, N = 7071) or initiating a second or later cART regimen (ART-experienced, N = 3730) from 1996-2006. We measured ART adherence through 12 months (pharmacy fill and refill records) and determined HIV viral load levels below limits of quantification at 12 months. Provider experience, updated annually, was measured as (1) HIV panel size (0-10 patients as reference strata), (2) years treating HIV (less than 1 year as reference), and (3) specialty ( noninfectious disease specialty, non-HIV expert as reference). We assessed associations by utilizing mixed modeling analyses (clustered by provider and medical center), controlling for patient age, sex, race/ethnicity, HIV risk behavior, hepatitis C coinfection, ART regimen class, and calendar year. RESULTS: Among the ART-experienced, improved adherence was associated with greater years experience (mean increase 3.1% 2-5 years experience; 3.7% 5-10 years; 2.7% 11-20 years; P = 0.07, categorical). In adjusted analyses, viral suppression among ART-naive was positively associated with panel size (odds ratio 26-50 patients: 1.31, P = 0.03, categorical), but negatively associated with years experience (18% less for greater than 100 patients; P = 0.003). No provider characteristic was significantly associated with improved adherence among ART-naive or odds of maximal viral suppression among ART-experienced in adjusted analysis. CONCLUSIONS: Except for panel size and years experience among ART-naive, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression.
Authors: Horberg MA; Hurley LB; Towner WJ; Allerton MW; Tang BT; Catz SL; Silverberg MJ; Quesenberry CP
HIV AIDS (Auckl). 2012;4:125-33. Epub 2012 Aug 15.
Epidemiologic and Clinical Features of Bell’s Palsy among Children in Northern California
BACKGROUND: Bell’s palsy (BP) is an acute, idiopathic, and usually unilateral paralysis of the facial nerve. Large population-based studies of BP among children are lacking. We determined epidemiologic and clinical features of BP among children enrolled in a large integrated health care delivery system. METHODS: From 2001 through 2006, all children
Authors: Rowhani-Rahbar A; Baxter R; Rasgon B; Ray P; Black S; Klein JO; Klein NP
Neuroepidemiology. 2012;38(4):252-8. Epub 2012 Jun 5.
HIV Infection, Immunodeficiency, Viral Replication, and the Risk of Cancer
BACKGROUND: Few studies have compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.METHODS: We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996 to 2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity.RESULTS: We observed elevated RRs for Kaposi sarcoma (KS; RR = 199; P < 0.001), non-Hodgkin lymphoma (NHL; RR = 15; P < 0.001), anal cancer (RR = 55; P < 0.001), Hodgkin lymphoma (HL; RR = 19; P < 0.001), melanoma (RR = 1.8; P = 0.001), and liver cancer (RR = 1.8; P = 0.013), a reduced RR for prostate cancer (RR = 0.8; P = 0.012), and no increased risk for oral cavity/pharynx (RR = 1.4; P = 0.14), lung (RR = 1.2; P = 0.15), or colorectal (RR = 0.9; P = 0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P < 0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 < 200 cells/muL and for melanoma and liver cancer with CD4 < 500 cells/muL. Only KS and NHL were associated with HIV RNA.CONCLUSION: Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors.Impact: Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population. Cancer Epidemiol Biomarkers Prev; 20(12); 1-9. (c)2011 AACR.
Authors: Silverberg MJ; Chao C; Leyden WA; Xu L; Horberg MA; Klein D; Towner WJ; Dubrow R; Quesenberry CP Jr; Neugebauer RS; Abrams DI
Cancer Epidemiol Biomarkers Prev. 2011 Dec;20(12):2551-9. Epub 2011 Nov 22.
Developing the next generation of vaccinologists
Authors: Klein NP; DeStefano F; et al.
Vaccine. 2011 Nov 21;29(50):9296-7. Epub 2011 Apr 19.
Association of increased upper trunk and decreased leg fat with 2-h glucose in control and HIV-infected persons
OBJECTIVE: Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects. RESEARCH DESIGN AND METHODS: A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters. RESULTS: The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants. CONCLUSIONS: In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
Authors: Kosmiski LA; Scherzer R; Heymsfield SB; Rimland D; Simberkoff MS; Sidney S; Shlipak MG; Bacchetti P; Biggs ML; Grunfeld C; Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM);
Diabetes Care. 2011 Nov;34(11):2448-53. Epub 2011 Sep 16.
Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination
BACKGROUND: Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. METHODS: Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR section sign314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. RESULTS: 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barre Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as ‘possibly’ related (33%), 108 as ‘unlikely’ related (51%), and 20 as ‘unrelated’ (9%) to H1N1 vaccination; none were classified as ‘probable’ or ‘definite’ and 12 were unclassifiable (6%). CONCLUSION: The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.
Authors: Williams SE; Klein NP; Edwards KM; et al.
Vaccine. 2011 Oct 26;29(46):8302-8. Epub 2011 Sep 3.
Monitoring the safety of quadrivalent human papillomavirus vaccine: Findings from the Vaccine Safety Datalink
BACKGROUND: In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9-26 year-old female vaccine recipients between August 2006 and October 2009. METHODS: Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan-Barre Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis. RESULTS: A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9-17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization). CONCLUSIONS: In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted.
Authors: Gee J; Fireman B; Klein NP; Weintraub ES; et al.
Vaccine. 2011 Oct 26;29(46):8279-84. Epub 2011 Sep 9.
Overview of the Clinical Consult Case Review of adverse events following immunization: Clinical Immunization Safety Assessment (CISA) network 2004-2009
BACKGROUND: In 2004 the Clinical Consult Case Review (CCCR) working group was formed within the CDC-funded Clinical Immunization Safety Assessment (CISA) Network to review individual cases of adverse events following immunizations (AEFI). METHODS: Cases were referred by practitioners, health departments, or CDC employees. Vaccine Adverse Event Reporting System (VAERS) searches and literature reviews for similar cases were performed prior to review. After CCCR discussion, AEFI were assessed for a causal relationship with vaccination and recommendations regarding future immunizations were relayed back to the referring physicians. In 2010, surveys were sent to referring physicians to determine the utility and effectiveness of the CCCR service. RESULTS: CISA investigators reviewed 76 cases during 68 conference calls between April 2004 and December 2009. Almost half of the cases (35/76) were neurological in nature. Similar AEFI for the specific vaccines received were discovered for 63 cases through VAERS searches and for 38 cases through PubMed searches. Causality assessment using the modified WHO criteria resulted in classifying 3 cases as definitely related to vaccine administration, 12 as probably related, 16 as possibly related, 18 as unlikely related, 10 as unrelated, and 17 had insufficient information to assign causality. The physician satisfaction survey was returned by 30 (57.7%) of those surveyed and a majority of respondents (93.3%) felt that the CCCR service was useful. CONCLUSIONS: The CCCR provides advice about AEFI to practitioners, assigns potential causality, and contributes to an improved understanding of adverse health events following immunizations.
Authors: Williams SE; Klein NP; Edwards KM; et al.
Vaccine. 2011 Sep 16;29(40):6920-7. Epub 2011 Jul 27.
Risk factors for tuberculosis after highly active antiretroviral therapy initiation in the United States and Canada: implications for tuberculosis screening
BACKGROUND: Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts. METHODS: Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995-August 2009. Parametric survival models identified factors associated with tuberculosis occurrence. RESULTS: Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131-333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk. CONCLUSIONS: Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm(3) or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.
Authors: Sterling TR; Silverberg MJ; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA); et al.
J Infect Dis. 2011 Sep 15;204(6):893-901.
Missing data on the estimation of the prevalence of accumulated human immunodeficiency virus drug resistance in patients treated with antiretroviral drugs in north america
Determination of the prevalence of accumulated antiretroviral drug resistance among persons infected with human immunodeficiency virus (HIV) is complicated by the lack of routine measurement in clinical care. By using data from 8 clinic-based cohorts from the North American AIDS Cohort Collaboration on Research and Design; drug-resistance mutations from those with genotype tests were determined and scored using the Genotypic Resistance Interpretation Algorithm developed at Stanford University. For each year from 2000 through 2005; the prevalence was calculated using data from the tested subset; assumptions that incorporated clinical knowledge; and multiple imputation methods to yield a complete data set. A total of 9;289 patients contributed data to the analysis; 3;959 had at least 1 viral load above 1;000 copies/mL; of whom 2;962 (75%) had undergone at least 1 genotype test. Using these methods; the authors estimated that the prevalence of accumulated resistance to 2 or more antiretroviral drug classes had increased from 14% in 2000 to 17% in 2005 (P < 0.001). In contrast; the prevalence of resistance in the tested subset declined from 57% to 36% for 2 or more classes. The authors' use of clinical knowledge and multiple imputation methods revealed trends in HIV drug resistance among patients in care that were markedly different from those observed using only data from patients who had undergone genotype tests.
Authors: Abraham AG; Silverberg M; North American AIDS Cohort Collaboration on Research and Design of the International Epidemiologic Databases to Evaluate AIDS; et al.
Am J Epidemiol. 2011 Sep 15;174(6):727-35. Epub 2011 Aug 3.
HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons
OBJECTIVE: Experimental studies suggested that HMG-CoA reductase inhibitors (‘statins’) may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons. DESIGN: A nested case-control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization. METHODS: Cases were incident HIV+ NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente’s electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV + NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT). RESULTS: A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV + NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31-0.95), 0.64 (0.31-1.28), and 0.50 (0.23-1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed. CONCLUSION: Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups.
Authors: Chao C; Xu L; Abrams DI; Towner WJ; Horberg MA; Leyden WA; Silverberg MJ
AIDS. 2011 Sep 10;25(14):1771-7.
Risk of rheumatoid arthritis following vaccination with tetanus, influenza and hepatitis B vaccines among persons 15-59 years of age
BACKGROUND: Associations between vaccinations, particularly hepatitis B, and onset of rheumatoid arthritis (RA) have been reported, but examined in few large-scale studies. METHOD: Onset of RA cases and dates of vaccination against hepatitis B, tetanus, and influenza were identified in a retrospective chart review of approximately 1 million Kaiser Permanente Northern California members ages 15-59 years from 1997 through 1999. In a cohort analysis, rates of new-onset RA were compared between vaccinated and unvaccinated within 90, 180, and 365 days. In a case-control analysis, rates of vaccination during exposure intervals (90, 180, 365, and 730 days) were compared between cases and controls using conditional logistic regression. RESULTS: 378 RA cases were included in the cohort analysis; 37 additional cases were included in the case-control analysis. In the cohort analysis the relative risks of RA onset within 90, 180, or 365 days of hepatitis B vaccination were not significant (R.R.=1.44, p=0.53; R.R.=1.67, p=0.22; R.R.=1.23, p=0.59 respectively). We found a possible association between RA and influenza vaccine in the previous 180 and 365 days in the cohort analysis (R.R=1.36, p=0.03; R.R.=1.34, p=0.01 respectively), but in the case-control analysis, cases were no more likely than controls to have received any of the three vaccines. CONCLUSIONS: In this large retrospective study we found no statistically significant association between exposure to hepatitis B vaccine and onset of RA. A possible association between RA and influenza vaccination in the cohort study was not borne out in the larger case-control analysis.
Authors: Ray P; Black S; Shinefield H; Dillon A; Carpenter D; Lewis E; Ross P; Chen RT; Klein NP; Baxter R; Vaccine Safety Datalink Team
Vaccine. 2011 Sep 2;29(38):6592-7. Epub 2011 Jul 16.
Immunogenicity and Safety of an Inactivated Hepatitis A Vaccine When Coadministered With Diphtheria-tetanus-acellular Pertussis and Haemophilus influenzae Type B Vaccines in Children 15 Months of Age
BACKGROUND: This study (NCT00197236) evaluated the safety and immunogenicity of a hepatitis A virus (HAV) vaccine when coadministered with diphtheria-tetanus-acellular pertussis (DTaP) and Haemophilus influenzae type b (Hib) vaccines in children 15 months of age. METHODS: This was an open-labeled, multicenter study with healthy subjects enrolled and randomized (1:1:1) into 3 treatment groups. A total of 394 subjects received the first study vaccinations at 15 months of age. Group HAV (N = 135) received 2 doses of HAV vaccine 6 to 9 months apart. Group HAV+DTaP+Hib (N = 127) received HAV vaccine coadministered with DTaP and Hib vaccines and the second dose of HAV vaccine, 6 to 9 months later. Group DTaP+Hib–>HAV (N = 132) received the DTaP and Hib vaccines at 15 months of age, followed by HAV vaccine 30 days later and the second dose of HAV vaccine 7 to 10 months after the DTaP+Hib vaccines. Immune responses were evaluated before the first study vaccination and 30 days after each vaccine dose. Solicited, unsolicited, and serious adverse events were collected. RESULTS: After 2 doses of the HAV vaccine, all subjects in the 3 groups were seropositive. The geometric mean concentration of anti-HAV antibodies ranged between 1625.1 and 1904.4 mIU/mL. Coadministration of the 3 vaccines did not impact immunogenicity of the HAV, DTaP, or Hib vaccines. Vaccines were well tolerated in all groups. CONCLUSIONS: A 2-dose schedule of HAV vaccine was well tolerated and immunogenic when administered to children starting at 15 months of age. Immune responses to the DTaP or Hib vaccines were similar whether they were administered alone or were coadministered with the HAV vaccine.
Authors: Trofa AF; Klein NP; Paul IM; Michaels MG; Goessler M; Chandrasekaran V; Blatter M
Pediatr Infect Dis J. 2011 Sep;30(9):e164-9.
Safety of trivalent inactivated influenza vaccine in children aged 24 to 59 months in the vaccine safety datalink
OBJECTIVES: To evaluate the safety of trivalent inactivated influenza vaccine (TIV) in children aged 24 to 59 months and to evaluate the risk of medically attended events (MAEs) in a subcohort of children who had multiple annual doses of TIV over their lifetimes. DESIGN: Self-controlled screening study. SETTING: Seven US managed care organizations from October 1, 2002, to March 31, 2006. PARTICIPANTS: Children aged 24 to 59 months who received at least 1 TIV dose (66 283 children and 91 692 TIV doses). EXPOSURE: Vaccination with TIV. MAIN OUTCOME MEASURES: Medically attended events in inpatient and emergency department settings in one of the following risk windows: 0 to 2, 1 to 14, or 1 to 42 days after vaccination. All MAEs that met the screening criteria of incidence rate ratios (IRRs) exceeding 1.0 and P
Authors: Glanz JM; Klein NP; Weintraub ES; et al.
Arch Pediatr Adolesc Med. 2011 Aug;165(8):749-55.
H1N1 and seasonal influenza vaccine safety in the vaccine safety datalink project
BACKGROUND: The emergence of pandemic H1N1 influenza virus in early 2009 prompted the rapid licensure and use of H1N1 monovalent inactivated (MIV) and live, attenuated (LAMV) vaccines separate from seasonal trivalent inactivated (TIV) and live, attenuated (LAIV) influenza vaccines. A robust influenza immunization program in the U.S. requires ongoing monitoring of potential adverse events associated with vaccination. PURPOSE: To prospectively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009-2010 season. METHODS: The Vaccine Safety Datalink (VSD) Project monitors approximately 9.2 million members in eight U.S. medical care organizations. Electronic data on vaccines and pre-specified adverse events were updated and analyzed weekly for signal detection from November 2009 to April 2010 using either a self-controlled design or a current versus historical comparison. Statistical signals were further evaluated using alternative approaches to identify temporal clusters and to control for time-varying confounders. RESULTS: As of May 1, 2010, a total of 1,345,663 MIV, 267,715 LAMV, 2,741,150 TIV, and 157,838 LAIV doses were administered in VSD. No significant associations were noted during sequential analyses for Guillain-Barre syndrome, most other neurologic outcomes, and allergic and cardiac events. For MIV, a statistical signal was observed for Bell’s palsy for adults aged >/=25 years on March 31, 2010, using the self-controlled approach. Subsequent analyses revealed no significant temporal cluster. Case-centered logistic regression adjusting for seasonality demonstrated an OR for Bell’s palsy of 1.26 (95% CI=0.97, 1.63). CONCLUSIONS: No major safety problems following H1N1 or seasonal influenza vaccines were detected in the 2009-2010 season in weekly sequential analyses. Seasonality likely contributed to the Bell’s palsy signal following MIV. Prospective safety monitoring followed by rigorous signal refinement is critical to inform decision-making by regulatory and public health agencies.
Authors: Lee GM; Fireman BH; Vaccine Safety Datalink Project; et al.
Am J Prev Med. 2011 Aug;41(2):121-8.
Regional fat deposition and cardiovascular risk in HIV infection: the FRAM study
HIV-infected individuals are at increased risk for cardiovascular disease (CVD) and lipodystrophy, but the relationship between regional adipose tissue (AT) depots and CVD risk is not well described. We determined regional AT volumes and CVD risk in an analysis of 586 HIV-infected and 280 control FRAM study subjects using whole-body magnetic resonance imaging (MRI) and the Framingham Risk Score (FRS). Median FRS and FRS >10% were higher in HIV than control men (4.7% vs. 3.7%, p=0.0002; 16% vs. 4%, p<0.0001). HIV and control women had similarly low FRS (1.1% vs. 1.2%, p=0.91). In controls, total AT and all regional AT depots showed strong positive correlations with FRS (p<0.001) in men and weaker positive correlations in women. Greater visceral AT (VAT) and lower leg subcutaneous AT (SAT) volumes were associated with elevated FRS in HIV subjects with a trend for upper trunk SAT. Controls in the lowest quartile of leg SAT had the lowest FRS (1.5%), whereas HIV with similarly low leg SAT had the highest FRS (4.0%, p<0.001 vs. controls). Increased VAT is associated with CVD risk, but the risk is higher in HIV-infected individuals relative to controls at every level of VAT. Peripheral lipoatrophy (as measured by leg SAT) is associated with striking increased CVD risk in HIV-infected patients even after controlling for VAT, whereas low leg SAT is associated with low CVD risk in controls.
Authors: Lake JE; Wohl D; Scherzer R; Grunfeld C; Tien PC; Sidney S; Currier JS
AIDS Care. 2011 Aug;23(8):929-38. Epub 2011 Jun 24.
Impact of health facility-based insecticide treated bednet distribution in Malawi: progress and challenges towards achieving universal coverage.
BACKGROUND: High levels of insecticide treated bednet (ITN) use reduce malaria burden in countries with intense transmission such as Malawi. Since 2007 Malawi has implemented free health facility-based ITN distribution for pregnant women and children <5 years old (under-5s). We evaluated the progress of this targeted approach toward achieving universal ITN coverage. METHODS: We conducted a cross-sectional household survey in eight districts in April 2009. We assessed household ITN possession, ITN use by all household members, and P. falciparum asexual parasitemia and anemia (hemoglobin <11 grams/deciliter) in under-5s. RESULTS: We surveyed 7,407 households containing 29,806 persons. Fifty-nine percent of all households (95% confidence interval [95% CI]: 56-62), 67% (95% CI: 64-70) of eligible households (i.e., households with pregnant women or under-5s), and 40% (95% CI: 36-45) of ineligible households owned an ITN. In households with at least one ITN, 76% (95% CI: 74-78) of all household members, 88% (95% CI: 87-90) of under-5s and 90% (95% CI: 85-94) of pregnant women used an ITN the previous night. Of 6,677 ITNs, 92% (95% CI: 90-94) were used the previous night with a mean of 2.4 persons sleeping under each ITN. In multivariable models adjusting for district, socioeconomic status and indoor residual spraying use, ITN use by under-5s was associated with a significant reduction in asexual parasitemia (adjusted odds ratio (aOR) 0.79; 95% CI: 0.64-0.98; p-value 0.03) and anemia (aOR 0.79; 95% CI 0.62-0.99; p-value 0.04). Of potential targeted and non-targeted mass distribution strategies, a campaign distributing 1 ITN per household might increase coverage to 2.1 household members per ITN, and thus achieve near universal coverage often defined as 2 household members per ITN. CONCLUSIONS: Malawi has substantially increased ITN coverage using health facility-based distribution targeting pregnant women and under-5s, but needs to supplement these activities with non-targeted mass distribution campaigns to achieve universal coverage and maximum public health impact.
Authors: Skarbinski J; Mwandama D; Luka M; Jafali J; Wolkon A; Townes D; Campbell C; Zoya J; Ali D; Mathanga DP
PLoS One. 2011;6(7):e21995. doi: 10.1371/journal.pone.0021995. Epub 2011 Jul 21.
Attitudes and beliefs of parents concerned about vaccines: impact of timing of immunization information
OBJECTIVES: To determine if giving vaccine-information materials before the 2-month vaccination visit to mothers with concerns about vaccine safety positively changed their attitudes and beliefs about vaccine safety. METHODS: Mothers who indicated concerns about infant vaccinations were recruited from 2 separate sites in Tennessee and California and were given vaccine information at 1 of 3 times: during a prenatal visit; a 1-week postpartum well-child visit; or a 2-month vaccination visit. A separate group of concerned mothers was assigned to be followed longitudinally at all 3 time points and was analyzed separately. The mothers reviewed a new vaccine-information pamphlet and Vaccine Information Statements (VIS) from the Centers for Disease Control and Prevention. Attitudes and beliefs about immunization were assessed both before and after the review of materials with written surveys. RESULTS: A total of 272 mothers with immunization concerns participated in the study. After review of the materials, mothers in all groups were significantly more likely to respond positively to questions and statements supporting the safety and importance of vaccines. Mothers who received this information at earlier visits were not significantly more likely to respond positively than mothers who received the information at the child’s 2-month vaccination visit; however, participating mothers did indicate a preference for receiving vaccine information before the first vaccination visit. CONCLUSIONS: Distribution of the vaccine-information pamphlet and Vaccine Information Statements significantly improved attitudes about vaccination regardless of at what visit they were provided. Allowing adequate time to review vaccine information, even if done at the vaccination visit, may benefit concerned mothers.
Authors: Vannice KS; Salmon DA; Shui I; Omer SB; Kissner J; Edwards KM; Sparks R; Dekker CL; Klein NP; Gust DA
Pediatrics. 2011 May;127 Suppl 1:S120-6. Epub 2011 Apr 18.
The Vaccine Safety Datalink: a model for monitoring immunization safety
The Vaccine Safety Datalink (VSD) project is a collaborative project between the Centers for Disease Control and Prevention and 8 managed care organizations (MCOs) in the United States. Established in 1990 to conduct postmarketing evaluations of vaccine safety, the project has created an infrastructure that allows for high-quality research and surveillance. The 8 participating MCOs comprise a large population of 8.8 million members annually (3% of the US population), which enables researchers to conduct studies that assess adverse events after immunization. Each MCO prepares computerized data files by using a standardized data dictionary containing demographic and medical information on its members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. Other information sources, such as medical chart review, member surveys, and pharmacy, laboratory, and radiology data, are often used in VSD studies to validate outcomes and vaccination data. Since 2000, the VSD has undergone significant changes including an increase in the number of participating MCOs and enrolled population, changes in data-collection procedures, the creation of near real-time data files, and the development of near real-time postmarketing surveillance for newly licensed vaccines or changes in vaccine recommendations. Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency through data-sharing and external input. With its recent enhancements, the VSD provides scientific expertise, continues to develop innovative approaches for vaccine-safety research, and may serve as a model for other patient safety collaborative research projects.
Authors: Baggs J; Klein NP; Weintraub E; et al.
Pediatrics. 2011 May;127 Suppl 1:S45-53. Epub 2011 Apr 18.
Understanding the role of human variation in vaccine adverse events: the Clinical Immunization Safety Assessment Network
The Clinical Immunization Safety Assessment (CISA) Network is a collaboration between the Centers for Disease Control and Prevention (CDC) and 6 academic medical centers to provide support for immunization safety assessment and research. The CISA Network was established by the CDC in 2001 with 4 primary goals: (1) develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (AEFI); (2) improve the understanding of AEFI at the individual level, including determining possible genetic and other risk factors for predisposed people and subpopulations at high risk; (3) develop evidence-based algorithms for vaccination of people at risk of serious AEFI; and (4) serve as subject-matter experts for clinical vaccine-safety inquiries. CISA Network investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of AEFI. CISA Network researchers conduct expert reviews of clinically significant adverse events and determine the validity of the recorded diagnoses on the basis of clinical and laboratory criteria. They also conduct special studies to investigate the possible pathogenesis of adverse events, assess relationships between vaccines and adverse events, and maintain a centralized repository for clinical specimens. The CISA Network provides specific clinical guidance to both health care providers who administer vaccines and those who evaluate and treat patients with possible AEFI. The CISA Network plays an important role in providing critical immunization-safety data and expertise to inform vaccine policy-makers. The CISA Network serves as a unique resource for vaccine-safety monitoring efforts conducted at the CDC.
Authors: Larussa PS; Edwards KM; Dekker CL; Klein NP; Halsey NA; Marchant C; Baxter R; Engler RJ; Kissner J; Slade BA
Pediatrics. 2011 May;127 Suppl 1:S65-73. Epub 2011 Apr 18.
Active surveillance for adverse events: the experience of the Vaccine Safety Datalink project
OBJECTIVE: To describe the Vaccine Safety Datalink (VSD) project’s experience with population-based, active surveillance for vaccine safety and draw lessons that may be useful for similar efforts. PATIENTS AND METHODS: The VSD comprises a population of 9.2 million people annually in 8 geographically diverse US health care organizations. Data on vaccinations and diagnoses are updated and extracted weekly. The safety of 5 vaccines was monitored, each with 5 to 7 prespecified outcomes. With sequential analytic methods, the number of cases of each outcome was compared with the number of cases observed in a comparison group or the number expected on the basis of background rates. If the test statistic exceeded a threshold, it was a signal of a possible vaccine-safety problem. Signals were investigated by using temporal scan statistics and analyses such as logistic regression. RESULTS: Ten signals appeared over 3 years of surveillance: 1 signal was reported to external stakeholders and ultimately led to a change in national vaccination policy, and 9 signals were found to be spurious after rigorous internal investigation. Causes of spurious signals included imprecision in estimated background rates, changes in true incidence or coding over time, other confounding, inappropriate comparison groups, miscoding of outcomes in electronic medical records, and chance. In the absence of signals, estimates of adverse-event rates, relative risks, and attributable risks from up-to-date VSD data have provided rapid assessment of vaccine safety to policy-makers when concerns about a specific vaccine have arisen elsewhere. CONCLUSIONS: Care with data quality, outcome definitions, comparison groups, and length of surveillance are required to enable detection of true safety problems while minimizing false signals. Some causes of false signals in the VSD system were preventable and have been corrected, whereas others will be unavoidable in any active surveillance system. Temporal scan statistics, analyses to control for confounding, and chart review are indispensable tools in signal investigation. The VSD’s experience may inform new systems for active safety surveillance.
Authors: Yih WK; Fireman BH; Klein NP; Lieu TA; et al.
Pediatrics. 2011 May;127 Suppl 1:S54-64. Epub 2011 Apr 18.
Evaluation of immunization rates and safety among children with inborn errors of metabolism
BACKGROUND: Children with inherited metabolic disorders are a potential high-risk group for vaccine-preventable diseases, yet information regarding immunization rates and vaccine safety within this population is limited. METHODS: Using Northern California Kaiser Permanente’s electronic medical record, we identified children with inborn errors of metabolism from 1990 to 2007. We assessed immunization rates among infants with inborn errors of metabolism born at Northern California Kaiser Permanente matched to healthy infants (1 to 20), comparing both vaccines received by 2 years of age and age at vaccination. We assessed postvaccination adverse events among children up to 18 years old with inborn errors of metabolism, separately comparing emergency-department visits and hospitalizations during postvaccine days 0 to 30 (primary) and days 0 to 14 (secondary). RESULTS: Comparing infants with inborn errors of metabolism (n = 77) versus matched control subjects (n = 1540), similar proportions were up to date for vaccines at 2 years of age, and there was no evidence of delay in receipt of recommended vaccines during the first year. Vaccination of children with inborn errors of metabolism (n = 271) was not associated with any significant increase in emergency-department visits or hospitalizations during the 30 days after vaccination. Secondary analyses suggested that there may be increased rates of hospitalizations 2 weeks after vaccination for the sickest 1- to 4-year-old children. CONCLUSIONS: Children with inborn errors of metabolism at Northern California Kaiser Permanente received vaccines on the same immunization schedule as healthy infants. Immunization was not associated with increased risk for serious adverse events during the month after vaccination, providing overall reassurance that routine vaccination of children with inborn errors of metabolism does not result in adverse effects.
Authors: Klein NP; Aukes L; Lee J; Fireman B; Shapira SK; Slade B; Baxter R; Summar M
Pediatrics. 2011 May;127(5):e1139-46. Epub 2011 Apr 11.
Clinical implications of the nelfinavir-proton pump inhibitor drug interaction in patients with human immunodeficiency virus
STUDY OBJECTIVE: To determine if the concomitant use of nelfinavir and proton pump inhibitors (PPIs) in patients with human immunodeficiency virus (HIV) infection results in the loss of virologic control. DESIGN: Retrospective cohort study. DATA SOURCE: Pharmacy, laboratory, and administrative databases of a large integrated health care system in northern California. PATIENTS: A total of 1147 HIV-positive adults who started nelfinavir therapy between November 1, 1998, and June 20, 2003; within this cohort, 141 patients (12.3%) were also prescribed PPIs. MEASUREMENTS AND MAIN RESULTS: The effects on two virologic outcomes–achievement of undetectable HIV viral load and subsequent virologic rebound–were compared between patients receiving nelfinavir alone and those receiving nelfinavir with PPIs. Cox proportional hazards models were used, with adjustments for age, sex, race, HIV risk factors, hepatitis B or C coinfection, and other concurrent drugs known to affect the metabolism of nelfinavir. The use of PPIs had little effect on the ability to achieve an undetectable HIV viral load (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58-1.19, p=0.29), but there was an approximate 50% increased risk of virologic rebound with the concurrent use of PPIs (adjusted HR 1.53, 95% CI 1.06-2.19, p=0.02). Short-term use of PPIs (defined as within 30 days of initial PPI dispensation) was not associated with increased risk of virologic rebound (HR 1.07, 95% CI 0.26-4.41, p=0.93) compared with no use of PPIs. CONCLUSION: Use of PPIs should be minimized or avoided in patients who have attained an undetectable HIV viral load while taking a nelfinavir-based antiretroviral regimen. However, concomitant use of these drugs may be acceptable for indications where PPIs are required for fewer than 30 days.
Authors: Saberi P; Ranatunga DK; Quesenberry CP; Silverberg MJ
Pharmacotherapy. 2011 Mar;31(3):253-61.
Vaccine safety in special populations
Studies evaluating the safety of vaccines routinely administered to a population of healthy infants and children may not provide adequate reassurance for members of special populations such as premature infants and children with chronic conditions. However, evaluating the safety of vaccines administered to special populations presents a host of challenges, including limited numbers of subjects, lack of appropriate comparisons groups and substantial complexity in both collecting and evaluating the data. Improving the available immunization safety data for those in special populations will provide substantial benefit to the clinicians caring for these vulnerable patients.
Authors: Klein NP;
Hum Vaccin. 2011 Feb;7(2):269-71. Epub 2011 Feb 1.
Hospitalized patients with 2009 pandemic influenza A (H1N1) virus infection in the United States–September-October 2009.
Given the potential worsening clinical severity of 2009 pandemic influenza A (H1N1) virus (pH1N1) infection from spring to fall 2009, we conducted a clinical case series among patients hospitalized with pH1N1 infection from September through October 2009. A case patient was defined as a hospitalized person who had test results positive for pH1N1 virus by real-time reverse-transcription polymerase chain reaction. Among 255 hospitalized patients, 34% were admitted to an intensive care unit and 8% died. Thirty-four percent of patients were children <18 years of age, 8% were adults >/= 65 years of age, and 67% had an underlying medical condition. Chest radiographs obtained at hospital admission that had findings that were consistent with pneumonia were noted in 103 (46%) of 255 patients. Among 255 hospitalized patients, 208 (82%) received neuraminidase inhibitors, but only 47% had treatment started
Authors: Skarbinski J; Jain S; Bramley A; Lee EJ; Huang J; Kirschke D; Stone A; Wedlake T; Richards SM; Page S; Ragan P; Bullion L; Neises D; Williams RM; Petruccelli BP; Vandermeer M; Lofy KH; Gindler J; Finelli L
Clin Infect Dis. 2011 Jan 1;52 Suppl 1:S50-9. doi: 10.1093/cid/ciq021.
HIV quality performance measures in a large integrated health care system
HIV quality performance measurements are critical to evaluating a care program’s success in areas of testing, access to and retention in care, care processes and outcomes. Kaiser Permanente (KP) provides care to over 8 million Americans and over 19,000 HIV-infected adults. We undertook a quality performance measurement program to assess the care and outcomes for our HIV-positive patient population. We also examined HIV testing practices among our HIV-uninfected patients presenting with a sexually transmitted infection. Our metrics were extracted electronically (encompassing two time periods: July 1, 2005 through June 30, 2006 and the entire calendar year 2007) and did not require any manual data extraction, which was a primary objective of our strategy. For most individual care measures, improvement over time was noted, with 85% or more performance seen on some measures (accessing care and initiating antiretroviral therapy). Opportunities for improvement were identified on other measures, such as diagnosing HIV at an earlier stage of infection, and more consistent Pneumocystis jiroveci pneumonia prophylaxis. Over 90% of our patients on antiretroviral therapy had maximal viral control, along with high median antiretroviral medication adherence. Our results compare favorably to those of other organizations, with a KP HIV mortality rate less than 50% of the overall U.S. rate. These results have implications for improving our care process going forward, as well as for the new U.S. domestic HIV/AIDS Strategy.
Authors: Horberg M; Quesenberry C; Silverberg M; Johnson M; et al.
AIDS Patient Care STDS. 2011 Jan;25(1):21-8.
Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C
Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non-invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naive patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81-0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4-6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.
Authors: Parkes J; Guha IN; Roderick P; Harris S; Cross R; Manos MM; Irving W; Zaitoun A; Wheatley M; Ryder S; Rosenberg W
J Viral Hepat. 2011 Jan;18(1):23-31.
Comparison of the safety and immunogenicity of an investigational and a licensed quadrivalent meningococcal conjugate vaccine in children 2-10 years of age
BACKGROUND: Routine administration of quadrivalent meningococcal conjugate vaccine to adolescents and certain high risk groups is recommended in the United States and Canada. We compared the immunogenicity and safety of an investigational quadrivalent meningococcal vaccine conjugated to CRM-197 (MenACWY-CRM) with a licensed quadrivalent vaccine conjugated to diphtheria toxoid (MCV4) in children aged 2-10 years. METHODS: Eligible 2-5-year-olds were randomized 1:2:2 to receive either 2 doses of MenACWY-CRM, or 1 dose of MenACWY-CRM or MCV4; 6-10-year-olds were randomized 1:1 to receive a single dose of MenACWY-CRM or MCV4. The primary immunogenicity assessment was seroresponse separately for the two age cohorts 28 days following a single dose of MenACWY-CRM or MCV4. Noninferiority and superiority criteria were predefined. Solicited injection-site and systemic reactions were collected for the 7 days postvaccination. RESULTS: A total of 2907 children were randomized to receive study vaccine. MenACWY-CRM met statistical superiority criteria vs. MCV4 for groups W and Y and was noninferior for group C in both age strata. For group A, noninferiority criteria were not met; the group A seroresponse rates for MenACWY-CRM and MCV4, respectively were 72% (95% confidence interval 68-75%) and 77% (73-80%) in 2-5-year-olds and 77% (73-80%) and 83% (79-86%) in 6-10-year-olds. When the two age strata were combined (2-10-year-old children), MenACWY-CRM was noninferior to MCV4 for all four groups, and statistically superior for groups C, W, and Y. Safety parameters were similar across age cohorts and vaccines groups. CONCLUSIONS: MenACWY-CRM and MCV4 were immunogenic and well tolerated in children aged 2-10 years. Seroresponse to MenACWY-CRM was statistically noninferior to MCV4 for all groups, and statistically superior for groups C, W, and Y. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00616421.
Authors: Halperin SA; Gupta A; Jeanfreau R; Klein NP; Reisinger K; Walter E; Bedell L; Gill C; Dull PM
Vaccine. 2010 Nov 23;28(50):7865-72. Epub 2010 Oct 29.
Effect of influenza vaccination on hospitalizations in persons aged 50 years and older
OBJECTIVE: To estimate influenza vaccine effectiveness (VE) in preventing hospitalizations in persons over 50 years of age. DESIGN: We performed a retrospective, population based study, using a ‘difference-in-differences’ approach to determine the association between hospitalization and prior vaccination. We examined this association when influenza was not circulating and compared it to the association found when influenza was circulating. VE was estimated from the difference in the association between hospitalization and prior vaccination, inside vs. outside influenza seasons. SETTING: Kaiser Permanente in Northern California. PATIENTS: Health plan members aged 50 years and older during the September 1997 to August 2008 study period, when there were about 68,000 pneumonia hospitalizations in 10 million person-years. RESULTS: Vaccination was associated with lower risk of hospitalization for pneumonia and influenza, even before flu season, presumably due to unmeasured confounders. When influenza arrived the hospitalization-vaccination association strengthened, yielding an adjusted VE estimate of 12.4% (95% CI: 1.6-22.0) in persons aged 50-64, and 8.5% (95% CI: 3.3-13.5) in those aged 65 years and older. There was no significant effect on hospitalizations for ischemic heart disease (IHD), congestive heart failure (CHF), cerebrovascular disease (CVD), or trauma. CONCLUSIONS: Influenza vaccination has a modest but significant effect on prevention of hospitalization for pneumonia and influenza in persons 50 years of age and older.
Authors: Baxter R; Ray GT; Fireman BH
Vaccine. 2010 Oct 21;28(45):7267-72. Epub 2010 Sep 9.
A Phase III evaluation of immunogenicity and safety of two trivalent inactivated seasonal influenza vaccines in US children
BACKGROUND: This study (NCT00383123) compared the immunogenicity and safety of 2 trivalent inactivated influenza vaccines: Fluarix [GlaxoSmithKline (study vaccine)] and Fluzone [Sanofi Pasteur (control vaccine)] in children 6 months to <18 years. METHODS: Children, stratified by age and randomized, received either study (N = 2115) or control vaccine (N = 1210) at day 0 (and day 28 for previously unvaccinated children younger than 9 years). Children 6 months to <5 years comprised the according-to-protocol (ATP) cohort for immunogenicity, whereas the reactogenicity/safety group included all children 6 months to <18 years. The study aimed to demonstrate immunologic noninferiority of study vaccine versus control vaccine. RESULTS: For children 6 months to <5 years, the predefined noninferiority criteria were not reached, mainly due to the differences in immune response in children 6 months to <3 years with no influenza vaccination history. All reactogenicity/safety endpoints were within the same range in both vaccine groups. CONCLUSIONS: The study vaccine demonstrated a good safety and reactogenicity profile; however, it did not meet the predefined noninferiority criteria in children 6 months to <5 years. The study vaccine was as immunogenic as the control vaccine in children aged 3 to <5 years.
Authors: Baxter R; Jeanfreau R; Block SL; Blatter M; Pichichero M; Jain VK; Dewe W; Innis BL
Pediatr Infect Dis J. 2010 Oct;29(10):924-30.
Vaccine effectiveness against laboratory-confirmed influenza in infants: A matched case control study
Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient’s positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group.
Authors: Cochran LW; Black S; Klein NP; Dekker CL; Lewis E; Reingold AL
Hum Vaccin. 2010 Sep 23;6(9). Epub 2010-09-23.
Development of national and multiagency HIV care quality measures
BACKGROUND: Human immunodeficiency virus (HIV) is now a complex, chronic disease requiring high quality care. Demonstration of quality HIV care requires uniform, aligned HIV care quality measurement. METHODS: In September 2007, the National Committee for Quality Assurance, under contract with the Health Resources and Services Administration, the Physician Consortium for Performance Improvement of the American Medical Association, and HIV Medicine Association of the Infectious Disease Society of America jointly sponsored and convened an expert panel as a HIV/AIDS Work Group to draft national HIV/AIDS performance measures for individual patient-level and system-level quality improvement. RESULTS: A total of 17 measures were developed to assess processes and outcomes of HIV/AIDS care for patients established in care, defined as having at least 2 visits in a 12-month period; thus, measures of HIV screening, testing, linkage, and access to care were not included. As a set, the measures assess a wide range of care, including patient retention, screening and prophylaxis for opportunistic infections, immunization, and initiation and monitoring of potent antiretroviral therapy. Since development, the HIV/AIDS measures’ specifications have been fully determined and are being beta tested, and a majority have been endorsed by the National Quality Forum and have been adopted and implemented by the sponsoring organizations. CONCLUSIONS: HIV care quality measurement should be assessed with greater uniformity. The measures presented offer opportunities for such alignment.
Authors: Horberg MA; Aberg JA; Cheever LW; Renner P; O'Brien Kaleba E; Asch SM
Clin Infect Dis. 2010 Sep 15;51(6):732-8.
Risk of fever and sepsis evaluations after routine immunizations in the neonatal intensive care unit
OBJECTIVE: Premature infants can experience cardiorespiratory events such as apnea after immunization in the neonatal intensive care unit (NICU). These changes in clinical status may precipitate sepsis evaluations. This study evaluated whether sepsis evaluations are increased after immunizations in the NICU. STUDY DESIGN: We conducted a retrospective cohort study of infants older than 53 days who were vaccinated in the NICU at the KPMCP (Kaiser Permanente Medical Care Program). Chart reviews were carried out before and after all immunizations were administered and for all sepsis evaluations after age 53 days. The clinical characteristics of infants on the day before receiving a sepsis evaluation were compared between children undergoing post-immunization sepsis evaluations and children undergoing sepsis evaluation at other times. The incidence rate of sepsis evaluations in the post-immunization period was compared with the rate in a control time period not following immunization using Poisson regression. RESULT: A total of 490 infants met the inclusion criteria. The rate of fever was increased in the 24 h period after vaccination (2.3%, P<0.05). The incidence rate of sepsis evaluations was 40% lower after immunization than during the control period, although this was not statistically significant (P=0.09). Infants undergoing a sepsis evaluation after immunization were more likely to have an apneic, bradycardic or moderate-to-severe cardiorespiratory event in the day before the evaluation than were infants undergoing sepsis evaluations at other times (P<0.05). CONCLUSION: Despite an increase in fever and cardiorespiratory events after immunization in the NICU, routine vaccination was not associated with increased risk of receiving sepsis evaluations. Providers may be deferring immunizations until infants are clinically stable, or may have a higher threshold for initiating sepsis evaluations after immunization than at other times.
Authors: Navar-Boggan AM; Halsey NA; Golden WC; Escobar GJ; Massolo M; Klein NP
J Perinatol. 2010 Sep;30(9):604-9. Epub 2010 Feb 25.
Lack of association between acellular pertussis vaccine and seizures in early childhood
OBJECTIVES: Receipt of diphtheria-tetanus-whole-cell pertussis vaccine (diphtheria-tetanus toxoids-pertussis [DTP]) is associated with seizures. Limited population-based studies have been conducted on the risk for seizures after receipt of diphtheria-tetanus-acellular pertussis vaccine (diphtheria-tetanus-acellular pertussis [DTaP]). METHODS: We conducted a retrospective study from 1997-2006 by using risk-interval cohort and self-controlled case series (SCCS) analyses on automated data at 7 managed care organizations that participate in the Vaccine Safety Datalink (VSD). Eligible children included the 1997-2006 VSD cohort of patients who were aged 6 weeks to 23 months and had not received DTP during the study period. A seizure event (febrile or afebrile) was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses assigned to an inpatient or emergency department setting. The exposed period was composed of a predefined 4 person-days after each DTaP dose. All of the remaining observation periods outside the exposed periods were categorized as unexposed. The risk-interval cohort method compared the incidence of seizures between the exposed and unexposed cohorts. In the SCCS method, the comparison was performed between the same patient’s exposed and unexposed period. RESULTS: We identified 7191 seizure events among 433,654 children. The adjusted incidence rate ratio of seizures across all doses was 0.87 in cohort analysis and 0.91 in SCCS analysis. CONCLUSIONS: We did not observe an increased risk for seizures after DTaP vaccination among children who were aged 6 weeks to 23 months. These findings provide reassuring evidence on the safety of DTaP with respect to seizures.
Authors: Huang WT; Gargiullo PM; Broder KR; Weintraub ES; Iskander JK; Klein NP; Baggs JM; Vaccine Safety Datalink Team
Pediatrics. 2010 Aug;126(2):263-9. Epub 2010 Jul 19.
Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy
OBJECTIVE: To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. uninfected patients from the same integrated healthcare system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy. DESIGN: A cohort study. METHODS: Incident NHL diagnosed between 1996 and 2005 were identified from members of Kaiser Permanente California Health Plans. Two-year all-cause and lymphoma-specific mortality by HIV status were examined using multivariable Poisson regression. Among HIV-infected patients, prognostic factors of demographics, lymphoma, and HIV-related characteristics for the same outcomes were also examined. RESULTS: A total of 259 HIV-infected and 8230 HIV-uninfected incident NHL patients were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis as compared with 30% of HIV-uninfected patients. HIV status was independently associated with a doubling of 2-year all-cause mortality (relative risk = 2.0, 95% confidence interval 1.7-2.3). This elevated mortality risk for HIV-infected patients was similar for all race groups, lymphoma stages, and histologic subtypes. HIV-infected patients with CD4 cell count below 200 cells/microl, prior AIDS-defining illness, or both were also at increased risk for lymphoma-specific mortality as compared with HIV-uninfected patients. Among HIV-infected NHL patients, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitt’s subtype. CONCLUSION: HIV-infected patients with NHL in the combined antiretroviral therapy era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL. Better management and therapeutic approaches to extend survival time for HIV-related NHL are needed.
Authors: Chao C; Xu L; Abrams D; Leyden W; Horberg M; Towner W; Klein D; Tang B; Silverberg M
AIDS. 2010 Jul 17;24(11):1765-70.
Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures
OBJECTIVE: In February 2008, we alerted the Advisory Committee on Immunization Practices to preliminary evidence of a twofold increased risk of febrile seizures after the combination measles-mumps-rubella-varicella (MMRV) vaccine when compared with separate measles-mumps-rubella (MMR) and varicella vaccines. Now with data on twice as many vaccine recipients, our goal was to reexamine seizure risk after MMRV vaccine. METHODS: Using 2000-2008 Vaccine Safety Datalink data, we assessed seizures and fever visits among children aged 12 to 23 months after MMRV and separate MMR + varicella vaccines. We compared seizure risk after MMRV vaccine to that after MMR + varicella vaccines by using Poisson regression as well as with supplementary regressions that incorporated chart-review results and self-controlled analyses. RESULTS: MMRV vaccine recipients (83,107) were compared with recipients of MMR + varicella vaccines (376,354). Seizure and fever significantly clustered 7 to 10 days after vaccination with all measles-containing vaccines but not after varicella vaccination alone. Seizure risk during days 7 to 10 was higher after MMRV than after MMR + varicella vaccination (relative risk: 1.98 [95% confidence interval: 1.43-2.73]). Supplementary analyses yielded similar results. The excess risk for febrile seizures 7 to 10 days after MMRV compared with separate MMR + varicella vaccination was 4.3 per 10,000 doses (95% confidence interval: 2.6-5.6). CONCLUSIONS: Among 12- to 23-month-olds who received their first dose of measles-containing vaccine, fever and seizure were elevated 7 to 10 days after vaccination. Vaccination with MMRV results in 1 additional febrile seizure for every 2300 doses given instead of separate MMR + varicella vaccines. Providers who recommend MMRV should communicate to parents that it increases the risk of fever and seizure over that already associated with measles-containing vaccines.
Authors: Klein NP; Fireman B; Vaccine Safety Datalink; et al.
Pediatrics. 2010 Jul;126(1):e1-8. Epub 2010 Jun 29.
Post-marketing safety evaluation of a tetanus toxoid, reduced diphtheria toxoid and 3-component acellular pertussis vaccine administered to a cohort of adolescents in a United States health maintenance organization
BACKGROUND: Prelicensure clinical studies may not include sufficient numbers of subjects to assess the potential for rare postvaccination adverse events. The aim of this postlicensure study (NCT00297856) was to evaluate uncommon outcomes following vaccination with a tetanus, reduced-antigen-content diphtheria, and acellular pertussis vaccine (Tdap, Boostrix GlaxoSmithKline) in a large adolescent cohort. METHODS: We monitored safety outcomes among 13,427 10 to 18-year-old adolescents enrolled in the Northern California Kaiser Permanente Health Care Plan who received Tdap vaccination as part of their normal health care. Subjects were evaluated using self-control analysis comparing days 0 to 29 to days 30 to 59 postvaccination for neurologic events, hematologic events and allergic reactions. We evaluated new onset chronic illnesses within 6 months of Tdap vaccination by comparing with historical Td controls matched for age at vaccination, season, sex, and geographic area. We also compared the incidence of events of interest between the Tdap and historical cohorts as exploratory analyses. RESULTS: No increased risk for medically attended neurologic (odds ratio [OR], 0.962; 95% confidence interval [CI], 0.533-1.733) or allergic reactions (OR, 1.091; 95% CI, 0.441-2.729) was observed following Tdap vaccination when comparing the first 30 postvaccination days to the second 30 postvaccination days. There was one hematologic event within 30 days of Tdap, compared with 0 events within days 30 to 59 (P = 1.0). When compared with matched historical Td recipients, no increase in new onset chronic illnesses (OR, 0.634; 95% CI, 0.475-0.840) was seen after Tdap. No deaths occurred in the Tdap cohort during the study. CONCLUSIONS: This study provides no evidence for an increased risk for neurologic, hematologic, allergic events, or new onset of chronic illnesses among adolescents vaccinated with Tdap.
Authors: Klein NP; Hansen J; Lewis E; Lyon L; Nguyen B; Black S; Weston WM; Wu S; Li P; Howe B; Friedland LR
Pediatr Infect Dis J. 2010 Jul;29(7):613-7.
An update on the use of Atripla in the treatment of HIV in the United States
Atripla((R)) (Gilead Sciences Inc, Foster City, CA, USA and Bristol-Myers Squibb, New York City, NY, USA) is a coformulated single pill composed of efavirenz, emtricitabine, and tenofovir disoproxil, intended as a once-daily potent combination antiretroviral therapeutic agent. Its efficacy is equivalent to the 3 component drugs taken in a combination as single medications. The coformulated antiretroviral regimen can be quite effective in patients whose human immunodeficiency virus is sensitive to all 3 components of Atripla. However, women at risk of pregnancy, already pregnant, or nursing mothers should not take Atripla, due to the teratogenic potential of the efavirenz moiety. Adverse effects are similar to those seen with the constituent medications, including potential central nervous system effects and renal toxicity. Since its US Food and Drug administration approval, prescriptions for Atripla have increased steadily.
Authors: Horberg MA; Klein DB
HIV AIDS (Auckl). 2010;2:135-40. Epub 2010 Jun 18.
Late presentation for human immunodeficiency virus care in the United States and Canada
BACKGROUND. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. METHODS. We analyzed data from 44,491 HIV-infected patients enrolled in the North American-AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4(+) T lymphocyte (CD4) count and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. RESULTS. Median age at first presentation for HIV care increased over time (range, 40-43 years; P < .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26% to 14%; P < .01) and heterosexual transmission risk increased (from 16% to 23%; P < .01). Median CD4 count at presentation increased from 256 cells/mm(3) (interquartile range, 96-455 cells/mm(3)) to 317 cells/mm(3) (interquartile range, 135-517 cells/mm(3)) from 1997 to 2007 (P < .01). The percentage of patients with a CD4 count > or = 350 cells/mm(3) at first presentation also increased from 1997 to 2007 (from 38% to 46%; P < .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm(3) per year (95% confidence interval, 5-7 cells/mm(3) per year). CONCLUSION. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained <350 cells/mm(3), which suggests the urgent need for earlier HIV diagnosis and treatment.
Authors: Althoff KN; Silverberg MJ; Moore RD; et al.
Clin Infect Dis. 2010 Jun 1;50(11):1512-20.
Reports from today’s health care environment on the implementation of screening, diagnosis, and treatment recommendations
Authors: Kim WR; Valdiserri RO; Wright LN; Manos MM; Do ST
J Fam Pract. 2010 Apr;59(4 Suppl):S43-50.
Effect of once-daily FDC treatment era on initiation of cART
OBJECTIVES: Combination antiretroviral therapy (cART) is associated with increased survival among HIV-infected persons. Yet, no research to date has examined whether introduction of once-daily fixed-dosed combinations (FDC) affects the likelihood of cART initiation. We aimed to determine whether implementation of once-daily FDC regimens was associated with changes to cART initiation. We also identified clinical, treatment regimen, and provider characteristics possibly associated with cART initiation. STUDY DESIGN: Retrospective observational analysis. METHODS: We queried electronic medical records between July 1999-June 2006 to identify incident cases of detectable HIV infection in antiretroviral-naive adults. Cox regression with time-dependent covariates was used to examine the effects of once-daily FDC era, clinical, provider, and treatment regimen characteristics on cART initiation. RESULTS: Once-daily FDC availability did not change the likelihood of cART initiation, but other characteristics were associated with an increased likelihood: AIDS diagnosis, above-median daily pill consumption, and 16+ yrs of physician HIV experience. Decreased likelihood of cART initiation was associated with CD4 201-350 cells/muL, HIV RNA < 100,000 copies/mL, and with CD4 > 350 cells/muL (any HIV RNA level), compared to CD4
Authors: Mosen DM; Horberg M; Roblin D; Gullion CM; Meenan R; Leyden W; Hu W
HIV AIDS (Auckl). 2010;2:19-26. Epub 2010 Feb 15.
Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies
Safety monitoring following new vaccine introduction includes assessment of potential new onset autoimmune diseases (AID). As knowledge regarding AID background rates is limited, we evaluated the incidence of 11 AID in Northern California Kaiser Permanente. AID cases were identified using electronic records of members aged 10-62 years from 1998 to 2004, excluding those with AID diagnoses from 1996 to 1997. Using prespecified criteria, all identified cases of rare diseases were verified by medical record review, while a sample of cases was reviewed for common diseases; incidence rates were calculated based on the proportion of confirmed cases. Overall, the incidence of AID varied from 0.8/100,000 person-years (PY) for autoimmune hemolytic anemia (AIHA) to 54.1/100,000 PY for thyroiditis. Incidence rates in increasing order were AIHA, juvenile rheumatoid arthritis, Guillain-Barre Syndrome, idiopathic thromobocytopenia purpura, transverse myelitis, systemic lupus erythematosus, uveitis, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes mellitus and thyroiditis; incidence rates also varied according to age and gender. These background incidence rates should prove useful for future observational vaccine safety studies and will help guide evaluation of potential vaccine AID events following introduction of new vaccines.
Authors: Klein NP; Ray P; Carpenter D; Hansen J; Lewis E; Fireman B; Black S; Galindo C; Schmidt J; Baxter R
Vaccine. 2010 Jan 22;28(4):1062-8. Epub 2009 Nov 5.
Near real-time surveillance for influenza vaccine safety: proof-of-concept in the Vaccine Safety Datalink Project
The emergence of pandemic H1N1 influenza in 2009 has prompted public health responses, including production and licensure of new influenza A (H1N1) 2009 monovalent vaccines. Safety monitoring is a critical component of vaccination programs. As proof-of-concept, the authors mimicked near real-time prospective surveillance for prespecified neurologic and allergic adverse events among enrollees in 8 medical care organizations (the Vaccine Safety Datalink Project) who received seasonal trivalent inactivated influenza vaccine during the 2005/06-2007/08 influenza seasons. In self-controlled case series analysis, the risk of adverse events in a prespecified exposure period following vaccination was compared with the risk in 1 control period for the same individual either before or after vaccination. In difference-in-difference analysis, the relative risk in exposed versus control periods each season was compared with the relative risk in previous seasons since 2000/01. The authors used Poisson-based analysis to compare the risk of Guillain-Barre syndrome following vaccination in each season with that in previous seasons. Maximized sequential probability ratio tests were used to adjust for repeated analyses on weekly data. With administration of 1,195,552 doses to children under age 18 years and 4,773,956 doses to adults, no elevated risk of adverse events was identified. Near real-time surveillance for selected adverse events can be implemented prospectively to rapidly assess seasonal and pandemic influenza vaccine safety.
Authors: Greene SK; Fireman BH; Lee GM; et al.
Am J Epidemiol. 2010 Jan 15;171(2):177-88. Epub 2009 Dec 4.
Evidence of bias in studies of influenza vaccine effectiveness in elderly patients
Although studies have shown influenza vaccines to be effective in preventing death in the elderly population, these findings may be the result of selection bias. We examined the relationship between vaccination, age, underlying morbidity, and probability of death in the upcoming year. Vaccination coverage varied in a curvilinear fashion with age, morbidity, and risk of death. Forgoing vaccination predicted death in those who had received vaccinations in the previous 5 years, but it predicted survival in patients who had never before received a vaccination. We conclude that bias is inherent in studies of influenza vaccination and death among elderly patients.
Authors: Baxter R; Lee J; Fireman B
J Infect Dis. 2010 Jan 15;201(2):186-9.
Preterm infants’ T cell responses to inactivated poliovirus vaccine
BACKGROUND: The antigen-specific T cell responses of preterm infants to immunization are not well understood. The aim of the present study was to compare the T cell responses of preterm infants after inactivated poliovirus vaccination with those of term infants. METHODS: We prospectively enrolled 2-month-old preterm (gestational age, 33 weeks) and term (gestational age, 37 weeks) infants to receive 3 doses of diphtheria-tetanus toxoids-acellular pertussis-hepatitis B virus-inactivated poliovirus vaccine. Whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated with poliovirus vaccine, and memory T cell activation was analyzed by flow cytometry and lymphoproliferation, respectively. Levels of poliovirus neutralizing antibodies were measured in serum. RESULTS: We enrolled 33 preterm and 50 term infants. Preterm infants had fewer circulating CD4(+)CD45RO(+) memory (P = .005) and CD4(+)CD69(+)IFN-gamma(+) cells activated by staphylococcus enterotoxin B at 2 (P = .015) and 7 (P = .05) months of age. After immunization, preterm and term infants had comparable frequencies of poliovirus-specific CD4(+)CD45RO(+)CD69(+)IFN-gamma(+) memory T cells (P = .79). PBMCs from preterm infants had diminished poliovirus-specific lymphoproliferation (P<.001). Although all infants developed seroprotective poliovirus antibody titers, serotype 1 titers were lower among preterm infants (P = .03). CONCLUSIONS: Preterm infants develop poliovirus-specific T cell responses that are comparable to those of term infants. However, they demonstrate nonspecific and poliovirus-specific functional T cell limitations, suggesting that investigations into whether T cell differences remain as preterm infants mature are warranted.
Authors: Klein NP; Gans HA; Sung P; Yasukawa LL; Johnson J; Sarafanov A; Chumakov K; Hansen J; Black S; Dekker CL
J Infect Dis. 2010 Jan 15;201(2):214-22.
Immunogenicity and tolerability of a quadrivalent meningococcal glycoconjugate vaccine in children 2-10 years of age
Meningococcal disease incidence is highest in infants, but a significant burden of disease also occurs in children. In this Phase II, single-centre US study, 619 healthy children (2-10 years of age) received one dose of an investigational quadrivalent meningococcal CRM(197)-conjugated vaccine (MenACWY-CRM) or a licensed quadrivalent meningococcal polysaccharide vaccine (MPSV4). Immunogenicity was assessed using the serum bactericidal assay with human complement (hSBA) at 1 and 12 months post-vaccination. Local and systemic reactions were recorded for 7 days, all adverse events (AEs) for 1 month, and medically significant and serious AEs (SAEs) for 12 months post-vaccination. For all four serogroups, more MenACWY-CRM recipients achieved an hSBA titre >or=1:4 at 1 month post-vaccination (A: 82%; C: 83%; W-135: 95%; Y: 91%) compared with the group that received MPSV4 (A: 45%; C: 66%; W-135: 71%; Y: 61%); this difference persisted through to 12 months post-vaccination. Both vaccines were well tolerated. In children 2-10 years of age, MenACWY-CRM induced a higher immune response than that of MPSV4, and was well tolerated.
Authors: Black S; Klein NP; Shah J; Bedell L; Karsten A; Dull PM
Vaccine. 2010 Jan 8;28(3):657-63. Epub 2009 Nov 4.
Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients
OBJECTIVE: To better characterize the long-term effects of tenofovir on renal function in a large managed care organization. METHODS: We performed a retrospective cohort analysis in Kaiser Permanente for years 2002 to 2005 comparing renal function among antiretroviral naive patients initiating a tenofovir-containing regimen (964 patients) or tenofovir-sparing regimens (683 patients). We evaluated glomerular filtration rate (GFR, [Modification of Diet in Renal Disease equation]), serum creatinine, and the development of renal proximal tubular dysfunction. We report multivariable hazard ratios (HR, Cox modeling) and linear outcomes (repeated measures) with predictors retained if P < 0.10 (backward selection). Potential predictor variables included in multivariate models were age, sex, Black race, baseline laboratories (including CD4 count), history of diabetes mellitus, hypertension, malignancy, hepatitis, and concurrent medications. RESULTS: Overall, tenofovir-exposed patients had a larger relative decline in GFR through 104 weeks (-7.6 mL/min/1.73 m(2) relative to tenofovir-sparing, P < 0.001); the degree of the difference varied by baseline GFR, with the greatest effect seen in those patients with GFR greater than 80 mL/min/1.73 m(2). Tenofovir-exposed patients had greater development of proximal tubular dysfunction over time (at 52 wk: HR(adjusted) = 1.95 [P = 0.01] and at 104 wk: HR(adjusted) = 5.23 [P = 0.0004]) and had greater risk of medication discontinuation (HR(adjusted) = 1.21, P = 0.02), especially as renal function worsened. Viral control and CD4 count changes were similar between the two groups. CONCLUSIONS: Tenofovir is associated with greater effect on decline in renal function and a higher risk of proximal tubular dysfunction in antiretroviral naive patients initiating antiretroviral therapy.
Authors: Horberg M; Tang B; Towner W; Silverberg M; Bersoff-Matcha S; Hurley L; Chang J; Blank J; Quesenberry C Jr; Klein D
J Acquir Immune Defic Syndr. 2010 Jan 1;53(1):62-9.
Real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine
BACKGROUND: A pentavalent, bovine-derived rotavirus vaccine (RotaTeq, Merck) was licensed in 2006 for use in infants. A previously licensed rotavirus vaccine was withdrawn due to elevated risk of intussusception. We prospectively evaluated the risk of intussusception and other pre-specified adverse events among RotaTeq recipients in the Vaccine Safety Datalink. METHODS: The exposed population included children from age 4 to 48 weeks who received RotaTeq between May 2006 and May 2008. Adverse events over the subsequent 30 days were ascertained from inpatient, outpatient, and emergency department files; cases of intussusception were validated by medical record review. An adaptation of sequential probability ratio testing was employed to compare the cumulative number of observed and expected adverse events on a weekly basis, and a ‘signal’ was generated if the log-likelihood ratio reached a predetermined threshold. This allowed near real-time monitoring to detect selected adverse events. The expected number of cases of intussusception was determined from historical rates in the VSD population. RESULTS: There were 207,621 doses of RotaTeq administered to the study population; 42% were first doses. Five children had computerized diagnosis codes for intussusception, and 6.75 cases were expected based on historical rates (relative risk = 0.74). No elevation in risk was identified for intussusception or any other adverse event. Two of five children with suspected intussusception based on diagnosis codes met the case criteria after medical record review. CONCLUSIONS: This study illustrates the feasibility of rapid vaccine safety assessment and provides additional evidence that RotaTeq is not associated with an increased risk of intussusception.
Authors: Belongia EA; Lewis E; Vaccine Safety Datalink Investigation Group; et al.
Pediatr Infect Dis J. 2010 Jan;29(1):1-5.
CD4 count at presentation for HIV care in the United States and Canada: Are those over 50 years more likely to have a delayed presentation?
ABSTRACT: We assessed CD4 count at initial presentation for HIV care among >/=50-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to <50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals ([,]) were determined using linear regression stratified by age category and adjusted for gender, race/ethnicity, HIV transmission risk and cohort. From 1997-2007, the proportion of individuals presenting for HIV care who were >/=50-years-old increased from 17% to 27% (p-value < 0.01). The median CD4 count among >/=50 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant (p-value <0.01) with both age groups experiencing modest annual improvements over time (< 50-year-olds: 5 [4 , 6] cells/mm3; >/=50-year-olds: 7 [5 , 9] cells/mm(3)), after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals (13% vs. 10%, respectively). Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults >/=50-year-old at first presentation for HIV care, renewed HIV testing efforts are needed.
Authors: Althoff KN; Silverberg MJ; for the North American AIDS Cohort Collaboration on Research and Design; et al.
AIDS Res Ther. 2010 Dec 15;7:45.
Syphilis epidemiology and clinical outcomes in HIV-infected and HIV-uninfected patients in Kaiser Permanente Northern California
BACKGROUND: Syphilis rates are rising in California, but the impact of HIV infection on syphilis infection remains uncertain. We describe differences between HIV-infected and HIV-uninfected patients diagnosed with syphilis within Kaiser Permanente Northern California. METHODS: We performed retrospective analyses of patients diagnosed with incident syphilis from 1995 to 2005 (622 cases/9989 HIV-infected patients and 3584/4,442,780 HIV-uninfected). Among cases, we ascertained demographic, clinical characteristics, and laboratory (including baseline labs and repeated RPR titers) data. We performed Poisson regression (incidence) and Cox proportional hazard modeling (reduction in RPR and serologic failure after syphilis therapy) adjusting for age, gender, and HIV status and among HIV-infected cases only by use of antiretroviral therapy (ART). RESULTS: HIV-infected patients had incident syphilis rates of 62.3/1000 person-years compared with 0.8/1000 HIV-uninfected patients, corresponding to an adjusted rate ratio of 86.0 (P <0.001); rate differences increased significantly over time. HIV-infected patients had a greater likelihood of reduction in RPR and serologic failure after syphilis therapy (HR = 2.5 and 2.6 respectively [P <0.001 both]). Among HIV-infected only, patients on ART had lower rates of infection but higher likelihood of reduction in RPR after syphilis therapy and serologic failure compared with patients not on ART. CONCLUSIONS: HIV-infected patients had greater rate of incident syphilis compared with HIV-uninfected, a disparity which increased over time. HIV-infected patients had greater likelihood of decline in RPR and serologic failure. HIV-infected patients should be screened for syphilis regularly.
Authors: Horberg MA; Ranatunga DK; Quesenberry CP; Klein DB; Silverberg MJ
Sex Transm Dis. 2010 Jan;37(1):53-8.
Differential maternal responses to a newly developed vaccine information pamphlet
We compared the response to a new vaccine information pamphlet with the current CDC Vaccine Information Statements (VIS) among recently delivered mothers who were screened to identify those with concerns about immunization. Eligible mothers (n=226) were randomly assigned to one of three equal groups; those reviewing only the new pamphlet, those receiving only VIS, or those receiving both. Among those mothers reviewing both, 61% preferred the new pamphlet for its visual appeal (P<0.0001) and ease of understanding (P=0.005). Overall, mothers expressed increased confidence and fewer concerns regarding multiple injections after reviewing the pamphlet. However, older, more-highly educated mothers were less likely to report improved vaccine confidence after reviewing either the pamphlet or the VIS. Mothers in all three groups stated a preference for receiving the vaccine information during pregnancy or prior to the actual immunization visit. These data suggest that early provision of tailored immunization material along with the VIS to new mothers may enhance their overall confidence in vaccines and that additional strategies targeted toward certain mothers may be needed.
Authors: Klein NP; Kissner J; Aguirre A; Sparks R; Campbell S; Edwards KM; Dekker CL; Shui I; Gust DA
Vaccine. 2009 Dec 11;28(2):323-8. Epub 2009 Oct 30.
Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America
BACKGROUND: Although combination antiretroviral therapy continues to evolve, with potentially more effective options emerging each year, the ability of therapy to prevent multiple regimen failure and mortality in clinical practice remains poorly defined. METHODS: Sixteen cohorts representing over 60 sites contributed data on all individuals who initiated combination antiretroviral therapy. We identified those individuals who experienced virologic failure (defined as a human immunodeficiency virus [HIV] RNA level >1000 copies/mL), received modified therapy, and subsequently had a second episode of virologic failure. Multivariate Cox regression was used to assess factors associated with time to second regimen failure and the time to death after the onset of second regimen failure. RESULTS: Of the 42,790 individuals who received therapy, 7159 experienced a second virologic failure. The risk of second virologic failure decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; P < .001). The cumulative mortality after onset of second virologic failure was 26% at 5 years and decreased over time. A history of AIDS, a lower CD4(+) T cell count, and a higher plasma HIV RNA level were each independently associated with mortality. Similar trends were observed when analysis was limited to the subset of previously treatment-naive patients CONCLUSIONS: Although the rates of multiple regimen failure have decreased dramatically over the past decade, mortality rates for those who have experienced failure of at least 2 regimens have remained high. Plasma HIV RNA levels, CD4(+) T cell counts at time of treatment failure, and a history of AIDS remain independent risk factors for death, which emphasizes that these factors remain important targets for those in need of more-aggressive therapeutic interventions.
Authors: Deeks SG; Silverberg MJ; Moore RD; et al.
Clin Infect Dis. 2009 Nov 15;49(10):1582-90.
HIV infection and the risk of cancers with and without a known infectious cause
OBJECTIVE: To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. DESIGN: Retrospective cohort study. METHODS: Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkin’s lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). RESULTS: We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7-44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7-11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkin's lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2-1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). CONCLUSION: In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.
Authors: Silverberg MJ; Chao C; Leyden WA; Xu L; Tang B; Horberg MA; Klein D; Quesenberry CP Jr; Towner WJ; Abrams DI
AIDS. 2009 Nov 13;23(17):2337-45.
Compliance with multiple-dose vaccine schedules among older children, adolescents, and adults: results from a vaccine safety datalink study
OBJECTIVES: We studied compliance with multiple-dose vaccine schedules, assessed factors associated with noncompliance, and examined timeliness of series completion among older children, adolescents, and adults. METHODS: We conducted a large, multisite, retrospective cohort study of older children, adolescents, and adults in the Vaccine Safety Datalink population from 1996 through 2004. We quantified the rates of completion of all required doses for varicella, hepatitis A, and hepatitis B vaccines according to their recommended schedules. RESULTS: Among those who received a first dose of varicella (n = 16 075), hepatitis A (n = 594 917), and hepatitis B (n = 590 445) vaccine, relatively few completed the series (55%-65% for hepatitis B vaccine and 40%-50% for hepatitis A and varicella vaccines in most age groups). Compliance was lowest among adolescents (35.9%) and Medicaid recipients (29.7%) who received varicella vaccine and among younger adult age groups who received hepatitis A vaccine (25%-35% across those age groups). Even among series completers, there was a relatively long interval of undervaccination between the first and last doses. CONCLUSIONS: Compliance with multiple-dose vaccine series among older children, adolescents, and adults is suboptimal. Further evaluations of strategies to improve compliance in these populations are needed.
Authors: Nelson JC; Klein NP; Jackson LA; et al.
Am J Public Health. 2009 Oct;99 Suppl 2:S389-97.
Serum uric acid and risk of multiple sclerosis
Because of evidence implicating oxidative stress in multiple sclerosis pathogenesis, it has been postulated that high levels of urate, a potent antioxidant, could reduce risk or favorably influence disease progression. We conducted a prospective study to determine whether serum urate levels contribute to prediction of multiple sclerosis risk. Analyses included 31 cases with blood collected a median of 1.9 years before multiple sclerosis onset from the Nurses’ Health Study and Nurses’ Health Study II cohorts, and 42 cases with collection a median of 14.5 years before onset from the Kaiser Permanente Northern California health plan cohort. Relative risks were estimated by unconditional logistic regression, including 26 controls in the Nurses’ cohorts and 130 controls in the Kaiser cohort. In analyses including only cases in the Nurses’ cohorts where blood was collected shortly before onset, there was a trend toward a lower risk of multiple sclerosis among individuals with higher serum urate, but the association was not significant (multivariable relative risk 0.52, 95% CI 0.22, 1.20, p value 0.13). In contrast, there was no evidence of a decline in risk with increasing serum urate in the Kaiser cohort where there was a longer period of time between blood collection and onset (multivariable relative risk 1.36, 95% CI 0.87, 2.14, p value 0.18). The results of this study suggest that serum urate is not a strong predictor of MS risk. This lack of association is consistent with the interpretation that the lower urate levels among multiple sclerosis cases are a consequence rather than a cause of the disease.
Authors: Massa J; O'Reilly E; Munger KL; Delorenze GN; Ascherio A
J Neurol. 2009 Oct;256(10):1643-8. Epub 2009 May 26.
Increased rates of appendicitis in HIV-infected men: 1991-2005
Authors: Klein DB; Hurley LB; Horberg MA; Silverberg MJ; Follansbee SE; Flamm JA; Green GM
J Acquir Immune Defic Syndr. 2009 Sep 1;52(1):139-40.
Prevalence and predictors of hepatic steatosis in adults with newly diagnosed chronic liver disease due to hepatitis C
Obesity appears to be a risk factor for hepatic steatosis, which has been implicated in the development of hepatic fibrosis in patients with hepatitis C virus infection. We conducted the current study to examine whether obesity is associated with hepatic steatosis among patients with chronic hepatitis C identified from a population-based cohort. Study participants were persons with chronic hepatitis C who had had a liver biopsy, identified from a population-based study of persons with newly identified chronic liver disease conducted in gastroenterology practices. Data were collected through patient interviews, medical record abstraction, and review of previously performed liver biopsies. The outcome variable of interest was significant steatosis, defined as steatosis grade or =2 determined from liver biopsy samples. Univariate and multivariate analyses were performed using logistic regression techniques. The analysis included 450 patients with chronic hepatitis C with available liver biopsy slides. Overall, only 15.8% of subjects had significant hepatic steatosis (grade or =2), while 35.9% of obese subjects had significant steatosis. In multivariate analysis, significant fibrosis (defined as or = grade 2) (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.59-7.37), obesity (OR, 3.32; 95% CI, 1.84-5.98), genotype 3 (OR, 2.5; 95% CI, 1.09-5.75), and the presence of multiple metabolic comorbidities (OR, 1.91; 95% CI, 0.88-4.11) were independently associated with steatosis. In this unique United States cohort of patients with newly diagnosed chronic liver disease due to hepatitis C, obesity was independently associated with hepatic steatosis. The results of this study provide additional evidence that obesity worsens liver damage in patients with chronic hepatitis C, and suggest a role for weight loss as a treatment modality in these patients.
Authors: Hayman AV; Sofair AN; Manos MM; Thomas A; Terrault N; Ness GV; Stabach N; Robert M; Rumore G; Corless C; Bell B; Bialek S; Zaman A
Medicine (Baltimore). 2009 Sep;88(5):302-6.
Race/ethnicity and risk of AIDS and death among HIV-infected patients with access to care
BACKGROUND: Prior studies evaluating racial/ethnic differences in responses to antiretroviral therapy (ART) among HIV-infected patients have not adequately accounted for many potential confounders, and few have included Hispanic patients. OBJECTIVE: To identify racial/ethnic differences in ART adherence, and risk of AIDS and death after ART initiation for HIV patients with similar access to care. DESIGN: Retrospective cohort study. PARTICIPANTS: 4,686 HIV-infected patients (66% White, 20% Black, and 14% Hispanic) initiating ART and who were enrolled in an integrated healthcare system. MEASUREMENTS: Main outcomes evaluated were ART adherence, new AIDS clinical events, and all-cause mortality. The potential confounding effects of demographics, socioeconomic status, ART parameters, HIV disease stage, and other clinical parameters were considered in multivariable models. RESULTS: Adjusted mean adherence levels were higher among White (70.1%; ref) compared with Black (64.2%; P < 0.001) and Hispanic patients (65.2%; P < 0.001). Adjusted hazard ratios (HR) for the risk of new AIDS events (White patients as reference) were 1.3 (P = 0.09) for Black and 0.9 (P = 0.64) for Hispanic patients. The adjusted HR for AIDS comparing Hispanic to Black patients was 0.7 (P = 0.11). Hispanic patients had fewer deaths compared with other racial/ethnic groups, particularly cancer and cardiovascular-related. However, adjusted HRs for death were 1.2 (P = 0.37) and 0.9 (P = 0.62) for Black and Hispanic patients, respectively, compared with White patients and 0.9 (P = 0.63) for Hispanic compared with Black patients. Adjustment for adherence did not change inferences for AIDS or death. CONCLUSIONS: In the setting of similar access to care, we did not observe a disparity for the risk of clinical events for racial/ethnic minorities, despite lower ART adherence.
Authors: Silverberg MJ; Leyden W; Quesenberry CP Jr; Horberg MA
J Gen Intern Med. 2009 Sep;24(9):1065-72. Epub 2009 Jul 16.
Influenza vaccination and mortality: differentiating vaccine effects from bias
It is widely believed that influenza (flu) vaccination of the elderly reduces all-cause mortality, yet randomized trials for assessing vaccine effectiveness are not feasible and the observational research has been controversial. Efforts to differentiate vaccine effectiveness from selection bias have been problematic. The authors examined mortality before, during, and after 9 flu seasons in relation to time-varying vaccination status in an elderly California population in which 115,823 deaths occurred from 1996 to 2005, including 20,484 deaths during laboratory-defined flu seasons. Vaccine coverage averaged 63%; excess mortality when the flu virus was circulating averaged 7.8%. In analyses that omitted weeks when flu circulated, the odds ratio measuring the vaccination-mortality association increased monotonically from 0.34 early in November to 0.56 in January, 0.67 in April, and 0.76 in August. This reflects the trajectory of selection effects in the absence of flu. In analyses that included weeks with flu and adjustment for selection effects, flu season multiplied the odds ratio by 0.954. The corresponding vaccine effectiveness estimate was 4.6% (95% confidence interval: 0.7, 8.3). To differentiate vaccine effects from selection bias, the authors used logistic regression with a novel case-centered specification that may be useful in other population-based studies when the exposure-outcome association varies markedly over time.
Authors: Fireman B; Lee J; Lewis N; Bembom O; van der Laan M; Baxter R
Am J Epidemiol. 2009 Sep 1;170(5):650-6. Epub 2009 Jul 22.
The incidence of diabetes in atypical antipsychotic users differs according to agent–results from a multisite epidemiologic study
PURPOSE: The purpose of this study was to examine the association between atypical antipsychotics, including the newer agents, aripiprazole and ziprasidone, and newly treated diabetes, using the largest post-marketing cohort of patients exposed to these newer treatments that has been studied to date. METHODS: Identified two overlapping cohorts-a simple cohort (all antipsychotic users) and an inception cohort (new users of antipsychotics)-using automated data from three United States sites (60.4 million covered lives). Patients exposed to antipsychotics > or = 45 days were identified and followed for incident diagnoses of treated diabetes. Data analysis accounted for drug switching and non-consistent drug use. RESULTS: In the 55 287-member inception cohort, 357 cases of newly treated diabetes were identified. Compared with current use of typical antipsychotics, current users of aripiprazole (adjusted hazard ratio (aHR) 0.93, 95% confidence interval (CI) 0.50-1.76), quetiapine (aHR 1.04, 95%CI, 0.67-1.62), risperidone (aHR 0.85, 95%CI, 0.54-1.36) and ziprasidone (aHR 1.05, 95%CI, 0.54-2.08) had similar low risk of diabetes. Patients exposed to olanzapine had an increased risk of diabetes (aHR 1.71, 95%CI, 1.12-2.61), and although the effect estimate is imprecise, clozapine-exposed patients had a trend towards an elevated hazard ratio (aHR 2.58, 95%CI, 0.76-8.80). Results for the simple cohort were similar. CONCLUSIONS: Relative to typical antipsychotics, aripiprazole, ziprasidone, risperidone and quetiapine were not associated with an increased risk of diabetes; olanzapine and clozapine were associated with an increased risk. This analysis constitutes the largest post-marketing pharmacoepidemiologic study to date that includes the newer agents.
Authors: Yood MU; DeLorenze G; Quesenberry CP Jr; Oliveria SA; Tsai AL; Willey VJ; McQuade R; Newcomer J; L'Italien G
Pharmacoepidemiol Drug Saf. 2009 Sep;18(9):791-9.
Virologic outcomes of changing enfuvirtide to raltegravir in HIV-1 patients well controlled on an enfuvirtide based regimen: 24-week results of the CHEER study
OBJECTIVES: To determine the safety and efficacy of changing enfuvirtide to raltegravir in HIV-1-infected patients with HIV-1 RNA below the level of quantification for at least 6 months on an enfuvirtide-containing antiretroviral regimen. DESIGN: Prospective, nonrandomized, historical control study. METHODS: Patients were recruited from 11 Kaiser Permanente HIV clinics in California. Those patients eligible for inclusion (or=18 years old, well controlled on antiretroviral medications) had enfuvirtide changed to raltegravir 400 mg, given twice daily orally; all other background antiretrovirals remained unchanged. The primary end point was percentage of patients with HIV-1 RNA below the limit of quantification after 24 weeks of raltegravir therapy. Analyses were by intention to treat. RESULTS: Fifty-two patients were enrolled in the trial. After 24 weeks of therapy with raltegravir, 49 (94.2%, confidence interval: 1.2% to 15.9%) patients had HIV-1 RNA levels below the limit of quantification. Patients had a median CD4 cell increase of 32 cells per cubic millimeter after 24 weeks of raltegravir therapy. Treatment satisfaction as measured by patient questionnaires improved with the raltegravir-containing regimen. Adverse events were infrequent and generally mild in nature. CONCLUSIONS: In treatment-experienced patients on a stable virologically suppressive enfuvirtide-containing regimen, raltegravir can safely be substituted for enfuvirtide.
Authors: Towner W; Klein D; Kerrigan HL; Follansbee S; Yu K; Horberg M
J Acquir Immune Defic Syndr. 2009 Aug 1;51(4):367-73.
Age and racial/ethnic differences in the prevalence of reported symptoms in human immunodeficiency virus-infected persons on antiretroviral therapy
Few studies have evaluated age and racial/ethnic differences in the prevalence of symptoms in human immunodeficiency virus (HIV)-infected persons. Thus, the objective of this study was to compare the prevalence of gastrointestinal, metabolic, general malaise, neurologic, or other self-reported symptoms by age and race/ethnicity among 1574 HIV-infected women enrolled in the Women’s Interagency HIV Study and 955 HIV-infected men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study. All patients had known dates of initiation of highly active antiretroviral therapy. It was observed that women aged 50 years or more were less likely to experience gastrointestinal symptoms (24% vs. 27%; multivariable P=0.024), but more likely to experience general malaise (47% vs. 37%; multivariable P=0.004), neurologic (44% vs. 38%; multivariable P=0.048), or other symptoms (40% vs. 28%; multivariable P<0.001) compared with women less than 40 years of age. Only neurologic symptoms had a higher prevalence among older MSM (52% vs. 37%; multivariable P=0.002), largely driven by paresthesias (48% vs. 31%; multivariable P=0.004), the most common individual symptom reported by men. Caucasian women generally had the highest prevalence of symptoms, and African American women had the lowest prevalence. Few racial/ethnic differences were noted for MSM. Depression and a prior diagnosis of acquired immunodeficiency syndrome were the strongest and most consistent predictors of clinical symptoms in both cohorts. In summary, the prevalence of reported symptoms varies with patient race/ethnicity, age, and modifiable factors, such as depression and HIV disease stage. Clinicians should consider these factors when counseling patients regarding potential adverse effects of antiretrovirals or symptoms associated with HIV disease.
Authors: Silverberg MJ; Jacobson LP; French AL; Witt MD; Gange SJ
J Pain Symptom Manage. 2009 Aug;38(2):197-207. Epub 2009 Mar 28.
Effect of malaria rapid diagnostic tests on the management of uncomplicated malaria with artemether-lumefantrine in Kenya: a cluster randomized trial.
Shortly after Kenya introduced artemether-lumefantrine (AL) for first-line treatment of uncomplicated malaria, we conducted a pre-post cluster randomized controlled trial to assess the effect of providing malaria rapid diagnostic tests (RDTs) on recommended treatment (patients with malaria prescribed AL) and overtreatment (patients without malaria prescribed AL) in outpatients >/= 5 years old. Sixty health facilities were randomized to receive either RDTs plus training, guidelines, and supervision (TGS) or TGS alone. Of 1,540 patients included in the analysis, 7% had uncomplicated malaria. The provision of RDTs coupled with TGS emphasizing AL use only after laboratory confirmation of malaria reduced recommended treatment by 63%-points (P = 0.04), because diagnostic test use did not change (-2%-points), but health workers significantly reduced presumptive treatment with AL for patients with a clinical diagnosis of malaria who did not undergo testing (-36%-points; P = 0.03). Health workers generally adhered to RDT results when prescribing AL: 88% of RDT-positive and 9% of RDT-negative patients were treated with AL, respectively. Overtreatment was low in both arms and was not significantly reduced by the provision of RDTs (-12%-points, P = 0.30). RDTs could potentially improve malaria case management, but we urgently need to develop more effective strategies for implementing guidelines before large scale implementation.
Authors: Skarbinski J; Ouma PO; Causer LM; Kariuki SK; Barnwell JW; Alaii JA; de Oliveira AM; Zurovac D; Larson BA; Snow RW; Rowe AK; Laserson KF; Akhwale WS; Slutsker L; Hamel MJ
Am J Trop Med Hyg. 2009 Jun;80(6):919-26.
Effect of early versus deferred antiretroviral therapy for HIV on survival
BACKGROUND: The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS: We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS: In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS: The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
Authors: Kitahata MM; Silverberg MJ; NA-ACCORD Investigators; et al.
N Engl J Med. 2009 Apr 30;360(18):1815-26. Epub 2009 Apr 1.
Response to newly prescribed lipid-lowering therapy in patients with and without HIV infection
BACKGROUND: Antiretroviral agents, particularly protease inhibitors (PIs), may adversely affect lipid levels in patients with HIV infection. However, it is not known whether HIV-associated dyslipidemia is more difficult to treat. OBJECTIVE: To compare the effectiveness and safety of lipid-lowering therapy in patients with and without HIV infection. DESIGN: Retrospective cohort study. SETTING: Integrated health care delivery system from 1996 to 2005. PATIENTS: 829 patients with HIV infection and 6941 patients without HIV infection beginning lipid-lowering therapy for elevated low-density lipoprotein cholesterol or triglyceride levels. MEASUREMENTS: Percentage change in lipids within 12 months and adverse liver- and muscle-related clinical and laboratory events. RESULTS: Compared with patients without HIV infection, patients with HIV infection beginning statin therapy had smaller reductions in low-density lipoprotein cholesterol levels (25.6% vs. 28.3%; P = 0.001), which did not vary by antiretroviral therapy class. Patients with HIV infection beginning gemfibrozil therapy had substantially smaller reductions in triglyceride levels than patients without HIV infection (44.2% vs. 59.3%; P < 0.001), and reductions with gemfibrozil varied by antiretroviral therapy class (44.0% [P = 0.001] in patients receiving PIs only, 26.4% [P < 0.001] in patients receiving PIs and nonnucleoside reverse transcriptase inhibitors [NNRTIs], and 60.3% [P = 0.94] in patients receiving NNRTIs only). Rhabdomyolysis was diagnosed in 3 patients with HIV infection and 1 patient without HIV infection. No clinically recognized cases of myositis or myopathy were observed. The risk for laboratory adverse events was low (<5%), although it was increased in patients with HIV infection. Limitations: Laboratory measurements were not uniformly performed according to HIV status, and adequate fasting before lipoprotein testing could not be verified. Results may not be completely generalizable to uninsured persons, women, or certain racial or ethnic minorities. CONCLUSION: Dyslipidemia, particularly hypertriglyceridemia, is more difficult to treat in patients with HIV infection than in the general population. However, patients with HIV infection receiving NNRTI-based antiretroviral therapy and gemfibrozil had triglyceride responses similar to those in patients without HIV infection. Funding: GlaxoSmithKline.
Authors: Silverberg MJ; Leyden W; Hurley L; Go AS; Quesenberry CP Jr; Klein D; Horberg MA
Ann Intern Med. 2009 Mar 3;150(5):301-13.
Smoking enhances risk for new external genital warts in men
Repeat episodes of HPV-related external genital warts reflect recurring or new infections. No study before has been sufficiently powered to delineate how tobacco use, prior history of EGWs and HIV infection affect the risk for new EGWs. Behavioral, laboratory and examination data for 2,835 Multicenter AIDS Cohort Study participants examined at 21,519 semi-annual visits were evaluated. Fourteen percent (391/2835) of men reported or were diagnosed with EGWs at 3% (675/21,519) of study visits. Multivariate analyses showed smoking, prior episodes of EGWs, HIV infection and CD4+ T-lymphocyte count among the infected, each differentially influenced the risk for new EGWs.
Authors: Wiley DJ; Elashoff D; Masongsong EV; Harper DM; Gylys KH; Silverberg MJ; Cook RL; Johnson-Hill LM
Int J Environ Res Public Health. 2009 Mar;6(3):1215-34. Epub 2009 Mar 20.
Varicella vaccination and ischemic stroke in children: is there an association?
BACKGROUND: Ischemic stroke is a known complication of varicella disease. Although there have been case reports of ischemic stroke after varicella vaccination, the existence and magnitude of any vaccine-associated risk has not been determined. OBJECTIVE. The purpose of this work was to determine whether varicella vaccination is associated with an increased risk of ischemic stroke and encephalitis in children within 12 months after vaccination. PATIENTS AND METHODS: We conducted a retrospective cohort study based on computerized data from children 11 months through 17 years old enrolled for > or =12 months in the Vaccine Safety DataLink from 1991 through 2004. International Classification of Disease codes identified cases of ischemic stroke (433-436, 437.1, 437.4, 437.6, 437.8-437.9) and encephalitis (052.0, 323.5, 323.8-9). Cox regression was used to model the risk in the 12 months after vaccination relative to all other person-time. Covariates included calendar time, gender, and stroke risk factors (eg, sickle cell disease). RESULTS: Varicella vaccine was administered to 35.3% of the 3.2 million children in the cohort. There were 203 new inpatient ischemic stroke diagnoses, including 8 that occurred within 12 months after vaccination; there was no temporal clustering. The adjusted stroke hazard ratio was not elevated during any of the time periods in the 12 months after vaccination. Stroke was strongly associated with known risk factors such as sickle cell disease and cardiac disease. None of the 243 encephalitis cases occurred during the first 30 days after vaccination, and there was no association between encephalitis and varicella vaccination at any time in the 12 months after vaccination. CONCLUSION: Our retrospective cohort study of >3 million children found no association between varicella vaccine and ischemic stroke.
Authors: Donahue JG; Klein NP; Vaccine Safety Datalink Team; et al.
Pediatrics. 2009 Feb;123(2):e228-34.
Recurrent sterile abscesses following aluminium adjuvant-containing vaccines
Abscess formation following immunisation is a previously reported complication, generally associated with microbial contamination of the vaccine. Less commonly, such abscesses have been sterile. Here we describe two children evaluated in the Center for Disease Control and Prevention (CDC)-funded Clinical Immunization Safety Assessment (CISA) network who developed recurrent sterile abscesses after administration of vaccines containing aluminium adjuvant, either individually or in combination. Although the abscesses healed without sequelae, these occurrences support an association between receipt of aluminium adjuvant and sterile abscesses in susceptible patients. For patients with similar symptoms, clinicians may wish to choose a vaccine formulation containing the least amount of aluminium adjuvant.
Authors: Klein NP; Edwards KM; Sparks RC; Dekker CL; Clinical Immunization Safety Assessment (CISA) Network
BMJ Case Rep. 2009;2009. Epub 2009 Mar 17.
Do antiretrovirals reduce the risk of non-AIDS-defining malignancies?
PURPOSE OF REVIEW: There is an increasing burden of non-AIDS-defining malignancies (NADMs) in the antiretroviral therapy (ART) era. The recent literature is reviewed with respect to NADM risk, ART use, and immune function. RECENT FINDINGS: Recent studies have increasingly focused on individual ART use, CD4 T-cell counts, and the risk of NADMs. Certain NADMs have been shown to have a reduced risk with ART use including liver, breast, colorectal, and lung cancers. NADMs associated with immunosuppression included Hodgkin’s lymphoma, oral/pharynx, lung, anal, and colorectal cancers. Despite the potential protective effect of ART on some NADMs, recent studies evaluating calendar era trends have noted an increased risk of Hodgkin’s lymphoma and anal cancer and no change in risk for lung cancer in the ART era. SUMMARY: Successful ART use and improvements in immune function for HIV-infected persons may reduce the risk of certain NADMs. However, a continued high risk in the ART era for certain cancers have been observed, including Hodgkin’s lymphoma and anal cancers. Future studies should monitor trends in NADMs in HIV-infected persons in the ART era, as well as changes in the prevalence of risk factors, coinfections, and screening practices in this population.
Authors: Silverberg MJ; Abrams D
Curr Opin HIV AIDS. 2009 Jan;4(1):42-51.
Efficacy and safety of ritonavir-boosted and unboosted atazanavir among antiretroviral-naive patients
PURPOSE: Evaluate responses and safety of ritonavir-boosted atazanavir (‘boosted atazanavir’) compared to unboosted atazanavir among antiretroviral-naive patients in the clinical managed care setting. METHOD: Observational cohort analysis of atazanavir use (comparing ritonavir-boosted to non-boosted) at Kaiser Permanente and Group Health Cooperative from 2003 to 2006. Antiretroviral-naive patients initiating atazanavir were followed through 52 weeks of treatment. RESULTS: 443 patients were prescribed atazanavir (69 non-boosted; 15.5%). Boosted and non-boosted atazanavir groups were similar with respect to gender and age. Boosted atazanavir use was associated with greater odds achieving HIV RNA <400 c/mL (odds ratio [OR] = 3.24, p = .008), greater decrease in HIV RNA (-0.37 log10/mL, p = .03), greater increase in CD4 T-cell count (+59 cells/microL, p = .01), and greater increase in total bilirubin (+1.21 mg/dL as opposed to +0.56 mg/dL, p .001). There were no statistically significant differences for glucose, liver transaminases, total cholesterol, or LDL cholesterol elevations. There were greater odds of maximal viral control when atazanavir was combined with tenofovir or zidovudine in combination with lamivudine (or emtricitabine). CONCLUSIONS: Ritonavir-boosted atazanavir is associated with greater virologic control and immune response through 52 weeks compared to non-boosted atazanavir, without greater risk of adverse events except elevated bilirubin. Thus, ritonavir-boosted atazanavir is the preferred method of prescribing atazanavir.
Authors: Horberg M; Klein D; Hurley L; Silverberg M; Towner W; Antoniskis D; Kovach D; Mogyoros M; Blake W; Dobrinich R; Dodge W
HIV Clin Trials. 2008 Nov-Dec;9(6):367-74.
Kinrix: a new combination DTaP-IPV vaccine for children aged 4-6 years
Combination vaccines allow the administration of multiple vaccine antigens without the need for multiple injections. Recently, a combined diphtheria toxoid, tetanus toxoid, acellular pertussis and inactivated poliomyelitis vaccine (DTaP-IPV), Kinrix, has been licensed in the USA for use as the fifth DTaP dose and fourth IPV dose in children 4-6 years of age. Clinical trials have shown Kinrix to be immunogenic in 4-6-year-old children, with a safety profile comparable with that of separate DTaP and IPV vaccination. The use of Kinrix reduces by one the number of injections required to provide this age group with all recommended immunizations. Strategies such as the use of combined vaccines can help to maintain high levels of coverage against diphtheria, tetanus, pertussis and poliomyelitis diseases.
Authors: Weston WM; Klein NP
Expert Rev Vaccines. 2008 Nov;7(9):1309-20.
The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance
OBJECTIVES: Chronic liver disease (CLD) is an important cause of morbidity and mortality, but the epidemiology is not well described. We conducted prospective population-based surveillance to estimate newly diagnosed CLD incidence, characterize etiology distribution, and determine disease stage. METHODS: We identified cases of CLD newly diagnosed during 1999-2001 among adult county residents seen in any gastroenterology practice in New Haven County, Connecticut; Multnomah County, Oregon; and Northern California Kaiser Permanente Medical Care Program (KPMCP, Oakland, California [total population 1.48 million]). We defined CLD as abnormal liver tests of at least 6 months’ duration or pathologic, clinical, or radiologic evidence of CLD. Consenting patients were interviewed, a blood specimen obtained, and the medical record reviewed. RESULTS: We identified 2,353 patients with newly diagnosed CLD (63.9 cases/100,000 population), including 1,225 hepatitis C patients (33.2 cases/100,000). Men aged 45-54 yr had the highest hepatitis C incidence rate (111.3/100,000). Among 1,040 enrolled patients, the median age was 48 yr (range 19-86 yr). Hepatitis C, either alone (442 [42%]) or in combination with alcohol-related liver disease (ALD) (228 [22%]), accounted for two-thirds of the cases. Other etiologies included nonalcoholic fatty liver disease (NAFLD, 95 [9%]), ALD (82 [8%]), and hepatitis B (36 [3%]). Other identified etiologies each accounted for 3% of the cases. A total of 184 patients (18%) presented with cirrhosis, including 44% of patients with ALD. CONCLUSIONS: Extrapolating from this population-based surveillance network to the adult U.S. population, approximately 150,000 patients with CLD were diagnosed in gastroenterology practices each year during 1999-2001. Most patients had hepatitis C; heavy alcohol consumption among these patients was common. Almost 20% of patients, an estimated 30,000 per year, had cirrhosis at presentation. These results provide population-level baseline data to evaluate trends in identification of patients with CLD in gastroenterology practices.
Authors: Bell BP; Manos MM; Zaman A; Terrault N; Thomas A; Navarro VJ; Dhotre KB; Murphy RC; Van Ness GR; Stabach N; Robert ME; Bower WA; Bialek SR; Sofair AN
Am J Gastroenterol. 2008 Nov;103(11):2727-36; quiz 2737. Epub 2008 Jul 31.
Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment
Standard death certificate-based methods for ascertaining deaths due to chronic liver disease (CLD), such as the U.S. vital statistics approach, rely on a limited set of diagnostic codes to define CLD. These codes do not include viral hepatitis or consider hepatocellular carcinoma (HCC) deaths, and thus, underestimate the true burden of CLD mortality. Deaths associated with CLD may be further misunderstood because of the inherent limitations of death record information. Using a comprehensive list of CLD-related codes to search death records, we investigated the CLD mortality rate and associated etiologies (derived from medical records) in a large managed care health plan. From the 16,970 deaths among health plan members in 2000, we confirmed 355 (2.1%) as CLD related, including 75 with HCC. The age-adjusted CLD mortality rate using the comprehensive codes was 11.9 per 100,000 compared with 6.3 per 100,000 using only conventional codes. Based on medical records, the underlying CLD was attributed to alcoholic liver disease (ALD) in 44% of deaths, HCV infection with ALD in 16%, HCV without ALD in 18%, and chronic HBV infection in 7%. Only 64% of HCV-associated, 48% of HBV-associated, and 64% of ALD-associated deaths ascertained by medical record had that specific etiology mentioned on the death certificate. Conclusion: CLD mortality burden was almost doubled by using a comprehensive list of mortality codes and considering HCC deaths as CLD related. Furthermore, the contributions of viral hepatitis and ALD to CLD mortality may be underestimated if based solely on death records.
Authors: Manos MM; Leyden WA; Murphy RC; Terrault NA; Bell BP
Hepatology. 2008 Apr;47(4):1150-7.
Diphtheria-tetanus-acellular pertussis and inactivated poliovirus vaccines given separately or combined for booster dosing at 4-6 years of age
BACKGROUND: In the United States, diphtheria-tetanus-acellular pertussis (DTaP) and inactivated poliovirus (IPV) booster vaccinations are recommended for children 4-6 years of age. A combined DTaP-IPV vaccine is being developed, which would reduce by one the number of injections in this age group. METHODS: Children 4-6 years of age were randomized (1:1:1:1) to receive booster vaccination with 1 of 3 combined DTaP-IPV lots plus the measles, mumps, and rubella vaccine (N = 3156 for pooled lots) or separate doses of DTaP + IPV + measles, mumps, and rubella vaccine (N = 1053). Immunogenicity was assessed in a subset of children (N = 1331). Safety (solicited and unsolicited symptoms) including detailed assessment of local swelling reactions, was assessed in all children. RESULTS: Increases in antibody geometric mean concentrations/titers 1 month after vaccination were observed for the diphtheria, tetanus, acellular pertussis, and polio antigens. At least 92.2% of combined DTaP-IPV subjects and 92.6% of separate DTaP + IPV subjects had a postvaccination booster response for one or more DTaP antigens. Booster responses to one or more poliovirus antigens were observed in at least 96.6% of combined DTaP-IPV subjects and 92.8% of separate DTaP + IPV subjects. The combined DTaP-IPV vaccine was noninferior to separately administered DTaP and IPV vaccines with respect to DTaP antigen booster response rates and poliovirus antibody geometric mean titers ratios. Reporting of solicited local and systemic events was comparable between both groups. CONCLUSIONS: The combination DTaP-IPV vaccine provided immunogenicity and reactogenicity that is comparable to separately administered DTaP and IPV vaccines, with the advantage of requiring one less injection.
Authors: Black S; Friedland LR; Ensor K; Weston WM; Howe B; Klein NP
Pediatr Infect Dis J. 2008 Apr;27(4):341-6.
Influence of prior antiretroviral experience on adherence and responses to new highly active antiretroviral therapy regimens
The impact of prior antiretroviral experience on adherence and clinical outcomes in patients initiating a new highly active antiretroviral therapy (HAART) regimen is not well defined. We performed an observational cohort analysis of antiretroviral-experienced or -naive HIV-infected patients prescribed a new HAART regimen (3538 patients) and enrolled in Kaiser Permanente Northern California from 1997 through 2002. Outcomes evaluated were HAART adherence and changes in HIV RNA level and CD4 T-cell counts over 12 and 24 months. The antiretroviral-naive group had a significantly greater odds of achieving >/=95% adherence to the HAART regimen over 12 months (adjusted odds ratio [OR] = 1.88, p < 0.001) and over 24 months (OR = 1.66, p < 0.001). The odds of achieving HIV RNA levels below limits of quantification also was higher among patients who were antiretroviral naive; over 24 months OR = 6.88, p < 0.001. Adjusted change in CD4 T-cell count was also greater among naive patients over 24 months (+67 cells/muL, p < 0.001), compared to antiretroviral-experienced patients. Years of antiretroviral experience did not affect adherence or any outcome measure. Adjusting for HAART adherence did not significantly affect HIV RNA results but did lessen CD4 T-cell count differences between antiretroviral-naive and -experienced patients. Thus, antiretroviral naive patients have improved HAART adherence, HIV RNA control, and CD4 T-cell count increases compared to antiretroviral-experienced patients regardless of years of antiretroviral experience. These findings should help direct HAART adherence efforts in HIV care clinics.
Authors: Horberg M; Silverberg M; Hurley L; Delorenze G; Quesenberry C
AIDS Patient Care STDS. 2008 Apr;22(4):301-12.
Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients
OBJECTIVES: To determine the impact of depression on highly active antiretroviral therapy (HAART) adherence and clinical measures and investigate if selective serotonin reuptake inhibitors (SSRIs) improve these measures. DESIGN: Retrospective cohort study. METHODS: In 2 large health maintenance organizations, we measured the effects of depression (with and without SSRI use) on adherence and changes in viral and immunologic control among HIV-infected patients starting a new HAART regimen. HAART adherence, HIV RNA levels, and changes in CD4 T-cell counts through 12 months were measured. RESULTS: A total of 3359 patients were evaluated; 42% had a depression diagnosis, and 15% used SSRIs during HAART. Depression without SSRI use was associated with significantly decreased odds of achieving > or =90% adherence to HAART (odds ratio [OR] = 0.81, 95% confidence interval [CI]: 0.70 to 0.98; P = 0.03). Depression was associated with significantly lower odds of an HIV RNA level <500 copies/mL (OR = 0.77, 95% CI: 0.62 to 0.95; P = 0.02). Depressed patients compliant with SSRI medication (>80% adherence to SSRI) had HAART adherence and viral control statistically similar to nondepressed HIV-infected patients taking HAART. Comparing depressed with nondepressed HIV-infected patients, CD4 T-cell responses were statistically similar; among depressed patients, those compliant with SSRI had statistically greater increases in CD4 cell responses. CONCLUSIONS: Depression significantly worsens HAART adherence and HIV viral control. Compliant SSRI use is associated with improved HIV adherence and laboratory parameters.
Authors: Horberg MA; Silverberg MJ; Quesenberry CP; Kovach DA; et al.
J Acquir Immune Defic Syndr. 2008 Mar 1;47(3):384-90.
Risk factors for developing apnea after immunization in the neonatal intensive care unit
OBJECTIVES: Among hospitalized NICU infants, preimmunization apnea is a well-recognized predictor of postimmunization apnea. However, predictors for postimmunization apnea among NICU infants without preimmunization apnea have not been investigated. METHODS: Using a large NICU database in the Northern California Kaiser Permanente Medical Care Program, we abstracted NICU charts of infants who were hospitalized for > or = 53 days and who were also immunized, capturing preimmunization (24 hours before immunization) and postimmunization (48 hours after immunization) events. We assessed factors associated with postimmunization apnea by using multivariate logistic regression. RESULTS: Of 16,146 infants admitted to the NICU, 557 received > or = 1 vaccine and 497 met the criteria for study entry. All infants with preimmunization apnea (n = 27) and all except 3 infants with postimmunization apnea (n = 65) had gestational ages of < 31 weeks. Multivariate analyses revealed preimmunization apnea as the most important predictor of postimmunization apnea, although higher 12-hour Score for Neonatal Acute Physiology II and age of < 67 days (mean cohort age) were also associated. Multivariate analysis exclusively among infants without preimmunization apnea similarly found elevated Score for Neonatal Acute Physiology II, age of < 67 days, and weight of < 2000 g to be associated with postimmunization apnea. Forty-nine infants without preimmunization apnea and with > or = 1 apnea predictor were discharged within 48 hours after immunization; 2 were subsequently readmitted because of apnea. CONCLUSIONS: For infants in the NICU without apnea during the 24 hours immediately before immunization, younger age, smaller size, and more severe illness at birth are important predictors of postimmunization apnea.
Authors: Klein NP; Massolo ML; Greene J; Dekker CL; Black S; Escobar GJ; Vaccine Safety Datalink
Pediatrics. 2008 Mar;121(3):463-9.
Illicit drug use and HIV treatment outcomes in a US cohort
OBJECTIVE: To determine the prevalence of illicit drug use and the impact on HIV treatment. DESIGN: Multivariable regression of cross-sectional data from 1163 HIV-infected and 294 controls from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). METHODS: An analysis of (1) prevalence of specific illicit drug use (ever, current), (2) being on HAART among those with an indication and (3) current HIV RNA and CD4 cell count among HAART users. RESULTS: Median age was 42 years, approximately 50% were non-Caucasian and 33% were women. Eighty-six percent of HIV-infected and 67% of controls reported ever using illicit drugs (P < 0.0001); 28% of HIV-infected and 16% of controls reported current use (P = 0.0001). In adjusted models, current cocaine use and past heroin use were associated with not currently being on HAART. Among HAART users, those reporting past heroin use were as likely to have an undetectable HIV viral load as those who had never used heroin. Current and past cocaine use and current heroin use was associated with lower odds of undetectable HIV RNA. Past amphetamine use was associated with having an undetectable HIV. Similar results were seen for CD4 lymphocyte counts. CONCLUSION: Illicit drug use in the US is common, although far fewer report current use than past use. Among HIV-infected patients, understanding of the type of illicit drugs used and whether drug use was in the past or ongoing is important, because of their differential effects on HIV treatment outcomes.
Authors: Cofrancesco J Jr; Scherzer R; Tien PC; Gibert CL; Southwell H; Sidney S; Dobs A; Grunfeld C
AIDS. 2008 Jan 30;22(3):357-65.
Prospective study of attitudinal and relationship predictors of sexual risk in the multicenter AIDS cohort study
We examined the influence of attitudes concerning HIV transmission, safe sex, and sexual sensation seeking, as well as negotiated risk reduction with primary partners, on the proportion of unprotected sexual partners (%UASP) among men who have sex with men (MSM). Participants were 263 HIV-seropositive and 238 HIV-seronegative MSM in the Multicenter AIDS Cohort Study between 1999 and 2003 who completed a 20-item attitude survey twice. Behavioral data were collected concurrently and 6-12 months after each survey. Among seropositives, decreased HIV concern and increased safer sex fatigue were associated with higher %UASP at 6 and 12 months. Among seronegatives, increased %UASP at 12 months was associated with safer sex fatigue. At 6 months and 12 months, risk reduction agreements were associated with increased %UASP among seronegatives in seroconcordant monogamous relationships, reflecting their abandonment of condoms in such partnerships. We conclude that HIV prevention efforts should target modifiable attitudes (reduced concern about HIV and safer sex fatigue) and increases in sexual risk-taking of MSM, particularly among HIV+ men having sex with serodiscordant partners.
Authors: Ostrow DG; Silverberg MJ; Cook RL; Chmiel JS; Johnson L; Li X; Jacobson LP; multicenter AIDS cohort study
AIDS Behav. 2008 Jan;12(1):127-38. Epub 2007 Apr 5.
Incidence of hepatocellular carcinoma among individuals with hepatitis B virus infection identified using an automated data algorithm
The purpose of this study was to develop an algorithm for identifying patients with chronic hepatitis B virus (HBV) using automated data sources from two US health systems and evaluate the algorithm’s performance by quantifying the incidence of hepatocellular carcinoma (HCC) among chronic HBV patients. To allow comparisons with estimates from automated databases that may not contain all data elements used in this algorithm, we created three definitions of chronic HBV infection and used these definitions to create three overlapping cohorts. We compared the incidence of HCC in each cohort with the incidence of HCC in a matched general population comparison cohort with no evidence of HBV. Patients who met the most stringent criteria for chronic HBV infection (based on the standard definition of 6 months of infection using repeat laboratory tests and record review) were 146 times more likely to develop HCC than matched comparison patients (adjusted hazard ratio = 146.5, 95% CI: 74.0-289.8). Those not meeting the stringent criteria, but who met the criterion of at least one positive hepatitis B surface antigen test were 30 times more likely to develop HCC than comparison patients (adjusted hazard ratio = 29.8, 95% CI: 16.5-53.6). Finally, patients who met the criterion based on at least one HBV diagnosis were 38 times more likely to develop HCC than matched comparison patients (adjusted hazard ratio = 37.8, 95% CI: 25.9-55.1). The magnitude of the relative increase in HCC risk seen using different criteria used to define HBV infection indicate that these automated data algorithms can identify patients with chronic HBV infection.
Authors: Ulcickas Yood M; Quesenberry CP Jr; Guo D; Wells K; Shan J; Sanders L; Skovron ML; Iloeje U; Caldwell C; Manos MM
J Viral Hepat. 2008 Jan;15(1):28-36. Epub 2007 Sep 24.
Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study
BACKGROUND: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors (‘statins’) in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients. METHODS: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy’s Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models. RESULTS: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints. CONCLUSIONS: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.
Authors: Avins AL; Manos MM; Ackerson L; Zhao W; Murphy R; Levin TR; Watson DJ; Hwang PM; Replogle A; Levine JG
Drug Saf. 2008;31(4):325-34.
Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients
OBJECTIVE: To determine which antibiotics increase or decrease the risk of Clostridium difficile-associated diarrhea (CDAD). DESIGN: Retrospective case-control study. SETTING: Nonprofit, integrated healthcare delivery system in Northern California. PATIENTS: Study participants included patients with cases of hospital-acquired CDAD that occurred during the period from 1999 through 2005 (n=1,142) and control patients (n= 3,351) matched for facility, calendar quarter during which hospitalization occurred, diagnosis related group for the index hospitalization, and length of hospital stay. All case and control patients had received antibiotics in the 60 days before the index date. For each antibiotic, the risk of CDAD was examined in relation to whether the patient received the antibiotic, after adjustment for use of other antibiotics, demographic characteristics, selected health conditions, and use of healthcare services. RESULTS: The following antibiotics were associated with a significantly increased risk of acquiring CDAD: imipenem-cilastin (odds ratio [OR], 2.77), clindamycin (OR, 2.31), cefuroxime (OR, 2.16), moxifloxacin (OR, 1.88), ceftazidime (OR, 1.82), cefpodoxime (OR, 1.58), ceftizoxime (OR, 1.57), and ceftriaxone (OR, 1.49). Metronidazole and doxycycline were associated with a significantly reduced risk of CDAD (OR for metronidazole, 0.67; OR for doxycycline, 0.41). Other factors associated with an increased risk of CDAD were older age, longer hospital stays, use of proton pump inhibitors, prior gastrointestinal disease, and prior infection (not including C. difficile infection.) CONCLUSIONS: Some antibiotics appear to increase the risk of acquiring CDAD, notably clindamycin, third-generation cephalosporins, and carbapenems, whereas metronidazole and doxycycline appear to be protective, compared with other antibiotics.
Authors: Baxter R; Ray GT; Fireman BH
Infect Control Hosp Epidemiol. 2008 Jan;29(1):44-50.
Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study
BACKGROUND: Although studies have reported a high prevalence of end-stage renal disease in human immunodeficiency virus (HIV)-infected individuals, little is known about moderate impairments in kidney function. Cystatin C measurement may be more sensitive than creatinine for detecting impaired kidney function in persons with HIV. METHODS: We evaluated kidney function in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort, a representative sample of 1008 HIV-infected persons and 290 controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study in the United States. RESULTS: Cystatin C level was elevated in HIV-infected individuals; the mean +/- SD cystatin C level was 0.92 +/- 0.22 mg/L in those infected with HIV and 0.76 +/- 0.15 mg/L in controls (P < .001). In contrast, both mean creatinine levels and estimated glomerular filtration rates appeared similar in HIV-infected individuals and controls (0.87 +/- 0.21 vs 0.85 +/- 0.19 mg/dL [to convert to micromoles per liter, multiply by 88.4] [P = .35] and 110 +/- 26 vs 106 +/- 23 mL/min/1.73 m(2) [P = .06], respectively). Persons with HIV infection were more likely to have a cystatin C level greater than 1.0 mg/L (OR, 9.8; 95% confidence interval, 4.4-22.0 [P <.001]), a threshold demonstrated to be associated with increased risk for death and cardiovascular and kidney disease. Among participants with HIV, potentially modifiable risk factors for kidney disease, hypertension, and low high-density lipoprotein concentration were associated with a higher cystatin C level, as were lower CD4 lymphocyte count and coinfection with hepatitis C virus (all P < .001). CONCLUSIONS: Individuals infected with HIV had substantially worse kidney function when measured by cystatin C level compared with HIV-negative controls, whereas mean creatinine levels and estimated glomerular filtration rates were similar. Cystatin C measurement could be a useful clinical tool to identify HIV-infected persons at increased risk for kidney and cardiovascular disease.
Authors: Odden MC; Scherzer R; Bacchetti P; Szczech LA; Sidney S; Grunfeld C; Shlipak MG
Arch Intern Med. 2007 Nov 12;167(20):2213-9.
Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study
Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.
Authors: Grunfeld C; Rimland D; Gibert CL; Powderly WG; Sidney S; Shlipak MG; Bacchetti P; Scherzer R; Haffner S; Heymsfield SB
J Acquir Immune Defic Syndr. 2007 Nov 1;46(3):283-90.
Surveillance for invasive pneumococcal disease during 2000-2005 in a population of children who received 7-valent pneumococcal conjugate vaccine
OBJECTIVES: To assess the incidence of invasive pneumococcal disease (IPD) in all children younger than 5 years of age in the Northern California Kaiser Permanente (NCKP) health care system during a 5-year surveillance period (2000-2005) after the introduction in April 2000 of routine use of 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: This was a laboratory-based surveillance study of all children younger than 5 years of age in the NCKP health care system from April 2000 to March 2005. The comparison group was all children younger than 5 years of age in the NCKP health care system from April 1996 to March 2000. Data obtained from clinical databases included microbiologic identification and susceptibility testing; serotyping of isolates; immunization records; and IPD diagnoses for inpatients and outpatients. IPD was defined as a positive culture of Streptococcus pneumoniae from a normally sterile body site. RESULTS: For all serotypes, the mean annual incidence of IPD during the postlicensure surveillance period was 15.3 cases/100,000 person-years (10(5) p-y) compared with 62.5 cases/10(5) p-y in the prelicensure years of 1996-2000. The average incidence of IPD caused by vaccine serotypes was reduced from 50.1 cases/10(5) p-y during the prelicensure years to 4.9 cases/10(5) p-y during the postlicensure period. The average incidences of IPD caused by cross-reactive and by nonvaccine serotypes were 5.8 and 5.3 cases/10(5) p-y, respectively, during the prelicensure years and 2.5 and 6.2 cases/10(5) p-y, respectively, during the postlicensure period. Of the 131 IPD cases observed during the postlicensure surveillance period, bacteremia (50.4%) and pneumonia (31.3%) were the most common diagnoses. During the 5-year postlicensure surveillance period, only 3 subjects who were identified to be fully vaccinated for age with PCV7 (3 doses by 7 months of age or 4 doses by 18 months of age) developed vaccine-serotype IPD. CONCLUSION: The incidence of IPD has significantly decreased in a large population of children after the introduction of PCV7. Vaccine-type IPD was rare in patients who received full 4-dose immunization with PCV7. There is no clear evidence of a significant increase in nonvaccine-serotype IPD. Introduction of a 4-dose infant schedule of PCV7 into this population has resulted in a marked and sustained reduction of IPD in children.
Authors: Black S; France EK; Isaacman D; Bracken L; Lewis E; Hansen J; Fireman B; Austrian R; Graepel J; Gray S; Klein NP
Pediatr Infect Dis J. 2007 Sep;26(9):771-7.
AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era
PURPOSE OF REVIEW: Effective antiretroviral therapy use has resulted in a large number of older individuals living with HIV. Recent literature is reviewed with respect to the incidence and risk factors for cancer in HIV patients. RECENT FINDINGS: Previous studies have demonstrated substantial declines in AIDS-defining malignancies in the era of antiretroviral therapy, with clear links to better immune function. Increases in non-AIDS-defining malignancies such as Hodgkin’s disease, skin, lung, anal, and kidney cancers have been noted by some but not all authors. Certain non-AIDS-defining malignancies may be related to immunodeficiency, although data are conflicting. Recent studies have indicated that confounding by traditional risk factors, including cigarette use, may account for some of the increased risk of lung and other cancers in HIV patients. SUMMARY: Non-AIDS-defining malignancies account for more morbidity and mortality than AIDS-defining malignancies in the antiretroviral therapy era. Traditional risk factors play a significant role in the increased risk of non-AIDS-defining malignancies for HIV-infected individuals, but do not entirely explain the excess cancer risk. Unanswered questions remain including the relationship of immunodeficiency and the risk of site-specific non-AIDS-defining malignancies, and the effect of antiretroviral therapy duration and drug class on cancer risk.
Authors: Silverberg MJ; Abrams DI
Curr Opin Oncol. 2007 Sep;19(5):446-51.
Incidence of non-Hodgkin’s lymphoma among individuals with chronic hepatitis B virus infection
Although hepatitis C virus (HCV) infection has been shown to be associated with development of non-Hodgkin’s lymphoma (NHL), few studies have investigated the association between chronic HBV infection and NHL. The purpose of this study was to compare the incidence of NHL between patients with and without chronic hepatitis B virus (HBV) infection. Using automated laboratory result and clinical data from two United States health systems, we identified individuals with chronic HBV infection from January 1, 1995 through December 31, 2001. Using each health system’s population-based tumor registry, we identified all cases of NHL diagnosed through December 31, 2002. We excluded any individual with a history of NHL or human immunodeficiency virus (HIV). We fit Cox proportional hazards models to calculate hazard ratios comparing the incidence of NHL between chronic HBV-infected patients (N = 3,888) and patients without HBV (N = 205,203) drawn from the source populations. We identified 8 NHL cases in the chronic HBV infection cohort and 111 cases in the comparison cohort. Patients with chronic HBV infection were 2.8 times more likely to develop NHL than matched comparison patients (adjusted hazard ratio = 2.80, 95% confidence interval = 1.16-6.75), after controlling for age, race, sex, income, Charlson comorbidity index, study site, and HCV infection. CONCLUSION: chronic HBV-infected patients were nearly 3 times more likely to develop NHL than comparison patients.
Authors: Ulcickas Yood M; Quesenberry CP Jr; Guo D; Caldwell C; Wells K; Shan J; Sanders L; Skovron ML; Iloeje U; Manos MM
Hepatology. 2007 Jul;46(1):107-12.
Microalbuminuria in HIV infection
OBJECTIVE: Microalbuminuria is associated with increased risk of cardiovascular disease and mortality. The objective of the study was to evaluate if HIV infection was an independent risk factor for microalbuminuria. DESIGN: Cross sectional. METHODS: The relationship between HIV infection and microalbuminuria was assessed using subjects enrolled in the study of Fat Redistribution and Metabolic Change in HIV Infection, which consists of HIV-positive and control men and women. Participants with proteinuria (dipstick >or= 1+) were excluded. RESULTS: Microalbuminuria (urinary albumin/creatinine ratio, ACR > 30 mg/g) was present in 11% of HIV infected, and 2% of control participants (P < 0.001); a fivefold odds after multivariate adjustment (odds ratio, 5.11; 95% confidence interval, 1.97-13.31; P=0.0008). Several cardiovascular risk factors were associated with higher ACR in HIV participants: insulin resistance (HOMA > 4; 32%, P < 0.0001), systolic blood pressure (21%, P = 0.01 for 120-140 versus < 120 mmHg, and 43%, P = 0.06 for > 140 versus < 120 mmHg), and family history of hypertension (17%, P = 0.03). Higher CD4 cell count was associated with lower albumin/creatinine ratio (-24%, P = 0.009 for 200-400 versus < 200 cells/ml and -26%, P = 0.005 for > 400 versus < 200 cells/ml). CONCLUSION: HIV infection had a strong and independent association with microalbuminuria, the severity of which was predicted by markers of insulin resistance, hypertension, and advanced HIV infection. These associations warrant further investigation, as the increased prevalence of microalbuminuria in HIV infection may be a harbinger of future risk of cardiovascular and kidney diseases.
Authors: Szczech LA; Grunfeld C; Scherzer R; Canchola JA; van der Horst C; Sidney S; Wohl D; Shlipak MG
AIDS. 2007 May 11;21(8):1003-9.
Effect of clinical pharmacists on utilization of and clinical response to antiretroviral therapy
OBJECTIVE: To determine the association of clinical pharmacists with health outcomes and utilization measures among HIV-infected patients. METHODS: Observational study of 1571 HIV-infected patients prescribed their initial highly active antiretroviral therapy (HAART) regimen in clinics with and without a clinical pharmacist. Outcomes analyzed were changes in plasma HIV RNA level, CD4 T-cell counts, and service utilization (hospital days, emergency department visits, and office visits) over 24 months based on exposure to a clinical pharmacist. RESULTS: Patients exposed to a clinical pharmacist tended to be more likely to achieve an HIV RNA level <500 copies/mL at 12 months (adjusted odds ratio [OR] = 2.01, 95% confidence interval [CI]: 0.92 to 4.37). At 24 months, however, results depended on the provider panel size; the ORs for panel sizes < or =50 and >50 HIV-infected patients were 1.67 (95% CI: 0.60 to 4.62) and 0.97 (95% CI: 0.39 to 2.41), respectively. CD4 T-cell counts were modestly but nonsignificantly higher for the patients exposed to a clinical pharmacist. Utilization also depended on the provider panel size; pharmacist exposure was associated with 64% (95% CI: 30% to 108%) and 9% (95% CI: -11% to 33%) increases in total hospital days for panel sizes < or =50 and >50 HIV-infected patients, respectively. Pharmacist exposure was also associated with a 19% (95% CI: -13% to -24%) decrease in office visits for panel sizes < or =50 HIV-infected patients, with minimal effect for larger panel sizes. CONCLUSION: Clinical pharmacists seem to contribute to lower office visit rates in antiretroviral-naive patients initiating HAART.
Authors: Horberg MA; Hurley LB; Silverberg MJ; Kinsman CJ; Quesenberry CP
J Acquir Immune Defic Syndr. 2007 Apr 15;44(5):531-9.
Older age and the response to and tolerability of antiretroviral therapy
BACKGROUND: The unique health needs of a growing older adult population infected with human immunodeficiency virus (HIV) require study, especially in terms of the response to and tolerability of highly active antiretroviral therapy (HAART). METHODS: Changes in HIV clinical markers after HAART initiation were compared among 2259 patients aged 18 to 39 years (reference group), 1834 patients aged 40 to 49 years, and 997 patients 50 years or older enrolled in an integrated health care system. RESULTS: Patients 50 years or older were more likely to achieve HIV RNA levels of less than 500 copies/mL within 1 year of HAART initiation (hazard ratio [HR], 1.15; P =.009), but adjustment for adherence attenuated this finding (HR, 1.03; P =.59). Subsequent HIV RNA level rebound (to > or =1000 copies/mL) was less likely among patients aged 40 to 49 years (HR, 0.81; P =.01), which persisted after adjustment for adherence (HR, 0.79; P =.004). In year 1 of HAART, younger patients had larger CD4 T-cell count increases (131.8, 121.3, and 111.8 CD4 T cells/microL per year among patients aged 18-39, 40-49, and > or =50 years, respectively; P =.046). In years 2 through 6, older patients had larger CD4 T-cell count increases (4.5, 11.6, and 9.7 CD4 T cells/microL per year among patients aged 18-39, 40-49, and > or =50 years, respectively; P =.04). After adjustment for adherence, age differences in CD4 T-cell count changes remained in year 1 (P =.02) but not in years 2 through 6 (P =.08). Other factors, including comorbidities, had no effect on study results. Metabolic (glucose and lipids), hematologic (absolute neutrophils and hemoglobin), and renal (creatinine) abnormalities were more likely among older patients. CONCLUSION: Despite a higher risk of adverse events, patients 50 years or older sustained high therapy adherence to maintain improved virological outcomes and to compensate for their early blunted CD4 T-cell count response compared with younger patients.
Authors: Silverberg MJ; Leyden W; Horberg MA; DeLorenze GN; Klein D; Quesenberry CP Jr
Arch Intern Med. 2007 Apr 9;167(7):684-91.
A role for genetics in the immune response to the varicella vaccine
BACKGROUND: A wide range in antibody titers has been found after immunization with the varicella vaccine, although the basis for these differences has not been described. METHODS: To evaluate the contribution of a genetic component in the immune response to the varicella vaccine, concordance for six-week postimmunization antibody titers was evaluated among 248 biologic siblings who participated in varicella vaccine clinical trials by comparing all pairs of siblings (151 pairs) to all possible unrelated, nonsibling pairs created from within this same cohort (30,477 pairs). RESULTS: Postimmunization antibody titers after 1 varicella vaccine dose were within the range observed historically among healthy vaccinees, with 85.4% of subjects having antibody responses greater than the approximate correlate of protection of 5 gpELISA units. Postimmunization antibody titers within sibling pairs clustered together more than or less than 10 gpELISA units when compared with within nonsibling pairs (P < 0.0001). Postimmunization titers within sibling pairs were also quantitatively closer together than were those within unrelated, nonsibling pairs (P = 0.022). The age-adjusted intraclass correlation coefficient indicated that the heritability of the varicella vaccine immune response is 45% (95% confidence interval of 15-75%). CONCLUSIONS: Similarities in siblings' response to varicella vaccine are supportive of the hypothesis that genetic factors play a role in the antibody response to the varicella vaccine.
Authors: Klein NP; Fireman B; Enright A; Ray P; Black S; Dekker CL; Clinical Immunization Safety Assessment Network
Pediatr Infect Dis J. 2007 Apr;26(4):300-5.
Respiratory distress and transient tachypnea of the newborn
Authors: Klein N
In: Zaoutis LB, Chiang VW, editors. Comprehensive pediatric hospital medicine. Philadelphia: Mosby/Elsevier, 2007.
Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs
BACKGROUND: A World Health Organization (WHO) working group in 2001 developed a method for standardizing interpretation of chest radiographs in children for epidemiologic purposes. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method. METHODS: Seven-valent pneumococcal conjugate vaccine was evaluated in a randomized, controlled study including 37,868 infants. Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading. There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers (A and B); discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists. RESULTS: Of the 2841 radiographs, 2446 were available for scanning and were reviewed using WHO-defined descriptive categories. Two hundred fifty of the 2446 radiographs were read as positive by both readers. An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the reviewers. The concordance rate between the 2 reviewers was 250 of 521 (48%). Of the 271 discordant radiographs, 45 of 129 (34.9%) of reader A and 66 of 142 (46.5%) for reader B were finalized as positive by the adjudicating panel. Overall, 361 radiographs were finalized as positive (12.7%). With these 361 images as the standard, the sensitivity and specificity of reader A were 82% and 97%, respectively, and for reader B, 88% and 97%, respectively. Kappa between the 2 readers was 0.58. Of 25 control radiographs read as positive by both A and B, 80% were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel. Using original readings by point-of-care radiologists, efficacy against first episode of radiograph confirmed pneumonia was 17.7% (95% confidence interval [CI] = 4.8-28.9%) in intent-to-treat and 20.5% (95% CI = 4.4-34%) in per protocol. Using the WHO method, the efficacy against first episode of radiograph confirmed pneumonia adjusting for age, gender and year of vaccination of 25.5% (95% CI = 6.5-40.7%, P = 0.011) for intent-to-treat and 30.3% (95% CI = 10.7-45.7%, P = 0.0043) for per protocol. CONCLUSION: Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity.
Authors: Hansen J; Black S; Shinefield H; Cherian T; Benson J; Fireman B; Lewis E; Ray P; Lee J
Pediatr Infect Dis J. 2006 Sep;25(9):779-81.
Cost-effectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects
BACKGROUND: Pneumococcal conjugate vaccine (PCV) has been in routine use in the United States for 5 years. Prior U.S. cost-effectiveness analyses have not taken into account the effect of the vaccine on nonvaccinated persons. METHODS: We revised a previously published model to simulate the effects of PCV on children vaccinated between 2000 and 2004, and to incorporate the effect of the vaccine in reducing invasive pneumococcal disease (IPD) in nonvaccinated persons during those years. Data from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention (2000-2004) were used to estimate changes in the burden of IPD in nonvaccinated adults since the introduction of PCV (compared with the baseline years 1997-1999). Results combined the simulated effects of the vaccine on the vaccinated and nonvaccinated populations. RESULTS: Before incorporating herd effects in the model, the PCV was estimated to have averted 38,000 cases of IPD during its first 5 years of use at a cost of dollar 112,000 per life-year saved. After incorporating the reductions in IPD for nonvaccinated individuals, the vaccine averted 109,000 cases of IPD at a cost of dollar 7500 per life-year saved. When the herd effect was assumed to be half that of the base case, the cost per life-year saved was dollar 18,000. CONCLUSIONS: IPD herd effects in the nonvaccinated population substantially reduce the cost, and substantially improve the cost-effectiveness, of PCV. The cost-effectiveness of PCV in actual use has been more favorable than predicted by estimates created before the vaccine was licensed.
Authors: Ray GT; Whitney CG; Fireman BH; Ciuryla V; Black SB
Pediatr Infect Dis J. 2006 Jun;25(6):494-501.
Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up
OBJECTIVE: To determine whether serum titers of anti-Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS). METHODS: Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with age-matched and sex-matched controls. RESULTS: The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter. CONCLUSION: The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.
Authors: DeLorenze GN; Munger KL; Lennette ET; Orentreich N; Vogelman JH; Ascherio A
Arch Neurol. 2006 Jun;63(6):839-44. Epub 2006 Apr 10.
The study of fat redistribution and metabolic change in HIV infection (FRAM): methods, design, and sample characteristics
The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.
Authors: Tien PC; Benson C; Zolopa AR; Sidney S; Osmond D; Grunfeld C
Am J Epidemiol. 2006 May 1;163(9):860-9. Epub 2006 Mar 8.
Impact of the use of heptavalent pneumococcal conjugate vaccine on disease epidemiology in children and adults
Pneumococcal conjugate vaccine was introduced for routine use in infants and toddlers in the United States in March 2000. We report on the impact of the introduction of this vaccine on disease epidemiology in young children as well as secondary effects due to herd immunity in unvaccinated children and adults. As of March 2003, 157,471 children had received one or more doses of PNCV7, but only 24% of those less than two years of age received all four doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children less than one year of age compared with an incidence ranging between 51.5 and 98.2 cases/100,000 person years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children less than five years of age. There was no evidence of any concomittant increase in pneumococcal disease caused by non-vaccine serotypes. High-level resistance of pneumococci to penicillin fell from a peak of 15% in year 2000 to 5% in the first half of 2003.
Authors: Black S; Shinefield H; Baxter R; Austrian R; Elvin L; Hansen J; Lewis E; Fireman B
Vaccine. 2006 Apr 12;24 Suppl 2:S2-79-80.
Serological detection of human papillomavirus type 16 infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women
Serial measurement of antibodies has not been used to provide evidence of active viral replication of human papillomavirus (HPV). Serum specimens from sequential study visits contributed by 642 human immunodeficiency virus (HIV)-positive and 116 HIV-negative participants enrolled in the Women’s Interagency HIV Study were used to detect significant rises in HPV type 16 (HPV-16) antibody levels. Factors associated with a significant rise were identified using multivariable logistic regression models with generalized estimating equations. Among HIV-positive women, 8.3% of 1,997 pairs showed antibody rises, compared to 6.1% of 361 pairs among HIV-negative women (P = 0.191). For HIV-positive women, rises were associated with current (odds ratio [OR], 23.4; P < 0.001) or past (OR, 8.9; P < 0.001) HPV-16 infection relative to never being HPV-16 infected and with CD4+ cell counts (OR per 100-cell increase, 0.8; P < 0.001) but not with sexual behavior. For HIV-negative women, rises were associated with past (OR, 10.9; P = 0.033) HPV-16 infection relative to no HPV-16, current cigarette smoking (OR, 5.0; P = 0.029) relative to no smoking history, and having 6 to 10 lifetime sexual partners compared to 0 to 5 partners (OR, 9.9; P = 0.036). Serial measurement of HPV-16 serum antibodies is a useful tool for identifying active HPV-16 viral replication. Rises among HIV-positive women may more often result from reactivation of a latent HPV infection in the context of HIV-induced immunosuppression, while rises among HIV-negative women may more often result from reinfection with HPV.
Authors: Silverberg MJ; Schneider MF; Silver B; Anastos KM; Burk RD; Minkoff H; Palefsky J; Levine AM; Viscidi RP
Clin Vaccine Immunol. 2006 Apr;13(4):511-9.
Medication error in the care of HIV/AIDS patients: electronic surveillance, confirmation, and adverse events
BACKGROUND: Medication error occurring during the care of HIV-infected patients may lead to treatment failure, drug toxicity, or even death. OBJECTIVE: The objective of this study was to ascertain and confirm 5 categories of medication error in the care of HIV-infected patients. RESEARCH DESIGN: This study was a retrospective study to describe the occurrence of preventable medication error and to determine if adverse events were associated with confirmed errors. A roster of medications for each category of potential errors was created. Computerized pharmacy records were scanned for all dispensing of these medications. Potential errors were confirmed by medical records abstraction. For the incorrect dosing, coadministration of contraindicated medications, and antiretroviral monotherapy error categories, random samples were chart reviewed for confirmation. For the remaining 2 error categories, all potential errors were chart reviewed. The positive predictive value (PPV) of potential errors, the incidence of confirmed error among all new prescription orders filled and the patient characteristics predicting likelihood of error confirmation were estimated for each error category. SUBJECTS: The study sample involved 5473 HIV-infected patients of the Kaiser Permanente Northern California (KPNC) health plan. RESULTS: Among the 5 error categories, PPVs ranged from a high of 80% for coadministration of contraindicated medications to <1% for antiretroviral monotherapy. Incidence of confirmed errors was 9.80 errors per 1000 new prescriptions dispensed for incorrect dosing, 9.51 errors per 1000 for contraindicated medications, and <1.00 for all other categories. Adverse events associated with confirmed errors were observed only in the contraindicated medications error category. The likelihood of a contraindicated medications error was significantly increased among patients >or=50 years of age and decreased among black patients. CONCLUSIONS: Use of electronic pharmacy records to ascertain true medication errors appears most reliable when conducting surveillance for contraindicated medications errors and less reliable for other error categories. Lack of confirmation is likely the result of patients’ lack of adherence to drug regimens or providers’ intentional deviation from accepted prescribing guidelines. Only confirmed contraindicated medications errors appear to be linked to adverse events.
Authors: DeLorenze GN; Follansbee SF; Nguyen DP; Klein DB; Horberg M; Quesenberry CP Jr; Blick NT; Tsai AL
Med Care. 2005 Sep;43(9 Suppl):III63-8.
Hospital-level rates of fluoroquinolone use and the risk of hospital-acquired infection with ciprofloxacin-nonsusceptible Pseudomonas aeruginosa
BACKGROUND: In recent years, Pseudomonas aeruginosa has become increasingly resistant to fluoroquinolones, and fluoroquinolone use in the United States has also increased. Our objective was to determine whether higher hospital-level rates of use of ciprofloxacin, levofloxacin, and moxifloxacin antimicrobials were predictors that a higher proportion of P. aeruginosa isolates from hospital-acquired infections (hereafter, ‘hospital-acquired isolates’) would be nonsusceptible to ciprofloxacin. METHODS: We identified all hospital-acquired isolates from 14 hospitals in the Northern California Kaiser Permanente health care delivery system between 1998 and 2003 and determined their susceptibility to ciprofloxacin. For each facility, we determined the number of days of fluoroquinolone use per 1000 patient-days, by calendar quarter. We used a logistic regression model to analyze the data, with susceptibility status as the outcome variable. Hospital-level rates of use of the 3 fluoroquinolones were the predictors of interest; we adjusted for year, for use of nonquinolone antimicrobials, and for patient variables, including the number of days spent in the hospital in the prior year and fluoroquinolone use in the prior year. The model tested whether isolates from those facilities with higher rates of use of antimicrobials were more likely to be nonsusceptible to ciprofloxacin. RESULTS: Of 6099 isolates tested, 15% were not susceptible to ciprofloxacin. The nonsusceptibility rate increased from 9% to 20% between 1998 and 2003. Both the overall rate of use at the hospital and prior patient-specific use of ciprofloxacin, levofloxacin, and moxifloxacin were found to be independent predictors that a subsequent P. aeruginosa isolate would be nonsusceptible to ciprofloxacin. CONCLUSIONS: Higher hospital-level rates of use of ciprofloxacin, levofloxacin, and moxifloxacin are each associated with an increased proportion of hospital-acquired P. aeruginosa isolates being nonsusceptible to ciprofloxacin.
Authors: Ray GT; Baxter R; DeLorenze GN
Clin Infect Dis. 2005 Aug 15;41(4):441-9. Epub 2005 Jul 12.
History of chickenpox and shingles and prevalence of antibodies to varicella-zoster virus and three other herpes viruses among adults with glioma and controls
Whether viruses or immunologic factors might cause or prevent human brain cancer is of interest. Statistically significant inverse associations of adult glioma with history of chickenpox and immunoglobulin G antibodies to varicella-zoster virus have been reported. The authors evaluate associations of immunoglobulin G antibodies to varicella-zoster virus and three other herpesviruses among 229 adults with glioma and 289 controls in the San Francisco Bay Area Adult Glioma Study (1997-2000). Cases were less likely than controls to report a history of chickenpox (for self-reported cases vs. controls: the age-, gender-, and ethnicity-adjusted odds ratio = 0.59, 95% confidence interval: 0.40, 0.86), and they also had lower levels of immunoglobulin G to varicella-zoster virus (for being in the highest quartile vs. the lowest quartile: the age-, gender-, and ethnicity-adjusted odds ratio = 0.41, 95% confidence interval: 0.24, 0.70). The inverse association with anti-varicella-zoster virus immunoglobulin G was most marked for glioblastoma multiforme cases versus controls and was only somewhat attenuated by excluding subjects taking high-dose steroids and other medications. Cases and controls did not differ notably for positivity to three other herpesviruses, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Cohort studies may help to clarify the nature of the association between immunity to and/or clinical manifestations of varicella-zoster virus and glioblastoma.
Authors: Wrensch M; Weinberg A; Wiencke J; Miike R; Sison J; Wiemels J; Barger G; DeLorenze G; Aldape K; Kelsey K
Am J Epidemiol. 2005 May 15;161(10):929-38.
Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants
The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends influenza vaccination for women who will be in the second or third trimester of pregnancy during the influenza season. We analyzed hospital admissions with principal diagnoses of influenza or pneumonia and influenza-like illness (ILI) outpatient visits to study the effectiveness of influenza vaccine during pregnancy in protecting women and infants from influenza-related morbidity. Estimates of influenza vaccine effectiveness across five flu seasons (Fall 1997 to Spring 2002) were calculated using Cox proportional hazards models for women and infant study populations in Kaiser Permanente Northern California. Outpatient utilization outcomes included physician visits with a diagnosis of upper respiratory infection, pharyngitis, otitis media, asthma, bronchial asthma, viral infection, pneumonia, fever, cough, or wheezing associated with respiratory illness. Inpatient outcomes included hospitalizations with principal diagnoses of influenza or pneumonia. Women who received influenza vaccine during pregnancy had the same risk for ILI visits compared with unvaccinated women, adjusting for women’s age and week of delivery. When asthma visits were excluded from the outcome measure, we also found no difference in the risk of outpatient visits for vaccinated and unvaccinated women. Hospital admissions for influenza or pneumonia for women in the study population were quite rare and no women died of respiratory illness during pregnancy. Infants born to women who received influenza vaccination had the same risks for influenza or pneumonia admissions compared with infants born to unvaccinated women, adjusting for infant’s gender, gestational age, week of birth, and birth facility. Maternal influenza vaccination was also not a significant determinant of risk of ILI (excluding otitis media) outpatient visits for infants, nor did it significantly affect the risk of otitis media visits. Influenza vaccination during pregnancy did not significantly affect the risk of cesarean section, adjusting for the woman’s age. It also did not affect the risk of preterm delivery. Although the immunogenicity of influenza vaccination in pregnancy in mother and infant has been well documented, in this study, we were unable to demonstrate the effectiveness of influenza vaccination with data for hospital admissions and physician visits. One possible interpretation of these findings is that typical influenza surveillance measures based on utilization data are not reliable in distinguishing influenza from other respiratory illness. Hospitalizations for respiratory illness were uncommon in both vaccinees and nonvaccinees.
Authors: Black SB; Shinefield HR; France EK; Fireman BH; Platt ST; Shay D; Vaccine Safety DW
Am J Perinatol. 2004 Aug;21(6):333-9.
Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente
OBJECTIVE: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. METHODS: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. RESULTS: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those <2 years of age received all 4 doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children <1 year of age compared with an incidence ranging between 51.5 and 98.2 cases per 100,000 person-years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children <5 years of age. There was no evidence of any concomitant increase in pneumococcal disease caused by nonvaccine serotypes. High level resistance of pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half of 2003. Similar trends were seen for other antibiotics. CONCLUSION: The PNCV7 vaccine is highly effective in reducing the burden of pneumococcal disease in children <5 years of age, and there is evidence of a herd effect as well as a decrease in the antibiotic resistant in strains causing disease. For invasive disease, there is no current evidence of serotype replacement.
Authors: Black S; Shinefield H; Baxter R; Austrian R; Bracken L; Hansen J; Lewis E; Fireman B
Pediatr Infect Dis J. 2004 Jun;23(6):485-9.
A prospective study of Chlamydia pneumoniae infection and risk of MS in two US cohorts
BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent in multiple sclerosis (MS). However, previous studies were cross-sectional and could not assess whether Cpn infection preceded the onset of MS. METHODS: The authors conducted a prospective nested case-control study among 3 million US Army personnel and 121,466 members of the Kaiser Permanente Medical Care Program (KPMCP) cohort. Serum samples collected prior to onset of MS symptoms were available for 83 MS cases in the Army and 46 in the KPMCP cohort. Two controls were matched to each case on age, sex, and date of blood collection. Microimmunofluorescence was used to measure serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers to Cpn; IgG titers or 1:16 were considered positive for past Cpn infection. RESULTS: Seropositivity for Cpn was not significantly associated with risk of MS in either cohort (Army: OR = 1.0; 95% CI 0.6, 1.8; KPMCP: OR = 1.5; 95% CI 0.7, 3.1) or in the pooled analysis (OR = 1.2; 95% CI 0.8, 1.9). Serum levels of anti-Cpn IgG antibody were also not associated with an increased risk of MS in the Army (OR for a fourfold difference in antibody titers = 0.9; 95% CI 0.7, 1.2) or in the pooled analysis (OR = 1.2; 95% CI 0.9, 1.4), but a significant increase in risk was seen in the KPMCP cohort (OR = 1.7; 95% CI 1.2, 2.5). The difference between these results in the Army and the KPMCP cohort was significant (p = 0.01). CONCLUSIONS: Neither Cpn seropositivity nor serum anti-Cpn IgG antibody titers predicted risk of developing MS. However, due to the heterogeneity of results between cohorts, we cannot exclude the possibility that infection with Cpn may modify the risk of MS.
Authors: Munger KL; DeLorenze GN; Levin LI; Rubertone MV; Vogelman JH; Peck CA; Peeling RW; Orentreich N; Ascherio A
Neurology. 2004 May 25;62(10):1799-803.
Pneumococcal conjugate vaccine in children
Authors: Davis RL; Fireman B; Shinefield HR
N Engl J Med. 2004 Jan 1;350(1):84-5; author reply 84-5.
Comparison between prototype hybrid capture 3 and hybrid capture 2 human papillomavirus DNA assays for detection of high-grade cervical intraepithelial neoplasia and cancer
We compared the performance of a prototype version of the Hybrid Capture 3 (HC3) human papillomavirus (HPV) DNA assay to the current generation Hybrid Capture 2 (HC2) assay, both of which target 13 oncogenic HPV types, for the detection of cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) with cervicovaginal lavage specimens collected at enrollment into a 10-year cohort study at Kaiser Permanente (Portland, Oreg.). HC3 results for a risk-stratified sample (n = 4,364) were compared to HC2 results for the entire cohort (n = 20,810) with receiver operating characteristics curves, and the optimal cut points for both tests (relative light units [RLU]/positive control [PC]) for the detection of CIN3+ were determined. Specimens were also tested for HPV16 and HPV18 with separate HC3 type-specific probes. The optimal cut point for detecting CIN3+ was 1.0 RLU/PC for HC2, as previously shown, and was 0.6 RLU/PC for HC3. At the optimal cut points, HC3 and HC2 had similar screening performance characteristics for CIN3+ diagnosed at the enrollment visit. In analyses that included cases CIN3+ at enrollment and those diagnosed during early follow-up, HC3 had nonsignificantly higher sensitivity and equal specificity for the detection of CIN3+ compared to HC2; this increase in sensitivity was primarily the result of increased detection of CIN3+ in women who were 30 years of age or older and were cytologically negative (P = 0.006). We also compared the performance of the hybrid capture tests to MY09/11 L1 consensus primer PCR results (n = 1,247). HC3 was less likely than HC2 to test positive for specimens that tested positive by PCR for any untargeted types (P < 0.001). HC3 was less likely than HC2 to test positive for untargeted PCR-detected single infections with HPV53 (P = 0.001) and HPV66 (P = 0.01). There was good agreement between test positivity by PCR and by single type-specific HC3 probes for HPV16 (kappa = 0.76; 95% confidence interval [CI] = 0.71 to 0.82) and for HPV18 (kappa = 0.73; 95% CI = 0.68 to 0.79). In conclusion, we suggest that HC3 (>/=0.6 RLU/PC) may be slightly more sensitive than and equally specific test as HC2 (>/=1.0 RLU/PC) for the detection of CIN3+ over the duration of typical screening intervals.
Authors: Castle PE; Lorincz AT; Scott DR; Sherman ME; Glass AG; Rush BB; Wacholder S; Burk RD; Manos MM; Schussler JE; Macomber P; Schiffman M
J Clin Microbiol. 2003 Sep;41(9):4022-30.
Review of medical encounters in the 5 years before a diagnosis of HIV-1 infection: implications for early detection
Early detection of HIV infection improves prognosis and reduces transmission, but 30%-40% of cases are diagnosed late. A comprehensive and systematic review of medical encounters before diagnosis has not been done. This study reviews 5 years of medical encounters before the diagnosis of HIV infection in members of a large managed care organization where access to care is reasonably good. Patient characteristics, HIV risk factors, and clinical events preceding diagnosis were examined and tested for association with late diagnosis (CD4 cell count of <200/microL at diagnosis). Of 440 HIV-infected patients, 62% had CD4 cell counts of <350/microL, 43% had CD4 cell counts of <200/microL, and 18% had CD4 cell counts of <50/microL at diagnosis. Twenty-six percent of all patients had risks documented >1 year before diagnosis. Only 22% of patients had one of eight clinical indicators suggested in the literature as reasons to test for HIV >1 year before diagnosis. In multiple logistic regression, older age, male sex, race, risk group, no prior HIV testing, physician-initiated testing, and having any of eight clinical indicators before diagnosis were each associated with late diagnosis (p Authors: Klein D; Hurley LB; Merrill D; Quesenberry CP Jr; Consortium for HIV/AIDS Interregional Research J Acquir Immune Defic Syndr. 2003 Feb 1;32(2):143-52.
Impact of the pneumococcal conjugate vaccine on otitis media
CONTEXT: The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for infants to protect against invasive disease, but its impact on otitis might also have public health importance. OBJECTIVE: To examine the impact of PCV on the incidence of otitis media, frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race, sex or season. DESIGN, SETTING AND PATIENTS: From 1995 to 1998, 37 868 children at Kaiser Permanente in Northern California were randomized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999. INTERVENTIONS: Children received a primary series at 2, 4 and 6 months of age and a booster at 12 to 15 months. MAIN OUTCOME MEASURES: Visits for otitis, frequent visits for otitis and tympanostomy tube procedures. Otitis was ascertained from diagnosis checklists routinely marked by physicians. RESULTS: Control children averaged 1.8 otitis visits per year. Children given PCV had fewer otitis visits than control children in every age group, sex, race and season examined. Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media (P < 0.0001). In children who completed the primary series per protocol, PCV reduced otitis visits by 7.8% [95% confidence interval (CI), 5.4 to 10.2%] and antibiotic prescriptions by 5.7% (CI 4.2 to 7.2%). Frequent otitis was reduced by amounts that increased with otitis frequency, from a 10% reduction in the risk of 3 visits to a 26% reduction in the risk of 10 visits within a 6-month period. Tube placements were reduced by 24% (CI 12 to 35%). CONCLUSION: In children followed up to 3.5 years, PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts.
Authors: Fireman B; Black SB; Shinefield HR; Lee J; Lewis E; Ray P
Pediatr Infect Dis J. 2003 Jan;22(1):10-6.
Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia
OBJECTIVE: To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children. METHODS: The heptavalent CRM(197) pneumococcal conjugate vaccine (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a randomized, double blind trial. Children were randomized to receive either the CRM(197) PCV (vaccine group) or the meningococcal type C CRM(197) conjugate vaccine (control group). The primary outcome of this trial was invasive pneumococcal disease. In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified, and the original reading of their radiographs by the radiologist was obtained from automated databases. Rates of clinically diagnosed pneumonia, of pneumonia with a radiograph obtained regardless of result, of pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups. In addition risk of disease pneumonia was evaluated by race and ethnicity. RESULTS: The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years. A radiograph was obtained in 61% of episodes, a positive radiograph in 21% and perihilar findings in an additional 5%. In per protocol follow-up of children given PCV, first episodes of all clinically diagnosed pneumonia were reduced by 4.3% [95% confidence interval (CI), -3.5, 11.5%, = 0.27], episodes with a radiograph were reduced by 9.8% (CI 0.1, 18.5%, < 0.05) and episodes with a positive radiograph were reduced by 20.5% (CI 4.4, 34.0, = 0.02). In the intent to treat analysis including all episodes after randomization, episodes with a positive radiograph were reduced by 17.7%, =.01). The greatest impact was in the first year of life with a 32.2% reduction and a 23.4% reduction in the first 2 years, but only a 9.1% reduction in children >2 years of age. Asians, blacks and Hispanics were at higher risk of pneumonia than were whites, but there was no evidence of ethnic variation in PCV effectiveness. Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group. CONCLUSION: The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children.
Authors: Black SB; Shinefield HR; Ling S; Hansen J; Fireman B; Spring D; Noyes J; Lewis E; Ray P; Lee J; Hackell J
Pediatr Infect Dis J. 2002 Sep;21(9):810-5.
Lack of association between receipt of conjugate haemophilus influenzae type B vaccine (HbOC) in infancy and risk of type 1 (juvenile onset) diabetes: long term follow-up of the HbOC efficacy trial cohort
We evaluated the effect of infant vaccination with HbOC Haemophilus influenzae type b (Hib) conjugate vaccine on the risk of onset of type 1 juvenile diabetes later in life by examining data from a large controlled prospective Phase III clinical efficacy trial conducted within Northern California Kaiser Permanente between 1988 and 1990. The overall study population included children who were offered the Hib conjugate vaccine (acceptors and refusers) as well as a cohort of children who were systemically excluded from the trial on the basis of their birth date. These children are now 10 to 12 years of age. We found no evidence that vaccination with Hib conjugate vaccine in infancy is associated with risk of diabetes later in life.
Authors: Black SB; Lewis E; Shinefield HR; Fireman B; Ray P; DeStefano F; Chen R
Pediatr Infect Dis J. 2002 Jun;21(6):568-9.
Observed costs and health care use of children in a randomized controlled trial of pneumococcal conjugate vaccine
BACKGROUND: Pneumococcal conjugate vaccine for infants has recently been found to be effective for prevention of meningitis, bacteremia, pneumonia and otitis media, but it is more costly than previously introduced vaccines. AIM: We sought to determine the savings in medical costs through 36 months of life attributable to the use of the vaccine in healthy infants in a large randomized trial. METHODS: We analyzed the actual medical costs of 36 471 children involved in a randomized trial of heptavalent pneumococcal conjugate vaccine conducted in the Northern California Kaiser Permanente Medical Care Program. The costs of the vaccine and vaccine administration were excluded. RESULTS: Compared with the control group, the vaccinated group experienced a 2% reduction in clinic related costs [$48; 95% confidence interval (CI), $10 to $83] and a nearly significant 14% reduction in outpatient hospitalization costs ($32; CI -$1 to $66). The savings in total medical costs were 1.2%, but this difference was not significant ($41; CI -$204 to $270). Inpatient hospital costs were highly variable and were responsible for the lack of precision in the difference in total cost. In a post hoc analysis that excluded hospital costs not believed to be potentially pneumococcal related, savings in medical costs were $78 and significant (CI $5 to $158). CONCLUSIONS: The pneumococcal conjugate vaccine reduced ambulatory care costs in children in the first 36 months of life, but without a larger trial, the magnitude of the savings in total medical costs is uncertain. These results indicate, however, that any medical cost savings that are associated with the vaccine are unlikely to be high enough to offset the cost of the vaccine at its current price.
Authors: Ray GT; Butler JC; Black SB; Shinefield HR; Fireman BH; Lieu TA
Pediatr Infect Dis J. 2002 May;21(5):361-5.
Efficacy, immunogenicity and safety of heptavalent pneumococcal conjugate vaccine in low birth weight and preterm infants
OBJECTIVE: To determine the efficacy, immunogenicity and safety of the heptavalent CRM197 pneumococcal conjugate vaccine (PCV) in low birth weight (LBW) and preterm (PT) infants against invasive pneumococcal disease caused by vaccine types. METHODS: In a randomized double blind trial of 37,868 infants given either PCV or meningococcal type C conjugate vaccine (MCV), 1756 infants <750 g <2500 g (LBW) and 4340 infants from 32 to <38 weeks old (PT) were identified. Risk of invasive pneumococcal disease in LBW and PT infants was compared with risk in normal birth weight (NBW) and full term (FT) infants. Local and systemic events observed within 48 h of recent vaccine were assessed by telephone interviews and similar comparisons made. Premature infant Emergency Department visits and hospitalization were also identified and compared with FT and NBW infants. RESULTS: Initiation of immunization and intervals between doses were similar for all groups. The risk ratio for invasive pneumococcal diseases for LBW infants compared with NBW infants was 2.6 (P = 0.03), and for PT compared with FT infants the risk ratio was 1.6 (P = 0.06). Vaccine efficacy for both groups was 100%. PCV was as immunogenic in LBW and PT as in NBW and FT infants. Fever and local events after PCV vaccination were similar when adjusted for clustering among multiple doses per child. When stratified for individual doses there was more redness and swelling for LBW infants and more swelling for PT infants after Dose 3. Isolated local and systemic reactions were more commonly seen with PCV than with MCV, a pattern similar to that in NBW and FT infants. Hospitalization rates were similar for PCV and MCV recipients. CONCLUSION: These data support the use of PCV in LBW infants and PT infants.
Authors: Shinefield H; Black S; Ray P; Fireman B; Schwalbe J; Lewis E
Pediatr Infect Dis J. 2002 Mar;21(3):182-6.
Sexual behavior, human papillomavirus type 16 (HPV 16) infection, and HPV 16 seropositivity
BACKGROUND: Sexual behaviors have been linked to seropositivity for human papillomavirus (HPV) but not with the magnitude of the seroreactivity. GOALS: The objective of this analysis was to examine the association of sexual behavior, cervical HPV 16 DNA positivity at enrollment (past) and at diagnosis (current), and other potential determinants with the likelihood and magnitude of HPV 16 seropositivity at diagnosis. STUDY DESIGN: With use of stored specimens from an incidence case-control study at Kaiser Permanente (Portland, OR), women were tested for seroreactivity to HPV 16 by enzyme-linked immunosorbent assay with virus-like particles at diagnosis and were tested for past and concurrent cervical HPV 16 DNA positivity with MY09/MY11 L1 consensus primer PCR. Questionnaire data were used to ascertain past sexual behavior. RESULTS: Increased lifetime number of sex partners (P(Trend) < 0.001), past HPV 16 DNA positivity (odds ratio = 6.9; 95% confidence interval = 1.5-31), and a current cytologic diagnosis (P(Trend) < 0.03) were independently associated with HPV 16 seropositivity. Among the seropositive, only lifetime number of sex partners (P(Trend) < 0.001) and past HPV 16 DNA positivity (P = 0.003) were independently associated with mean signal strength (optical density) in an age-adjusted analysis. Women negative for past and concurrent HPV 16 DNA had a significant trend of increasing optical densities associated with greater numbers of lifetime partners (P(Trend) < 0.001). Conversely, the mean signal strength for those women who were ever HPV 16 DNA-positive during the study did not depend on lifetime numbers of sex partners (P(Trend) = 0.36). CONCLUSIONS: HPV 16 seropositivity is a surrogate for past HPV 16 infection. Circulating levels of antibodies to HPV 16 may reflect recent HPV 16 infection or the frequency of past HPV 16 infection.
Authors: Castle PE; Shields T; Kirnbauer R; Manos MM; Burk RD; Glass AG; Scott DR; Sherman ME; Schiffman M
Sex Transm Dis. 2002 Mar;29(3):182-7.
Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis
BACKGROUND: In patients with decreased resistance to infection, Staphylococcus aureus is a major cause of bacteremia and its complications. The capsular polysaccharides are essential for the pathogenesis of and immunity to S. aureus infection and are targets for vaccines. METHODS: In a double-blind trial involving patients with end-stage renal disease who were receiving hemodialysis, we evaluated the safety, immunogenicity, and efficacy of a vaccine with S. aureus type 5 and 8 capsular polysaccharides conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A. Between April 1998 and August 1999, 1804 adult patients at 73 hemodialysis centers were randomly assigned to receive a single intramuscular injection of either vaccine or saline. IgG antibodies to S. aureus type 5 and 8 capsular polysaccharides were measured for up to two years, and episodes of S. aureus bacteremia were recorded. Efficacy was estimated by comparing the incidence of S. aureus bacteremia in the patients who received the vaccine with the incidence in the control patients. RESULTS: Reactions to the vaccine were generally mild to moderate, and most resolved within two days. The capsular polysaccharides elicited an antibody response of at least 80 microg per milliliter (the estimated minimal level conferring protection) in 80 percent of patients for type 5 and in 75 percent of patients for type 8. The efficacy during weeks 3 to 54 was only 26 percent (P=0.23). However, between weeks 3 and 40 after vaccination, S. aureus bacteremia developed in 11 of 892 patients in the vaccine group who could be evaluated for bacteremia, as compared with 26 of 906 patients in the control group (estimate of efficacy, 57 percent; 95 percent confidence interval, 10 to 81 percent; nominal P=0.02). CONCLUSIONS: In patients receiving hemodialysis, a conjugate vaccine can confer partial immunity against S. aureus bacteremia for approximately 40 weeks, after which protection wanes as antibody levels decrease.
Authors: Shinefield H; Fireman B; Naso R; et al.
N Engl J Med. 2002 Feb 14;346(7):491-6.
The burden of out-of-pocket payments for health care in Tbilisi, Republic of Georgia.
CONTEXT: In the 1990s, the Republic of Georgia instituted health care reforms to convert the centralized, state-operated health care system inherited from the Soviet Union to a decentralized, market-driven system of health care delivery. Under the new system, 87% of health care expenditures are financed through out-of-pocket payments at the point of service. OBJECTIVE: To describe the effects of health care reforms on access to care and health care financing among ill residents of Tbilisi, Georgia. DESIGN, SETTING, AND PARTICIPANTS: A probability-proportionate-to-size cluster survey conducted in 1999 of 248 households containing 306 household members who had been ill in the past 6 months in Tbilisi, Georgia. MAIN OUTCOME MEASURES: Reported health care utilization, out-of-pocket expenditures, and financing practices. RESULTS: Of sick household members, 51% used official health care services at hospitals and clinics; 49% did not use official services and sought advice from relatives or friends, used traditional medicines, or did nothing. Those with serious illness were more likely to seek care through official services (82%) than those with nonserious illness (27%). Ninety-three percent of respondents said costs were the major deterrent to obtaining health care. Ten percent of ill household members reported that they were unable to obtain health care because of high costs; 16% reported being unable to afford all the medications necessary to treat their illness. Sixty-one percent of ill household members used savings to pay for health care expenditures and 19% of those able to obtain care had to use strategies such as borrowing money or selling personal items to pay for health care. Total out-of-pocket health care expenditures (53%) were paid for by borrowing money or selling personal items. A significant portion of households with ill members (87%) reported an interest in purchasing health care insurance. CONCLUSIONS: Economic disruption and health care reforms have led to access problems and out-of-pocket financing strategies that include reliance on personal savings, selling personal items, and borrowing money. Future reforms should consider an appropriate system for health care insurance risk pooling for the population of Tbilisi, Georgia.
Authors: Skarbinski J; Walker HK; Baker LC; Kobaladze A; Kirtava Z; Raffin TA
JAMA. 2002 Feb 27;287(8):1043-9. doi: 10.1001/jama.287.8.1043.
HPV testing for clarifying borderline cervical smear results
Authors: Manos MM
BMJ. 2001 Apr 14;322(7291):878-9.
A prospective study of human papillomavirus (HPV) type 16 DNA detection by polymerase chain reaction and its association with acquisition and persistence of other HPV types
Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.
Authors: Liaw KL; Hildesheim A; Burk RD; Gravitt P; Wacholder S; Manos MM; Scott DR; Sherman ME; Kurman RJ; Glass AG; Anderson SM; Schiffman M
J Infect Dis. 2001 Jan 1;183(1):8-15. Epub 2000 Nov 16.
Seroreactivity to human papillomavirus types 16, 18, 31, and 45 virus-like particles in a case-control study of cervical squamous intraepithelial lesions
Serum IgG antibodies to human papillomavirus (HPV) types 16, 18, 31, and 45 virus-like particles were measured in a nested case-control study of cervical squamous intraepithelial lesions. HPV-16 seroreactivity was strongly associated with HPV-16 DNA detection (odds ratio, 9.0; 95% confidence interval, 4.4-19.4), and similar type specificity was observed for HPV-31 and -45. In contrast, seroreactivity to any type was associated with elevated seroreactivity to all others. Among cases and controls, HPV-16 showed the highest seroprevalence, with 23.8% of 80 cases and 10.5% of 258 controls seroreactive to HPV-16 alone, and another 27.5% and 5.4%, respectively, seroreactive to HPV-16 plus other types. Overall, 24 (30.0%) cases and 17 (6.6%) controls were seroreactive to multiple types. These data suggest that seroreactivity to a given type reflects mainly type-specific HPV infection as measured by DNA detection and may also signal past exposure to other types that are now only serologically detected.
Authors: Wideroff L; Schiffman M; Haderer P; Armstrong A; Greer CE; Manos MM; Burk RD; Scott DR; Sherman ME; Schiller JT; Hoover RN; Tarone RE; Kirnbauer R
J Infect Dis. 1999 Nov;180(5):1424-8.
Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers
OBJECTIVES: The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines. METHODS: This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose. RESULTS: After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer of > or =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer of > or =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective. CONCLUSION: We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.
Authors: Shinefield HR; Fireman B; Hansen J; et al.
Pediatr Infect Dis J. 1999 Sep;18(9):757-63.
Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results
CONTEXT: A Papanicolaou (Pap) test result of atypical squamous cells of undetermined significance (ASCUS) presents a clinical challenge. Only 5% to 10% of women with ASCUS harbor serious cervical disease, but more than one third of the high-grade squamous intraepithelial lesions (HSILs) in screening populations are identified from ASCUS Pap test results. OBJECTIVE: To determine whether human papillomavirus (HPV) DNA testing of residual material from liquid-based Pap tests and referral of cases found to be HPV-positive directly to colposcopy could provide sensitive detection of underlying HSILs in women with ASCUS Pap results, compared with repeat Pap testing. DESIGN AND SETTING: Natural history of women with ASCUS Pap smear results, all of whom had liquid-based cytology, HPV testing, and subsequent repeat Pap tests and colposcopy with histologic evaluation, conducted at 12 gynecology clinics in a large managed care organization between October 1995 and June 1996. PARTICIPANTS: From a cohort of 46009 women who had routine cervical examinations, 995 women with Pap test results of ASCUS who consented to participate were identified. MAIN OUTCOME MEASURES: Cervical histology, HPV test results, and repeat Pap smear results, and sensitivity of HPV testing to identify patients found to have HSIL+ histology. RESULTS: Of 995 participants with ASCUS Pap test results, 973 had both a definitive histologic diagnosis and HPV result. Sixty-five (6.7%) had histologic HSIL or cancer. For women with histologic HSIL+, the HPV test was positive in 89.2% (95% confidence interval [CI], 78.4%-95.2%), and the specificity was 64.1 % (95% CI, 60.9%-67.2%). The repeat Pap smear result was abnormal in 76.2% (95% CI, 63.5%-85.7%). Triage based on HPV testing only or on repeat Pap testing only would refer similar proportions (approximately 39%) to colposcopy. The sensitivity of HPV DNA testing for HSIL was equivalent to, if not greater than, that of the repeat Pap test. We further estimated that an HPV-based algorithm including the immediate colposcopy of HPV-positive women, and then repeat Pap testing of all others, would provide an overall sensitivity of 96.9% (95% CI, 88.3%-99.5%). CONCLUSIONS: For women with ASCUS Pap tests, HPV DNA testing of residual specimens collected for routine cervical cytology can help identify those who have underlying HSIL. By testing the specimen collected at initial screening, the majority of high-risk cases can be identified and referred for colposcopy based on a single screening.
Authors: Manos MM; Hiatt RA; et al.
JAMA. 1999 May 5;281(17):1605-10.
Safety and immunogenicity of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in infancy. The Northern California Kaiser Permanente Vaccine Study Center Pediatrics Group
The safety and immunogenicity of the HbOC conjugate vaccine have been evaluated in a study population of 61,080 children in the Kaiser Permanente Medical Care Program of Northern California. Half of the population served as controls. The vaccine was given as part of a three-dose regimen in the first year of life with the first dose given between 6 weeks and 6 months of age, a minimum interval of 1 month between doses and with the third dose given by 1 year of age. The vaccine was highly immunogenic with 97% of infants developing 1 microgram/ml or more of anti-polyribosyl phosphate antibody as measured by Farr assay 1 month after completion of the three-dose series and with 71% maintaining this concentration until a booster dose was given at approximately 18 months of age. There were three cases of Haemophilus influenzae type b disease after the first dose of vaccine and two of these children died. However, there was no statistically significant difference between either the incidence of H. influenzae type b disease or the mortality rate in infants after one dose of HbOC vaccine when compared with H. influenzae type b disease incidence and mortality in unvaccinated children of the same age. The rate of sudden infant death syndrome following HbOC vaccine was lower than that observed within the Kaiser Permanente Medical Care Program as a whole or in the three counties in which sudden infant death syndrome surveillance was tabulated. Immediate local and systemic reactions were evaluated by telephone interviews of 6887 infants within 72 hours of vaccine.(ABSTRACT TRUNCATED AT 250 WORDS).
Authors: Black SB; Shinefield HR; Lampert D; Fireman B; Hiatt RA; Polen M; Vittinghoff E
Pediatr Infect Dis J. 1991 Feb;10(2):92-6.
Efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States population of 61,080 children. The Northern California Kaiser Permanente Vaccine Study Center Pediatrics Group
The efficacy of the HbOC conjugate Haemophilus influenzae type b vaccine was evaluated in a study population of 61,080 infants in the Northern California Kaiser Permanente Medical Care Program. Between February, 1988, and June, 1990, the HbOC vaccine was given as part of a three-dose series at 2, 4, and 6 months of age to 20,800 infants. The study population included children with a well-care visit at a study center during the first 6 months of life. There were 25 cases of Haemophilus influenzae type b disease in the study population: 22 in unvaccinated children and 3 in children who received only one dose of HbOC vaccine. The efficacy of the full three-dose series was evaluated by several methods: a primary analysis comparing fully vaccinated children with unvaccinated children from 7 to 18 months of age; a stratified exact analysis adjusted for age and seasonality; and a case-control analysis which further adjusted for known risk factors. The efficacy of three doses of vaccine was 100% with the lower bound of the 95% confidence interval for the three analyses at 68, 71, and 64%, respectively. There were no cases of disease resulting from two doses of HbOC vaccine yielding an estimate of 100% efficacy (95% confidence interval, 47 to 100) for two doses of HbOC vaccine. However, for children who had received only one dose of HbOC vaccine, vaccine efficacy was estimated to be 26% and the possibility that one dose of HbOC vaccine had no efficacy could not be excluded.(ABSTRACT TRUNCATED AT 250 WORDS).
Authors: Black SB; Shinefield HR; Fireman B; Hiatt R; Polen M; Vittinghoff E
Pediatr Infect Dis J. 1991 Feb;10(2):97-104.
Efficacy of Haemophilus influenzae type b capsular polysaccharide vaccine
The efficacy of the Haemophilus influenzae type b (Hib) polyribose phosphate vaccine was evaluated in a population of 120,000 children from 23 through 71 months of age in the Kaiser Permanente Medical Care Program (KPMCP) in Northern California over the 2-year period from June 1, 1985, through May 31, 1987. Approximately 37% of the population were vaccinated by the end of the first year and 60% were vaccinated by the end of the second year. There were 35 cases of Hib disease, 4 of whom were vaccine failures. Cases of Hib disease were identified by multiple modality case ascertainment, consisting of: (1) active surveillance in KPMCP microbiology laboratories; (2) active surveillance on KPMCP pediatric wards by a study physician; (3) retrospective review of computer-stored hospital discharge diagnoses; and (4) a review of all hospitalizations outside the health plan. The medical records of cases, matched controls and a random sample of the population were reviewed to obtain information on vaccination and related variables. Efficacy was evaluated using two complementary methods. In a retrospective surveillance approach, efficacy was estimated to be 68% (95% confidence limits of 4, 89%). In a matched case-control analysis, efficacy was estimated to be 69% (95% confidence limits of -13, 91%). Adjustment for day care attendance and parental occupation slightly reduced the efficacy estimate. Other possible confounders including race, parental education and number of siblings were considered. Four cases of Hib disease were observed within 1 week following receipt of vaccine and before the time when immunity could have developed. There are several plausible explanations for the occurrence of these early cases including the possibility of chance alone.(ABSTRACT TRUNCATED AT 250 WORDS).
Authors: Black SB; Shinefield HR; Hiatt RA; Fireman BH; Kaiser Permanente Pediatric Vaccine Study Group
Pediatr Infect Dis J. 1988 Mar;7(3):149-56.
