Background: HIV-associated neurocognitive disorders (HAND) occur despite viral suppression in blood and cerebrospinal fluid on combined antiretroviral therapy (CART). One therapeutic option may be CART enhancement with Maraviroc (MA) as MA can penetrate the Central Nervous System (CNS) and has dual antiretroviral/anti-inflammatory activity.
Methods: 19 virally-suppressed HIV+ males (M=53 years old) with formally diagnosed HAND were enrolled in a prospective, randomized, double observer-blinded, open-label pilot RCT. Two subjects failed screening. One subject withdrew for personal issues, 2 were lost to follow-up. Of 14 subjects completing all study visits, 9 were randomized to receive MA enhancement and 5 to continue on existing CART. 2 MA and 1 control subject had confirmed CXCR4-tropic virus in blood; 1 control had confirmed CCR5-tropic virus. HIV tropism status was unavailable for other subjects. Subjects completed neurocognitive (NR) testing assessing 5 cognitive domains at baseline, 6- and 12-months. Primary endpoint was NR change across study period (defined as a global z-score averaging each domain z-score correcting for age and gender). Secondary endpoints were 1H-MR Spectroscopy (MRS) metabolite concentrations in the basal ganglia (BG) and frontal white matter (FWM) at Baseline and 12-months and quantified using LC Model. NR change was analyzed using mixed effect linear regression models with fixed effects: arm, time, arm*time interaction and subject as a random effect to account for attrition. In total, 38 subject visits were included in the analyses (MA: n=27; control: n=14). MRS change was analyzed using repeated measures ANOVA with same fixed effects. Trends p<.10 are reported as this represents pilot data in a small sample. Effect sizes Cohen’s d and β assist in interpretation of effect.
Results: A trend was found for arm*time interaction (p=.056), with 6-month effect size d=1.2 and 12-month effect size d=.45, in favour of improved NR performance in MA arm compared to control arm over time (Figure 1). BG glutamate concentration (a marker of excitotoxicity) was stable in MA arm but tended to increase in control arm at 12 months (interaction: p<.08; β=.-35).
Conclusions: This pilot study provides feasibility, tolerability, proof-of-concept and preliminary evidence for clinically significant neurocognitive improvement and potential stabilization of glutamate excitotoxicity in CART enhancement with MA in virally suppressed HAND patients.