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ACTG A5324: A RANDOMIZED TRIAL OF ART INTENSIFICATION FOR COGNITIVE IMPAIRMENT IN PWH
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CROI 2022 Feb 16
Scott Letendre, M.D.
University of California, San Diego
Mark Mascolini
Adding dolutegravir (DTG) with or without maraviroc (MVC) to suppressive antiretroviral therapy (ART) did not significantly improve neuropsychological test performance or ease depression compared with continuing the baseline regimen in ACTG A5324, the InMIND Trial [1]. In this double-blind, placebo-controlled trial enrolling 191 people with cognitive impairment, intensifying the regimen did boost CD4 and CD8 counts, but side effects were more frequent in people adding both dolutegravir and maraviroc to their regimen than in those adding just dolutegravir or those maintaining their initial ART.
In people taking ART with an undetectable viral load in blood, persistence of HIV in the brain could cause cognitive impairment, the ACTG team explained. To see if adding brain-penetrating antiretrovirals to ART that already keeps HIV undetectable in blood would affect neuropsychological performance or depression in people with cognitive impairment, ACTG A5324 investigators conducted a randomized, double-blind trial in the United States and other countries.
The trial recruited participants at 14 US sites and 11 international sites [2]. Participants had to be taking a suppressive antiretroviral regimen that did not contain an integrase inhibitor or maraviroc. They needed an HIV load in blood below 50 copies and performance more than 1 standard deviation below the normative mean on two neuropsychological tests in different domains. HIV infection could be the only cause of neuropsychological impairment.
Researchers randomized enrollees to add dolutegravir plus maraviroc, dolutegravir plus maraviroc placebo, or dolutegravir placebo plus maraviroc placebo. Participants had neuropsychological testing before randomization and at trial weeks 24, 48, 72, and 96. To gauge depression, the study group completed the Beck Depression Inventory-II and the Patient Health Questionnaire-9 (PHQ-9). The primary endpoint was change in normalized total z-score on the neuropsychological tests (the average of individual test z-scores) at week 48.
ACTG A5324 investigators assessed 357 people for trial eligibility and enrolled 191 (53.5%), most of them (82%) from the United States. The single most frequent reason for trial ineligibility was not having neuropsychological impairment when screened for the trial (13%). Of the 191 people enrolled, 61 got randomized to dolutegravir/maraviroc, 67 to dolutegravir/placebo, and 63 to dual placebo. Median age stood at 52 years and 29% of participants were female at birth. Half of participants, 51%, were black while 22% were Hispanic. While 35% of the study group had asymptomatic neurocognitive impairment, 56% had mild neurocognitive disorder, and 9% had HIV-associated dementia.
Seven people (11.5%) taking dolutegravir/maraviroc had an adverse event related to study drug, as did 5 (7.5%) taking dolutegravir/placebo and 3 (4.8%) taking two placebos. Creatinine clearance fell in 4 people (6.6%) randomized to dolutegravir/maraviroc, 2 (3%) taking dolutegravir/placebo, and 0 taking dual placebo. Fifteen people (8%) stopped a study drug because of an adverse event, with no significant difference between arms in time to stopping (P = 0.17).
The researchers confirmed virologic failure in 1 person (2%) in the dolutegravir/maraviroc arm, none in the dolutegravir/placebo group, and 4 (6%) in the dual-placebo group.
Total z-score on neuropsychological testing improved gradually in all three study arms, with no big difference between arms at any point. The Beck Depression Inventory and PHQ-9 also improved over time in all three arms with no difference between arms at any point. Results did not differ by sex, race, study site, efavirenz use, or baseline z-score. People randomized to dolutegravir/maraviroc gained significantly more CD4 cells and CD8 cells than people in the other two study arms (P < 0.05 for both). The dolutegravir/maraviroc group also had significantly greater gains in MIP-1beta in plasma (but not cerebrospinal fluid) than the other groups (P < 0.05). MIP-1beta induces synthesis and release of pro-inflammatory cytokines.
The researchers suggested repeated neuropsychological testing over time in this study-the practice effect-could explain the gradual improvement in scores in all study arms. They concluded that results do not support empiric ART intensification in an attempt to improve cognitive impairment in people taking a suppressive antiretroviral combination.
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