CD4/CD8 Ratio and Cancer Risk Among Adults With HIV

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.

Figure 1.

Adjusted hazard ratios (HR) and 95% confidence interval (CI) for cancer risk comparing the 6-month lagged, time-varying CD4/CD8 ratio values. Models for any cancer, lung cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, Kaposi sarcoma cancer, anal cancer, head and neck cancer, colorectal cancer included the covariates of age, sex, race and ethnicity, year of cohort entry, any history of chronic hepatitis C virus infection, and time-varying and time-updated CD4/CD8 ratio, CD4 cell count, HIV RNA, and history of AIDS-defining illness. The multivariable model for liver cancer included the covariates of age, sex, race, year of cohort entry, any history of chronic hepatitis C virus infection, history of chronic hepatitis B virus infection, history of heavy alcohol use, history of injection drug use, and time-varying and time-updated CD4/CD8 ratio, CD4 cell count, HIV RNA, history of AIDS-defining illness, and history of cirrhosis. The multivariable model for prostate cancer included only males and covariates age, race, year of cohort entry, any history of chronic hepatitis C virus infection, and time-varying and time-updated CD4/CD8 ratio, CD4 cell count, HIV RNA, and history of AIDS-defining illness. Models for breast cancer and cervical cancer included only females and included age, race (White vs non-White), and time-varying and lagged CD4/CD8 ratio, CD4 cell count, HIV RNA, and history of AIDS-defining illness. The error bars represent the 95% confidence intervals. Wald statistic was used to calculate P values (2-sided). Circles represent the adjusted hazard ratio comparing a CD4/CD8 value of 0.30 vs a CD4/CD8 value of 0.80. Triangles represent the adjusted hazard ratio comparing a CD4/CD8 value of 0.50 vs a CD4/CD8 value of 0.80.

Figure 2.

Adjusted hazard ratio for cancer risk and CD4/CD8 ratios lagged 6, 12, 18, and 24 months. Adjusted hazard ratio for CD4/CD8 ratio values lagged 6 months (solid orange lines), 12 months (dashed green lines), 18 months (dashed teal lines), and 24 months (dashed purple lines) for the following cancers (number of events for each model): A) any cancer (6 months n = 4940; 12 months n = 4597; 18 months n = 4308; 24 months n = 4043); B) anal cancer (6 months n= 395; 12 months n = 375; 18 months n = 361; 24 months n = 340); C) lung cancer (6 months n = 664; 12 months n = 645; 18 months n = 645; 24 months n = 564); D) non-Hodgkin lymphoma (6 months n = 433; 12 months n = 382; 18 months n = 333; 24 months n = 310); E) Hodgkin lymphoma (6 months n = 157; 12 months n = 145; 18 months n = 143; 24 months n = 124). Models included the covariates of age, year of cohort entry, sex, race and ethnicity, any history of chronic hepatitis C virus infection, and time-varying and lagged CD4/CD8 ratio, CD4 cell count, HIV RNA, and history of AIDS-defining illness.

Figure 3.

Sensitivity analyses including additional behavioral and body mass index covariates for the adjusted hazard ratios and 95% confidence interval (CI) for cancer outcomes comparing the 6-month lagged, time-varying CD4/CD8 ratio values. Only models for any cancer, lung cancer, non-Hodgkin lymphoma, Kaposi sarcoma cancer, and anal cancer performed due to number of events. All models included the covariates of age, sex, race, year of cohort entry, any history of chronic hepatitis C virus infection, history of smoking, history of heavy alcohol use, HIV acquisition risk factor, and time-varying and time-updated CD4/CD8 ratio, CD4 cell count, HIV RNA, history of AIDS-defining illness, and body mass index. The error bars represent the 95% confidence intervals. Wald statistic was used to calculate P values (2-sided). Circles represent the adjusted hazard ratio comparing a CD4/CD8 value of 0.30 vs a CD4/CD8 value of 0.80. Triangles represent the adjusted hazard ratio comparing a CD4/CD8 value of 0.50 vs a CD4/CD8 value of 0.80.