Dataset Information

Neurocognition with maraviroc compared with tenofovir in HIV.

ABSTRACT: The objective was to determine whether maraviroc (MVC) has unique neurocognitive benefits in the context of initial antiretroviral therapy (ART).Randomized, double-blind, placebo-controlled, 48-week trial.Participants were enrolled in US AIDS Clinical Trials Group clinical trial sites.Total 262 ART-naive, chemokine coreceptor 5 tropic HIV, and HIV RNA greater than 1000 copies/ml participants were randomized, 230 participants completed the study.Participants received MVC 150?mg or tenofovir disoproxil fumarate (TDF) 300?mg on a background of ritonavir-boosted darunavir and emtricitabine.The neuropsychological battery of 15 tests done at baseline, week 24 and week 48 assessed seven domains, and were standardized into z-scores then converted into deficit scores and a global deficit score. The 48-week changes from baseline in the neuropsychological scores and the global deficit score were compared by Wilcoxon or Kruskal-Wallis test between arms, and among baseline impairment groups [classified as normal, mild (2 deficit scores ?1) and moderate (2 deficit scores ?2)]. It was hypothesized that the MVC arm would have improved neuropsychological performance over TDF.In this double-blind, randomized, placebo-controlled trial, there were no differences in neuropsychological performance between MVC and TDF. Those with moderate neuropsychological impairment at baseline experienced greater ART-mediated neuropsychological improvement than those with mild or no neuropsychological impairment.Improvement in neurocognitive functioning was greater with more baseline impairment but was comparable with MVC or TDF.

SUBMITTER: Robertson KR

PROVIDER: S-EPMC5014739 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Neurocognition with maraviroc compared with tenofovir in HIV.

Robertson Kevin R KR Miyahara Sachiko S Lee Anthony A Brown Todd T TT Chan Ellen S ES Berzins Baiba B Rusin David D Eron Joseph J JJ Taiwo Babafemi O BO

AIDS (London, England) 20160901 15

<h4>Objective</h4>The objective was to determine whether maraviroc (MVC) has unique neurocognitive benefits in the context of initial antiretroviral therapy (ART).<h4>Design</h4>Randomized, double-blind, placebo-controlled, 48-week trial.<h4>Setting</h4>Participants were enrolled in US AIDS Clinical Trials Group clinical trial sites.<h4>Participants</h4>Total 262 ART-naive, chemokine coreceptor 5 tropic HIV, and HIV RNA greater than 1000 copies/ml participants were randomized, 230 participants c ...[more]

PMID: 27333088

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Project description:BACKGROUND:Intravaginal rings (IVRs) can deliver antiretroviral (ARV) agents for HIV pre-exposure prophylaxis (PrEP), theoretically overcoming adherence concerns associated with frequent dosing. However, topical vaginal ARV drug delivery has not simultaneously led to sufficient rectal drug exposure to likely protect from HIV infection as a result of receptive anal intercourse (RAI). Unprotected RAI has a higher risk of infection per sex act and, for women, also can be associated with vaginal exposure during a single sexual encounter, especially in higher-risk subsets of women. The physiologically inflamed, activated, immune-cell dense colorectal mucosa is increasingly appreciated as the sexual compartment with highly significant risk; this risk is increased in the setting of co-infections. Ex vivo studies have shown that colorectal tissue and rectal fluid concentrations correlated with HIV protection. Given these important results, efforts to document colorectal compartment ARV drug concentration from pod-IVR delivery was assessed to determine if vaginal application could provide protective ARV levels in both compartments. METHODOLOGY/PRINCIPAL FINDINGS:A crossover clinical trial (N = 6) evaluated 7 d of continuous TDF pod-IVR use, a wash-out phase, followed by 7 d with a TDF-FTC pod-IVR. A subsequent clinical trial (N = 6) consisted of 7 d of continuous TDF-FTC-MVC pod-IVR use. Rectal fluids were collected on Day 7 at IVR removal in all three ARV-exposures (two Phase 1 trials) and drug concentrations quantified by LC-MS/MS. Median rectal fluid concentrations of TFV, the hydrolysis product of the prodrug TDF, were between 0.66 ng mg-1 (TDF pod-IVR group) and 1.11 ng mg-1 (TDF-FTC pod-IVR group), but below the analytical lower limit of quantitation in 5/6 samples in the TDF-FTC-MVC pod-IVR group. Unexpectedly, median FTC (TDF-FTC pod-IVR, 20.3 ng mg-1; TDF-FTC-MVC pod-IVR, 0.18 ng mg-1), and MVC rectal fluid concentrations (0.84 ng mg-1) were quantifiable and higher than their respective in vitro EC50 values in most samples. Due to participant burden in these exploratory trials, rectal fluid was used as a surrogate for rectal tissue, where drug concentrations are expected to be higher. CONCLUSIONS/SIGNIFICANCE:The concentrations of FTC and MVC in rectal fluids obtained in two exploratory clinical trials of IVRs delivering ARV combinations exceeded levels associated with in vitro efficacy in HIV inhibition. Unexpectedly, MVC appeared to depress the distribution of TFV and FTC into the rectal lumen. Here we show that vaginal delivery of ARV combinations may provide adherence and coitally independent dual-compartment protection from HIV infection during both vaginal and receptive anal intercourse.

Dataset Information

Neurocognition with maraviroc compared with tenofovir in HIV.

Publications

Neurocognition with maraviroc compared with tenofovir in HIV.

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