Low CD4/CD8 ratios in HIV-infected (HIV+) persons may represent dysfunctional immune activation and have been found to be associated with increased non-AIDS associated mortality. Using data from a large cohort of HIV+ Veterans, we investigated the relationship between cumulative CD4/CD8 ratio and risk of incident non-AIDS defining (NADC) and AIDS defining (ADC) cancers.
We linked the Veterans Aging Cohort Study (VACS) to the Veterans Affairs Central Cancer Registry to yield a cohort of 26,115 HIV+ subjects followed for a minimum of 2 years, during 1997-2012. We categorized the primary exposure of interest, longitudinal CD4/CD8 ratio, using previously identified cut points for non-AIDS event risk (<0.7 vs ≥0.7). We calculated observation time from VACS enrolment to the earliest of: pathologically confirmed incident cancer, loss to follow-up, or death. Cancers were classified as NADC or ADC and then further subclassified by viral association and anatomic site. Our CD4/CD8 ratio measure was the 18-month simple moving average (SMA), lagged by 6 months (to minimize reverse causality). These lagged SMAs were then evaluated as time-updated covariates in separate Cox proportional hazard regression models for each cancer type (ADC, NADC, virus-related NADC, and the most common constituents of these groups). Models were adjusted for demographics, smoking, drug and alcohol use disorders, recent CD4 count, and hepatitis C virus infection.
We identified 1,259 and 229 incident NADCs and ADCs, respectively, in our cohort. Baseline median CD4/CD8 ratio and CD4 count was lower for subjects who were eventually diagnosed with both NADCs and ADCs compared to patients who never developed cancer. In Cox regression models (Table 1) cumulative CD4/CD8 ratio <0.7 was significantly associated with increased risk of NADCs (hazard ratio [HR]: 1.2; 95% CI: 1.1-1.4) but not with ADCs or the subset of NADCs specifically associated with viral co-infections after adjustment for potential confounders. Among NADCs only lung cancer (HR: 1.5; 95% CI: 1.1-2.1) and anal cancer (HR: 2.0; 95% CI: 1.1-3.8) were associated with low cumulative CD4/CD8 ratios after adjustment; there was no association with other NADCs.
In our large, antiretroviral therapy-era HIV cohort, we found that cumulative exposure to low CD4/CD8 ratio was associated with lung cancer and anal cancer risk after adjustment for potential confounders including recent CD4 count.