Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients

Objective: To investigate the relative predictive value of CD4⁺ metrics for serious clinical endpoints. Design: Observational. Methods: Patients (3012; 20 317 person-years) from control arms of ESPRIT and SILCAAT were followed prospectively. We used Cox regression to identify CD4⁺ metrics (latest, baseline and nadir CD4⁺ cell count, latest CD4 ⁺%, time spent with CD4⁺ count below certain thresholds and CD4⁺ slopes) independently predictive of all-cause mortality, non-AIDS deaths, non-AIDS (cardiovascular, hepatic, renal and non-AIDS malignancy) and AIDS events. Akaike information criteria (AIC) were calculated for each model. Significant metrics (P < 0.05) were then additionally adjusted for latest CD4⁺ cell count. Results: Non-AIDS deaths occurred at a higher rate than AIDS deaths [rate ratio: 6.48, 95% confidence interval (CI) 5.1-8.1], and non-AIDS events likewise (rate ratio: 1.72, 95% CI 1.65-1.79). Latest CD4⁺ cell count was strongly predictive of lower risk of death (hazard ratio per log2 rise: 0.48, 95% CI 0.43-0.54), with lowest AIC of all metrics. CD4⁺ slope over seven visits, after additional adjustment for latest CD4⁺ cell count, was the only metric to be an independent predictor for all-cause (hazard ratio for slope <-10 cells/μl per month vs. 0 ± 10: 3.04, 95% CI 1.98-4.67) and non-AIDS deaths (hazard ratio for slope <-10 cells/μl per month vs. 0 ± 10: 2.62, 95% CI 1.62-4.22). Latest CD4⁺ cell count (per log2 rise) was the best predictor across all four endpoints and predicted hepatic (hazard ratio 0.46, 95% CI 0.33-0.63) and renal events (hazard ratio 0.39, 95% CI 0.21-0.70), but not cardiovascular events (hazard ratio 1.05, 95% CI 0.77-1.43) or non-AIDS cancers (hazard ratio 0.78, 95% CI 0.59-1.03). Conclusion: Latest CD4 ⁺ cell count is the best predictor of serious endpoints. CD4 slope independently predicts all-cause and non-AIDS deaths.