Persons living with HIV (PLWH) are at increased risk for a number of cancers. Altered immunity is one proposed mechanism driving this excess risk of cancer. Low CD4/CD8 ratio in treated PLWH is associated with immune senescence, activation, and inflammation which may contribute to carcinogenesis. However, there is no clinical consensus of which ratio values that best predict cancer risk. This study examined whether low CD4/CD8 ratio predicted cancer risk (excluding non-melanoma skin cancer (NMSC)) in the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
Adults without a history of any cancer (excluding NMSC) prior to cohort entry and with ≥1 CD4/CD8 value in 12 NA-ACCORD cohorts between 1998-2016 were included. Cancer outcomes were validated in each cohort. Risk of cancer and 6-month-lagged CD4/CD8 ratio were evaluated in multivariable, time-updated Cox proportional hazard models adjusting for age, sex, race, hepatitis C virus coinfection, lagged CD4 count (cells/mL) and lagged, log-transformed HIV RNA (copies/mL). Models for any and for specific cancers were censored at earliest occurrence of death, other cancer diagnoses, loss to follow-up (gap in care ≥ 1.5 years), end of cohort observation period or December 31, 2016. Observation time was censored during periods of missing laboratory data. Continuous variables, including CD4/CD8, were modeled using restricted cubic splines with 4 knots.
Among 75,161 PLWH, there were 5046 incident cancer diagnoses. Most frequent cancers were lung cancer (n=714), non-Hodgkin lymphoma (NHL, n=459), Kaposi sarcoma (KS, n=440), and anal cancer (n=375). Median age at cohort entry was 43 years, 90% were male, and 44% were white. The median CD4/CD8 ratio during the observation period was 0.49 (interquartile range: 0.27-0.79). Adjusted hazard ratios for CD4/CD8 ratio and any cancer and specific cancers are shown in the Figure. For any cancer and specific cancers, non-linear CD4/CD8 ratio was inversely associated with cancer risk in adjusted models (p< 0.001).
Low CD4/CD8 ratio was consistently associated with increased cancer risk, independent of CD4 count and HIV RNA. Further research into the causes of CD8 cell inflation and persistent immunologic disturbance in PLWH is needed. CD4/CD8 ratio may serve as useful clinical biomarker for cancer risk in PLWH.