TY - JOUR
T1 - Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus
AU - Marconi, Vincent C.
AU - Moser, Carlee
AU - Gavegnano, Christina
AU - Deeks, Steven G.
AU - Lederman, Michael M.
AU - Overton, Edgar T.
AU - Tsibris, Athe
AU - Hunt, Peter W.
AU - Kantor, Amy
AU - Sekaly, Rafick Pierre
AU - Tressler, Randall
AU - Flexner, Charles
AU - Hurwitz, Selwyn J.
AU - Moisi, Daniela
AU - Clagett, Brian
AU - Hardin, William R.
AU - Del Rio, Carlos
AU - Schinazi, Raymond F.
AU - Lennox, Jeffrey J.
N1 - Publisher Copyright:
© 2021 Published by Oxford University Press for the Infectious Diseases Society of America.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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.
AB - 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.
KW - HIV
KW - Jak inhibitors
KW - immune activation
KW - inflammation
KW - reservoir
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U2 - 10.1093/cid/ciab212
DO - 10.1093/cid/ciab212
M3 - Article
C2 - 33693561
AN - SCOPUS:85123647545
SN - 1058-4838
VL - 74
SP - 95
EP - 104
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 1
ER -