Maraviroc-intensified Combined Antiretroviral Therapy Improves Cognition in Virally Suppressed HIV-associated Neurocognitive Disorder

Thomas M. Gates; Lucette A. Cysique; Krista J. Siefried; Joga Chaganti; Kirsten J. Moffat; Bruce J. Brew

Disclosures

AIDS. 2016;30(4):591-600. 

In This Article

Abstract and Introduction

Abstract

Objective: To investigate whether intensification of combined antiretroviral therapy (cART) with the CC chemokine receptor type 5 (CCR5) entry inhibitor maraviroc leads to improvement in global neurocognitive functioning in virally suppressed men with HIV-associated neurocognitive disorder (HAND).

Design: Prospective, double observer-blinded, open-label pilot randomized-controlled trial. Participants were randomized to remain on their existing cART regimen (control arm; n = 8) or receive maraviroc-intensification (maraviroc arm; n = 9).

Methods: Participants completed a five-domain neuropsychological battery at baseline, 6- and 12-month visits. Raw scores were transformed into age-corrected z-scores and averaged into a global z-score. Single voxel (1H)-magnetic resonance spectroscopy (MRS) major cerebral metabolite concentrations were collected at baseline and 12 months in the basal ganglia and frontal white matter and quantified using jMRUI. Neuroinflammatory biomarkers cerebrospinal fluid neopterin and β2-microglobulin were also measured.

Results: Fourteen of the 17 participants completed the study: nine maraviroc arm and five control. We found medium to large effect sizes in favour of improved global neurocognitive performance in the maraviroc arm over time {arm*time interaction: P < 0.05; 6 month: [β=–0.10, standard error (SE)= 0.04, 90% confidence interval (90%CI)= –0.18,.03; P < 0.03] yielding a large effect-size d = 0.77 (90%CI = –0.19,1.71); 12 month: [β=–0.01; SE = 0.05; 90%CI = –0.09, 0.06; P < 0.77] yielding a moderate effect-size d = 0.55 (90%CI = –0.47,1.55)}. No treatment-related changes were detected for 1H-MRS metabolites or cerebrospinal fluid biomarkers.

Conclusion: This pilot study provides feasibility, tolerability, proof-of-concept and preliminary evidence for clinically relevant neurocognitive improvement in cART enhancement with maraviroc in virally suppressed HAND patients. Lack of concomitant brain metabolite and biomarker change may be related to complex dynamics of brain repair.

Introduction

HIV affects the brain in 20–50% of infected patients leading to varying degrees of cognitive impairment, predominantly affecting psychomotor speed, attention/working memory, new learning/memory, and executive functioning.[1–4] Collectively, these neurological manifestations of HIV are termed HIV-associated neurocognitive disorders (HAND).[5] Despite the introduction of combined antiretroviral therapy (cART), milder forms of HAND such as asymptomatic neurocognitive disorder (ANI) and mild neurocognitive disorder (MND) remain common.[1,3,4,6,7] Both ANI and MND are functionally significant, predicting increased rate of mortality,[8] progression to more severe impairment,[9] unemployment,[10,11] and poor medication adherence.[12]

The continued presence of HAND in cART-treated patients may reflect ongoing low-level viral replication and/or chronic inflammation in the brain despite undetectable plasma and cerebrospinal fluid (CSF) HIV RNA. This may relate to differences in antiretroviral drugs' ability to cross the blood–brain barrier[13,14] and failure to inhibit post-integration transcription.[15,16] The concept of high central nervous system (CNS)-penetrating cART (neuro-cART) remains controversial. However, the majority of rigorous prospective studies to date support a beneficial effect in terms of improved neurocognition and reduced CSF HIV RNA.[15,17] Although a recent randomized-controlled trial (RCT) did not show a differential benefit of neuro-cART,[18] there were several notable methodological issues affecting interpretation including inadequate power,[19] relatively brief (16-week) follow-up period to observe neurocognitive benefits, possible antiretroviral instability prior to study entry (participants were cART-naive or stable for minimum 8 weeks) leading to imbalances in viral suppression between study arms, and high rate of hepatitis C co-infection in neuro-cART arm potentially impacting the likelihood of improvement at follow-up.

Neurovirological and neuropathological studies of HAND have shown that HIV replication within CNS target cells almost exclusively depends on interactions with the CCR5 chemokine co-receptor.[20–22] Therefore, the CCR5 antagonist maraviroc would be a suitable candidate for cART intensification. Maraviroc has a good resistance barrier rendering archived resistance unlikely,[23] good CSF penetration,[24,25] antineuroinflammatory properties, and inhibits CNS viral replication as demonstrated in simian immunodeficiency virus (SIV)-infected Macaque models[26] and humans.[27] The mechanism of maraviroc action in blocking HIV entry into uninfected cells not only inhibits cellular replication (as all antiretroviral drugs do), but indirectly inhibits postintegrase transcription, unlike protease inhibitors which act at the postintegration step of viral replication.[16] Preliminary data supporting a potential neurocognitive benefit of maraviroc-intensified cART was reported in a recent single-arm, open-label pilot study evaluating the impact of maraviroc on monocyte activation phenotypes. In this study, analyses of a subset (n = 6) of HIV-infected participants with some degree of cognitive impairment (global z-score < –0.5, derived from six cognitive domains) revealed moderate improvement over 24 weeks.[28] However, neuropsychological scores at follow-up were not corrected for practice effects, which is highly problematic especially in the absence of a control-comparison arm.[17] It was also unclear whether participants met current Frascati criteria for HAND,[5] leaving open the possibility of larger treatment effect sizes in patients with greater initial cognitive impairment.[29]

We conducted a pilot RCT to investigate the efficacy of cART intensification with maraviroc on neurocognition in virally suppressed (blood and CSF) HIV+ participants on stable cART with HAND. We hypothesized maraviroc intensification would result in improved neurocognitive performance over 12 months relative to continuation on background therapy, along with reversal of HIV-mediated neuropathology as assessed using single voxel (1H)-magnetic resonance spectroscopy (MRS) and CSF inflammatory biomarker panel.

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