Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults with HIV.

Background Inflammation is associated with end-organ disease and mortality for people with HIV (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without 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 ACTG A5336 was an open-label, multi-site, randomized-controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10mg twice-daily) plus stable ART for five weeks versus 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 IL-6. Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. Results Sixty participants enrolled from May 16, 2016 to January 10, 2018. Primary safety events occurred in 2.5% (one participant) for ruxolitinib and 0% for controls, (p=0.67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week five, differences in IL-6 (mean Fold Change (FC) 0.93 vs 1.10, p=0.18) and sCD14 levels (mean FC 0.96 vs 1.08, relative FC=0.96 (90%CI: 0.90,1.02)) for ruxolitinib versus controls was observed. Ruxolitinib reduced CD4+ T-cells expressing HLADR/CD38 (difference in means -0.34%, 90%CI: -0.66,-0.12)) and Bcl-2 (-3.30%, 90%CI: (-4.72,-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.