Jessica L Castilho1, Aihua Bian2, Cathy A Jenkins2, Bryan E Shepherd3, Keith Sigel4, M John Gill5, Mari M Kitahata6, Michael J Silverberg7, Angel M Mayor8, Sally B Coburn9, Dorothy Wiley10, Chad J Achenbach11, Vincent C Marconi12, Ronald J Bosch13, Michael A Horberg14, Charles S Rabkin15, Sonia Napravnik16, Richard M Novak17, W Christopher Mathews18, Jennifer E Thorne9,19, Jing Sun20, Keri N Althoff21, Richard D Moore22, Timothy R Sterling1, Staci L Sudenga23. 1. Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 2. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. 3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. 4. Division of Infectious Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA. 5. Department of Medicine, University of Calgary, Calgary, AB, Canada. 6. Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA. 7. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA. 8. Retrovirus Research Center, Internal Medicine Department, Universidad Central del Caribe School of Medicine, Bayamón, PR, USA. 9. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 10. School of Nursing, University of California Los Angeles, Los Angeles, CA, USA. 11. Division of Infectious Diseases, Department of Medicine, Northwestern Feinberg School of Medicine, Chicago, IL, USA. 12. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and Rollins School of Public Health, Atlanta, GA, USA. 13. Department of Biostatistics, T.H. Chan Harvard School of Public Health, Boston, MA, USA. 14. Kaiser Permanente Mid-Atlantic Medical Group and Research Institute, Washington, DC, USA. 15. Division of Cancer Epidemiology and Genetics, Infections and Immunoepidemiology Branch, National Cancer Institute, Rockville, MD, USA. 16. Division of Infectious Diseases, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. 17. Division of Infectious Diseases, Department of Medicine, University of Illinois Chicago School of Medicine, Chicago, IL, USA. 18. Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA, USA. 19. Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 20. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 21. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 22. Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 23. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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