Association of CD4:CD8 With Cause-Specific Mortality in Patients on Long-Term ART

Background: Patients with advanced HIV disease have low CD4:CD8 ratios. These improve with effective ART, but increases in ratios are largely due to higher CD4 counts with persistently high CD8 counts limiting further normalization of the ratio, even after 5 years of ART. Low CD4:CD8 ratios are associated with mortality in elderly HIV-negative people, and have been suggested to reflect HIV-related immune senescence. Methods: Adult patients from 12 European and North American cohorts contributing to the Antiretroviral Therapy Cohort Collaboration were followed for cause-specific mortality from 5 years after starting ART. Baseline CD4 and CD8 counts were those nearest to and within 3 months of 5 years after ART start. We used Cox models, stratified by cohort, to estimate hazard ratios (HR) for subsequent all-cause, AIDS-related, and non-AIDS related (excluding unnatural deaths) mortality comparing patients with CD4:CD8 ratio ≥0.5 and < 0.5 (reference group), stratified by CD4 count (< 350, ≥ 350, and ≥ 500 cells/mm3). We fitted models that were unadjusted; adjusted for CD4; and additionally adjusted for sex, age, IDU transmission group, ART start year, AIDS and viral suppression at 5 years. Results: During 98,438 person-years 902/20,464 patients died. Cause of death was available in 63% of deaths. Median (inter-quartile range) CD4:CD8 ratio 5 years after ART start was 0.61 (0.40, 0.89) and 0.41 (0.23, 0.72) in those who survived and died, respectively (0.23 (0.09, 0.41) for AIDS deaths; 0.45 (0.27, 0.77) for non-AIDS deaths). At 5 years, 9698 (47%) patients had CD4:CD8 ratio >1. Lower CD4:CD8 ratios were associated with mortality in all groups, but these associations were completely attenuated after adjustment for CD4 in those with CD4 counts <350 cells/mm3. By contrast, the adjusted HR (95% CI) in patients with CD4 ≥350 cells/mm3 was 0.68 (0.56, 0.84). In patients with CD4 ≥500 cells/mm3 the adjusted mortality HR (95% CI) for CD4:CD8 ≥ 0.5 (v. < 0.5) was 0.71 (0.32, 1.56). In patients with CD4 ≥ 350 cells/mm3 low CD4:CD8 was associated with both non-AIDS and AIDS-related deaths, but confidence intervals were wide. Conclusions: CD4:CD8 ratios may be useful for monitoring mortality risk in patients on long-term ART.