Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus

• Type of Material: Article
• Authors: Vincent Marconi, Emory University; Carlee Moser, Harvard T. H. Chan School of Public Health, Boston; Christina Gavegnano, Emory University; Steven G Deeks, University of California San Francisco; Michael M Lederman, Case Western Reserve University; Edgar T Overton, University of Alabama Birmingham; Athe Tsibris, Harvard Medical School; Peter W Hunt, University of California San Francisco; Amy Kantor, Harvard T. H. Chan School of Public Health, Boston; Rafick-Pierre Sekaly, Emory University; Randall Tressler, National Institutes of Health, Bethesda; Charles Flexner, Johns Hopkins University; Selwyn Hurwitz, Emory University; Daniela Moisi, Case Western Reserve University; Brian Clagett, Case Western Reserve University; William R Hardin, Duke University; Carlos Del Rio, Emory University; Raymond Schinazi, Emory University; Jeffrey Lennox, Emory University
• Language: English
• Date: 2022-01-01
• Publisher: OXFORD UNIV PRESS INC
• Publication Version: Final Published Version
• Copyright Statement: Published by Oxford University Press for the Infectious Diseases Society of America 2021.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1093/cid/ciab212
• Title of Journal or Parent Work: CLINICAL INFECTIOUS DISEASES
• Volume: 74
• Issue: 1
• Start Page: 95
• End Page: 104
• Grant/Funding Information: This work was supported by the NIAID/NIH (grant numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701 to V. C. M.); the National Institute of Mental Health (grant number R01-MH-116695 to R. F. S.); and the Emory Center for AIDS Research (grant number P30AI050409 to V. C. M. and R. F. S.). R. F. S. provided funding support for the study drug.
• Keywords: Immunology; reservoir; Microbiology; MARKERS; INFECTED PATIENTS; Infectious Diseases; INDIVIDUALS; Life Sciences & Biomedicine; Science & Technology; HIV; MYELOFIBROSIS; COAGULATION; immune activation; inflammation; Jak inhibitors; QUANTIFICATION; T-CELL-ACTIVATION; SUPPRESSION; INFLAMMATION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Public Health

Abstract

BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (P = .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; P = .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.