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Randomized Controlled Trial
. 2023 Sep 18;77(6):866-874.
doi: 10.1093/cid/ciad265.

Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus

Scott L Letendre  1 , Huichao Chen  2 , Ashley McKhann  2 , Jhoanna Roa  3 , Alyssa Vecchio  4 , Eric S Daar  5 , Baiba Berzins  6 , Peter W Hunt  7 , Christina M Marra  8 , Thomas B Campbell  9 , Robert W Coombs  8 , Qing Ma  10 , Shobha Swaminathan  11 , Bernard J C Macatangay  12 , Gene D Morse  10 , Thomas Miller  3 , David Rusin  3 , Alexander L Greninger  8 , Belinda Ha  13 , Beverly Alston-Smith  14 , Kevin Robertson  4 , Robert Paul  15 , Serena Spudich  16 ; A5324 Study Team
Affiliations
Randomized Controlled Trial

Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus

Scott L Letendre et al. Clin Infect Dis. .

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, 96-week 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. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48.

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 = .17). 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 = .006) and did not differ between arms (P > .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.

Keywords: HIV; antiretroviral therapy; brain; cognition.

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Conflict of interest statement

Potential conflicts of interest. S. L. L. reports a research grant from Merck & Co to the University at Buffalo (UB) with a subcontract from UB to the author's university. E. S. D. reports grants or contracts from Gilead Sciences, Merck, and ViiV Healthcare and consulting fees from Gilead Sciences, Merck, ViiV Healthcare, and Theratechnologies. P. W. H. reports a research grant to institution from Gilead Sciences; donation of drug for NIH-sponsored trial from Merck; consulting fees to author from ViiV Healthcare and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences and ViiV Healthcare; and participation on a data and safety monitoring board (DSMB) or advisory board with Longeveron. C. M. M. reports grants from NIH/NINDS paid to institution; royalties from Wolters Kluwer to author; consulting fees to author for review of patient charts for law firms; payment for course directorship and continuing medical education lectures at the American Academy of Neurology annual meeting and payment or honoraria for manuscript writing for Medlink Neurology; and a paid role on editorial boards for Medlink Neurology, Frontiers in Neurology. T. B. C. reports grants or contracts from NIH, consulting fees from ViiV Healthcare, and payment to institution for expert testimony from Sidley Austin, LLP. Q. M. reports consulting fees paid to author from Change Healthcare and a role as Toxicology Division chair-elect for the American Society for Pharmacology and Experimental Therapeutics. S. Sw. reports grants or contracts from Gilead Sciences for retrospective chart review (not related to this project) and Real World PrEP data and from Janssen Therapeutics for an HIV vaccine study; consulting fees to author from ViiV Healthcare, Gilead Sciences, and Moderna; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from ViiV Healthcare and Gilead Sciences. B. J. C. M. reports research support from Astra Zeneca. G. D. M. reports participation on a DSMB or advisory board. T. M. reports stock or stock options and other financial or nonfinancial interests from Science 37 (recent employer). A. L. G. reports contract testing to institution from Abbott, Cepheid, Novavax, Pfizer, Janssen Therapeutics, and Hologic and research support from the Bill & Melinda Gates Foundation and Gilead Sciences, outside of the described work. B. H. reports stock or stock options as an employee of ViiV Healthcare. S. Sp. reports grants from the NIH (from NIMH, NINDS, and NIDA), honorarium from the IAS-USA for lectures, and honorarium from academic institutions for grand rounds and other invited talks. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

None
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/challenges-in-the-long-term-management-of-patients-with-coccidioidal-meningitis-a-retrospective-analysis-of-treatment-and-outcomes
Figure 1.
Figure 1.
Time to discontinuation of study drug. Abbreviations: DTG, dolutegravir; MVC, maraviroc.
Figure 2.
Figure 2.
Summary of neuropsychological performance (A), IADLs (B), and BDI-II (C) over time by study arm. Abbreviations: BDI-II, Beck Depression Inventory-II; DTG, dolutegravir; IADL, instrumental activities of daily living; MVC, maraviroc.
See this image and copyright information in PMC

References

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