CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy

Objective: Despite immune recovery in individuals on combination antiretroviral therapy (CART), the frequency of HIV-associated neurocognitive disorders (HANDs) remains high. Immune recovery is typically achieved after initiation of ART from the nadir, or the lowest historical CD4. The present study evaluated the probability of neuropsychological impairment (NPI) and HAND as a function of CD4 ⁺ nadir in an HIV-positive cohort. Methods: One thousand five hundred and twenty-five HIV-positive participants enrolled in CNS HIV Antiretroviral Therapy Effects Research, a multisite, observational study that completed comprehensive neurobehavioral and neuromedical evaluations, including a neurocognitive test battery covering seven cognitive domains. Among impaired individuals, HAND was diagnosed if NPI could not be attributed to comorbidities. CD4 ⁺ nadir was obtained by self-report or observation. Potential modifiers of the relationship between CD4 ⁺ nadir and HAND, including demographic and HIV disease characteristics, were assessed in univariate and multivariate analyses. Results: The median CD4 ⁺ nadir (cells/μl) was 172, and 52% had NPI. Among impaired participants, 603 (75%) had HAND. Higher CD4 ⁺ nadirs were associated with lower odds of NPI such that for every 5-unit increase in square-root CD4 ⁺ nadir, the odds of NPI were reduced by 10%. In 589 virally suppressed participants on ART, higher CD4 ⁺ nadir was associated with lower odds of NPI after adjusting for demographic and clinical factors. Conclusion: As the risk of NPI was lowest in patients whose CD4 ⁺ cell count was never allowed to fall to low levels before CART initiation, our findings suggest that initiation of CART as early as possible might reduce the risk of developing HAND, the most common source of NPI among HIV-infected individuals.