No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts

Abstract

Objective: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl.

Design: Randomized trial.

Methods: The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350 cells/μl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models.

Results: The 592 participants had a median age of 34 years; median baseline CD4 count was 629 cells/μl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, P = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (P < 0.001 for increase from baseline).

Conclusion: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/μl.

Figure 1

Study design and CONSORT flow diagram.

Figure 2

(A) Percent of participants using ART, and percent with suppressed viral load (HIV RNA ≤ 200 copies/mL) over time; (B) ART use expressed as percent of follow-up time accrued; (C) Mean CD4 cell count levels (± 2 SE) over time.

Figure 3

(A) Change in mean QNPZ-8 scores from baseline through follow-up; (B) Change in mean z-scores for the individual tests, which are averaged to calculate the QNPZ-8 summary score.

Figure 4

Subgroup analyses for change in mean QNPZ-8 scores from baseline. When adjusting interaction p-values for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR) method, p≤0.004 provides evidence for heterogeneity of the treatment effect across subgroups at the FDR≤0.05 level. Subgroup analyses by age, education, HIV RNA level, pre-specified ART regimens, and their CNS penetration effectiveness score were specified a priori in the study protocol. In addition to the 8 subgroup factors shown, we analyzed subgroups by 16 baseline factors: by race, sex, employment status, urban residence, country of enrollment, time since HIV diagnosis, CD4 cell count, body mass index, diabetes, depression (CES-D≥16), prior psychiatric diagnosis, prior cardiovascular disease, 10-year Framingham risk of CHD, hematocrit, AST/SGOT, ALT/SGPT. The treatment effect was homogeneous across those 16 subgroups.