A large study with follow-up over 14 years offers a unique way of looking at the risk of cancer among HIV-positive individuals by accounting for the competing risk of death in the era of highly effective antiretroviral therapy (ART), as reported today in the Annals of Internal Medicine.
“This analysis provides easily interpretable information for HIV patients and their providers about their long-term cancer risk, and helps us identify where public health and clinical efforts should be focused to achieve the biggest impacts,” said co-author Richard D. Moore, MD, MHS, of the Johns Hopkins School of Medicine, and overall principal investigator of the North American Cohort Collaboration on Research and Design (NA-ACCORD).
“In the era before antiretroviral therapy, people who were infected with HIV were dying of AIDS. Now that use of this therapy is greatly increasing the lifespan of HIV-infected patients, their risk of developing other diseases, such as cancer, has increased,” said lead author Michael J. Silverberg, PhD, MPH, Research Scientist at the Kaiser Permanente Northern California Division of Research. “These patients have a higher burden of cancer compared with the general population due to impaired immune function and chronic inflammation, as well as a higher prevalence of risk factors including smoking and viral co-infections.”
The competing risk of death approach is not new, but this is one of the first times it has been applied to studies of cancer risk in HIV-infected patients. This approach provides estimates of the cumulative incidence of cancer by age 75 years, a measure that has not been reported previously in this population and may have clinical and public health utility since it approximates lifetime risk of cancer.
“Our approach allowed us to disentangle the effects of longevity from other factors on the risk of cancer,” explained Silverberg. “For example, we found that longevity was the main contribution to the increased risk over time for anal, colorectal and liver cancers. The risk for other cancers, such as lung cancer, melanoma and Hodgkin's lymphoma, did not appear to increase over time. This was because the increased risk with longevity was compensated for by other factors, such as decreases in smoking or adverse sun exposure behaviors.”
The study population consisted of 86,620 HIV-infected and 196,987 uninfected adults followed between 1996 and 2009 in 16 cohorts from the U.S. and Canada participating in the NA-ACCORD.
Researchers used the competing risk of death approach to estimate cumulative cancer incidence by HIV status and calendar era. Among HIV-infected subjects, the median CD4 count (a measure of the strength or weakness of the immune system) increased. Despite increasing age, the mortality rate decreased, but even in 2005-2009 the mortality rate was over three-fold higher than in uninfected subjects.
The researchers identified several clinical implications regarding cancer screening in HIV patients:
- The high smoking prevalence in HIV patients, along with high lung cancer incidence, suggests that HIV-infected smokers may benefit from new guidelines for annual lung cancer screening with low-dose computed tomography. In addition, development of targeted smoking cessation interventions for HIV patients should remain a priority.
- The rise in colorectal cancer risk among HIV patients, despite a decline in the general population, indicates the possible need for increased screening among HIV patients aged 50-75 years, as recommended for the general population.
- The increasing risk of liver cancer over time indicates a need to ensure universal hepatitis B virus (HBV) vaccination for HIV patients who are HBV seronegative, and to provide treatment of HBV infection using antiretroviral therapy (ART) regimens with anti-HBV activity and of hepatitis C virus (HCV) infection with recently approved interferon-free therapies.
- The highly effective human papillomavirus (HPV) vaccine, which was licensed in 2011 for the prevention of anal cancer, has been found to produce immunity in HIV patients, suggesting that vaccination has the potential to substantially decrease the burden of anal and possibly HPV-related oral cavity/pharyngeal cancers, although further research is needed.
- Research is also needed to follow-up on observational studies that suggest statin use by HIV patients may reduce cancer risk, presumably due to their anti-inflammatory effects.
- Efforts need to be intensified to promote early, sustained ART, the only known approach to prevention of Kaposi sarcoma and non-Hodgkin’s lymphoma and possibly other cancers linked to immunosuppression or inflammation.
“As the HIV-infected population ages, future estimates of lifetime cancer risk could be stratified by levels of cancer risk factors,” said Silverberg. “Factors such as CD4 count, smoking, alcohol consumption, and HBV or HCV infection, could more accurately inform patients and providers about risk and further target prevention efforts.”
The study was funded primarily by grants from the National Institutes of Health.
Other authors of the study include Bryan Lau, PhD, MHS, Gregory D. Kirk, MD, PhD, MPH, Sharada P. Modur, PhD, Yuezhou Jing, MS, Keri N. Althoff, PhD, MPH, and Gypsyamber D’Souza, PhD, Department of Medicine, Johns Hopkins School of Medicine, and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Chad J. Achenbach, MD, MPH, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL; Eric A. Engels, MD, MPH, and James J. Goedert, MD, National Cancer Institute, National Institutes of Health, Bethesda, MD; Nancy Hessol, MSPH, Department of Clinical Pharmacy, University of California, San Francisco; John T. Brooks, MD, and Pragna Patel, MD, MPH, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA; Ann N. Burchell, PhD, MSc, Ontario HIV Treatment Network and Dalla Lana School of Public Health, University of Toronto; M. John Gill, MB ChB, MSc, Department of Medicine, University of Calgary; Robert Hogg, PhD, British Columbia Centre for Excellence in HIV/AIDS, Vancouver; Michael A. Horberg, MD, HIV/AIDS, Mid-Atlantic Permanente Research Institute, Kaiser Permanente, Rockville, MD; Mari M. Kitahata, MD, MPH, Department of Medicine, University of Washington, Seattle, WA; Phillip T. Korthuis, MD, MPH, Department of Medicine, Oregon Health and Sciences University; William C. Mathews, MD, MSPH, Department of Medicine, University of California San Diego; Angel Mayor, MD, MSc, Retrovirus Research Center, Universidad Central del Caribe School of Medicine, Puerto Rico; Sonia Napravnik, PhD, Division of Infectious Diseases, School of Medicine, University of North Carolina; Richard M. Novak, MD, College of Medicine, University of Illinois at Chicago; Anita R. Rachlis, MD, MEd, FRCPC, Sunnybrook Health Sciences Centre, University of Toronto; Timothy R. Sterling, MD, Department of Medicine, Vanderbilt University, Nashville, TN; James H. Willig, MD. MSPH, Division of Infectious Diseases, University of Alabama; Amy C. Justice, MD, MSc, PhD, and Robert Dubrow, MD, PhD, VA Connecticut Healthcare System and Yale University Schools of Medicine and Public Health; for the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of IeDEA.