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

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.

Keywords: HIV; Jak inhibitors; immune activation; inflammation; reservoir.

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

Figures

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) flow diagram. Abbreviations: ARV, antiretroviral; AST, aspartate aminotransferase; HIV, human immunodeficiency virus; SGOT, serum glutamic-oxaloacetic transaminase.

Figure 2.

Longitudinal jitter plots of changes in plasma cytokines with or without 5 weeks of ruxolitinib for individuals virologically suppressed on antiretroviral therapy. Interleukin (IL)–6 (A), soluble CD14 (sCD14; B), tumor necrosis factor alpha (TNF-α; C), IL-1β (D), IL-7 (E), and IL-10 (F) measured at preentry and entry, and weeks 2, 4, 5, 10, and 12, depending on the marker (see x-axis); baseline is the average of preentry and entry, week 4/5 is the average of weeks 4 and 5, and week 10/12 is the average of weeks 10 and 12. Black circles and triangles represent the geometric mean, and error bars represent 95% confidence intervals. Jittered data points are shown as transparent circles and triangles.

Figure 3.

Longitudinal jitter plots of changes in cell surface markers with or without 5 weeks of ruxolitinib for individuals virologically suppressed on antiretroviral therapy. Percentage of CD4+CD38+HLA-DR+ (A), CD4+Bcl2+ (B), CD4+CD127+ (C), CD4+CD25Hi+CD127– (D), CD4+α4β7+ (E), and CD4+Ki 67+ measured at entry and at weeks 2, 5, and 12. Black circles and triangles represent the mean, and error bars represent 95% confidence intervals. Jittered data points are shown as transparent circles and triangles.

Figure 4.

Longitudinal jitter plots of changes in T-cell subsets with or without 5 weeks of ruxolitinib for individuals virologically suppressed on antiretroviral therapy. CD4 absolute count (A) and CD8 absolute count (B) measured at preentry and entry, and weeks 2, 5, and 12; baseline is the average of preentry and entry. Black circles and triangles represent the mean and error bars represent 95% confidence intervals. Jittered data points are shown as transparent circles and triangles.

Figure 5.

Longitudinal jitter plots of changes in human immunodeficiency virus (HIV) reservoir markers with or without 5 weeks of ruxolitinib for individuals virologically suppressed on antiretroviral therapy. Total HIV-1 DNA (A) and cell-associated RNA (B) copies per million CD4+ T cells measured at entry and weeks 2, 5, and 12. Among participants who were detectable at entry for each respective marker, total HIV-1 DNA (C) and cell-associated RNA (D) copies per million CD4+ T cells measured at entry and at weeks 2, 4, and 12. Black circles and triangles represent the geometric mean, and error bars represent 95% confidence intervals. Jittered data points are shown as transparent circles and triangles.