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Antiretroviral Therapy Intensification for Neurocognitive Impairment in HIV
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Download the PDF here -
Download the PDF here -
DISCUSSION
A5324 was the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The premise for the trial was that NCI in PWH who are taking ART is due to persistent HIV replication,50-54 but the findings do not support this conclusion: NC performance improved over 96 weeks and did not differ by arm. Stratification and sensitivity analyses did not identify subgroups who benefitted from active study drug, nor did adjustments for demographic or other characteristics. Results of NC testing were further supported by a lack of differences between arms in depressive symptoms, IADLs, or in concentrations of NfL in plasma or CSF.55,56 These findings provide strong evidence that ART intensification with currently available ART drugs is not an effective strategy to treat existing NCI in PWH who are already taking suppressive therapy. Instead, the negative findings support alternative explanations, such as prior CNS injury, cellular shedding of viral products54,57-59, persistent inflammation, or comorbid disease.60
Clinical Infectious Diseases
15 May 2023
Scott L. Letendre1, Huichao Chen2, Ashley McKhann2, Jhoanna Roa3, Alyssa Vecchio4, Eric S. Daar5, Baiba Berzins6, Peter W. Hunt7, Christina M. Marra8, Thomas B. Campbell9, Robert W. Coombs8, Qing Ma10, Shobha Swaminathan11, Bernard J.C. Macatangay12, Gene D. Morse10, Thomas Miller3, David Rusin3, Alexander L. Greninger8, Belinda Ha13, Beverly Alston-Smith14, Kevin Robertson (posthumous)4, Robert Paul15, Serena Spudich16, and the A5324 Study Team.
Abstract
Background
Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system.
Methods
A5324 was a randomized, double-blind, placebo-controlled trial of ART intensification with dolutegravir (DTG)+MVC, DTG+Placebo, or Dual-Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. Assessments were repeated at 24, 48, 72, and 96 weeks. The primary outcome was the change from baseline to week 48 on the normalized total z-score (i.e., the mean of the individual NC test z-scores).
Results
Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (p=0.19).
Total z-score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z-score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, p=0.006) and did not differ between arms (p>0.10).
Conclusions
This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.
Effects of the Intervention on NC Test Performance, Depressive Symptoms, and IADLs.
Global NC test performance, BDI-II values, and IADL values over time by treatment arm are shown in Figure 2. In all arms, the total z-score improved between baseline and the primary outcome timepoint, week 48 (mean 0.25, 95% CI 0.16-0.34), consistent with practice effects.48
This change did not differ between arms (DTG+Placebo vs. Dual-Placebo: p=0.60, DTG+MVC vs. Dual-Placebo: p=0.33). Total z-score also did not differ between arms over 96 weeks (DTG+Placebo vs. Dual-Placebo: p=0.79, DTG+MVC vs. Dual-Placebo: p=0.95). Individual domain z-scores also improved over time in the entire group and did not differ between arms (Table 2, all p values >0.05), except for Verbal Memory (weeks 48 and 72) and Verbal Learning (week 48) domains, which improved more in the DTG+MVC arm than in the Dual-Placebo arm. BDI-II and IADL values also improved over time and did not differ between arms (p>0.10).
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