Background:  Indirect evidence suggests that early initiation of ART may prevent HIV-associated neurocognitive disorders (HAND). Prevention is important since once HAND occurs, many individuals remain impaired despite effective viral suppression on ART. To determine whether earlier ART initiation protects against HAND, we evaluated the relationship between nadir CD4⁺ cell counts, a surrogate for worst immunosuppression prior to ART, and risk of HAND.
Methods:  Comprehensive medical and neuropsychological evaluations were performed on 1526 subjects in a multicenter cohort study, CNS HIV ART Effects Research (CHARTER). HAND was diagnosed by comprehensive neuropsychological and neuromedical testing according to published criteria. Co-morbid conditions contributing to neuropsychological impairment were evaluated by a single, experienced neuropsychological rater. Nadir CD4 was by self-report or observation.

Results:  The median (IQR) nadir CD4 was 172 (48 to 297). A total of 1080 subjects (71%) took ART; 589 of these (55%) had undetectable plasma viral loads; 799 (52.4%) were neuropsychologically impaire; and 692 (45.3%) had significant co-morbid conditions. HAND diagnosis was associated with substantial disability, as measured by a structured self-report instrument. Higher CD4 nadirs were associated with lower rates of neuropsychological impairment in the entire cohort, and in the subsets with minimal co-morbidities and on ART. Among 579 subjects on ART with minimal confounds, the odds ratios (95%CI) and corresponding rates of HAND at CD4 nadir levels of 200 to 349 (n = 127) and ≥350 (n = 51) compared to 0 to 199 (reference, n = 401, of whom 47% had HAND, were 0.72 (0.47 to 1.10; 39%) and 0.57 (0.30 to 1.10; 33%) (trend c = 4.9, P = 0.03). No threshold effect was seen; higher CD4 nadir conferred lower HAND risk at all levels. The association remained significant after adjusting for other predictors including plasma viral load, age, sex, ethnicity, and duration of HIV infection.

Conclusions:  These findings confirm prior reports that higher nadir CD4 is associated with a reduced risk of HAND. Results held true both for the cohort as a whole and for a subgroup of special interest comprising individuals currently taking ART and having no significant confounds. Because HAND is a common source of disability in HIV⁺ individuals on ART, these data suggest that earlier treatment initiation may protect patients from HAND.