CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection

Abstract

Background: Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients.

Objective: To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy.

Methods: CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations.

Results: A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/microl; 2.0 and 1.7 for counts of 200-350 cells/microl; and 0.7 and 0.7 for counts greater than 350 cells/microl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50-0.62, P < 0.01) and 14% (95% confidence interval for hazard ratio 0.77-0.96, P = 0.01), respectively, for each 100 cell/microl higher latest CD4+ count.

Conclusion: Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/microl.

Fig. 1. AIDS and non-AIDS disease rates by latest CD4+ count

Rates of AIDS (black) and non-AIDS diseases (gray) per 100 person-years are presented across three categories of latest CD4+ counts. Error bars represent upper 95% CI, and the univariate hazard ratios (HR) with 95% CI for each CD4+ category (reference: less than 200) are also presented. Rates for both AIDS and non-AIDS diseases decline with higher CD4+ counts, though the risk gradient is steeper for AIDS. Non-AIDS includes non-fatal and fatal events related to liver, cardiovascular, and renal diseases and non-AIDS defining cancers.

Fig. 2. Proportion of AIDS and non-AIDS events by latest CD4+ count

The proportion of severe events attributable to AIDS (black) and non-AIDS diseases (gray) is presented across three latest CD4+ count categories. Numbers of events are indicated within the respective bar, and total person-years at each CD4+ category are also presented. The relative frequency of non-AIDS events exceeds that of AIDS events at higher CD4+ counts. Non-AIDS includes non-fatal and fatal events related to liver, cardiovascular, and renal diseases and non-AIDS defining cancers.

Fig. 3. Risk of event by latest CD4+ count

Univariate (black) and multivariate (gray) hazard ratio (HR) estimates of risk for events are plotted per 100 cells/μl higher CD4+ count (a). ‘Non-AIDS’ includes nonfatal and fatal events related to liver, cardiovascular, and renal diseases and non-AIDS defining cancers. ‘All-cause mortality’ is death from any cause: ‘AIDS, non-AIDS, or Death’ is any non-fatal AIDS or non-AIDS event plus death from any cause. Multivariate HR are adjusted for latest HIV RNA and baseline covariates: age, sex, race/ethnicity, prior AIDS, and hepatitis B or C virus coinfection. Risk for individual non-AIDS diseases per 100 cells/μl higher CD4+ count are also presented (b). Point estimates to the left of 1 suggest a reduced risk at higher CD4+ levels.