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Author Notes:

V. C. Marconi, Emory University, Health Sciences Research Bldg, 1760 Haygood Dr NE, Rm W325, Atlanta, GA 30322

V. C. M., C. M., C. G., S. G. D., M. M. L., A. T., P. W. H., R. T., C. F., S. H., C. D. R., R. F. S., and J. J. L. developed the concept and designed the study. M. M. L., E. T. O., A. T., P. W. H., and R. P. S. provided study material or participants. C. M. and A. K. verified the data and performed the statistical analyses. V. C. M., C. M., C. G., and J. J. L. wrote the initial draft of the manuscript. All authors provided critical comments and editing, contributed to the data interpretation, and reviewed the analyses of this manuscript and approved its final version.

We are grateful to the participants, clinical staff, and study team members at the participating sites for their generous contributions to this work and especially the AIDS Clinical Trials Group (ACTG), Statistical and Data Management Center, participating Clinical Research Sites, and specialty laboratories including the Brigham and Women’s Hospital, Harvard Medical School, Case Western Reserve University, and Emory University School of Medicine. The following reagent was obtained through the AIDS Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH): Anti-Human α4-β7 integrin monoclonal (Act-1) (catalog number 11718) from Dr A. A. Ansari.

V. C. M. has received investigator-initiated research grants (to the institution) and consultation fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences, and ViiV. M. M. L. has received a competitive research grant award (to the institution) from Gilead and has consulted for Eli Lilly. C. F. received consultation fees unrelated to the current work from Merck, Mylan Pharmaceuticals, and ViiV Healthcare. S. D. reports grants from Gilead and Merck, and personal fees from Abbvie, Biotron, Eli Lilly, Enochian Biosciences, and ImmunoCore, outside the submitted work. C. F. also reports expert witness services to Gilead, outside the submitted work. A. T. reports grants from the ACTG. A. T. also reports grants from Merck and personal fees from Gilead Sciences and EBSCO/DynaMed, outside the submitted work.

P. H. reports grants from Gilead and personal fees from Gilead, ViiV, Janssen, and Biotron, outside the submitted work. J. L. reports grants and personal fees from ViiV Pharmaceuticals, outside the submitted work. C. M. reports grants from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases, outside the submitted work. R. F. S. and C. G. have served as unpaid consultants for Eli Lilly. In addition, R. F. S. owns shares in Eli Lilly and Incyte, the manufacturers of baricitinib and ruxolitinib, respectively. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. All other authors report no potential 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.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Infectious Diseases
  • Microbiology
  • HIV
  • inflammation
  • Jak inhibitors
  • immune activation
  • reservoir
  • T-CELL-ACTIVATION
  • INFECTED PATIENTS
  • INFLAMMATION
  • MARKERS
  • QUANTIFICATION
  • MYELOFIBROSIS
  • INDIVIDUALS
  • COAGULATION
  • SUPPRESSION

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

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Journal Title:

CLINICAL INFECTIOUS DISEASES

Volume:

Volume 74, Number 1

Publisher:

, Pages 95-104

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

Published by Oxford University Press for the Infectious Diseases Society of America 2021.

This is an Open Access work distributed under the terms of the Creative Commons Universal : Public Domain Dedication License (https://creativecommons.org/publicdomain/zero/1.0/rdf).
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