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 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.

The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency

“…Collectively due to these tandem mechanisms, it is not surprising that baricitinib and ruxolitinib confer blockade of key events driving reservoir establishment and maintenance in this system. HIV GKO is a single-round, replication deficient HIV, therefore, we cannot evaluate virus spreading in this model though it has been shown previously that ruxolitinib inhibits viral spreading in vitro with wild-type HIV infected cells (40), and has demonstrated efficacy towards blocking of HIV persistence markers and reservoir lifespan marker Bcl-2 in the A5336 study (39). Baricitinib (Olumiant.com) is cleared through the kidneys, significantly reducing potential for drug-drug interactions with co-administered agents that are cleared in the liver, which is a property of ruxolitinib (Jakafi.com).…”

“…Finally, we used this tool to test reactivation of latency and FDA-approved JAK1/2 inhibitors as a therapeutic intervention for silencing HIV transcription. The FDA-approved JAK1/2 inhibitor ruxolitinib was recently evaluated in an AIDS Clinical Trial Group multi-site Phase 2a study (A5336), and demonstrated safety and efficacy in virally suppressed people living with HIV, including a significant decrease in key markers associated with HIV persistence including HLA-DR/CD38, CD25, and sCD14, as well as cellular/reservoir lifespan marker Bcl-2 (39). Baricitinib is a second-generation orally bioavailable JAK1/2 inhibitor that has an improved safety profile versus ruxolitinib, is approved for chronic long-term use in adults and children as young as two years of age (Olumiant.com).…”

Ethical and practical considerations for interventional HIV cure-related research at the end-of-life: A qualitative study with key stakeholders in the United States

“…Our study was formative in nature; as such, we focused on broad categories of HIV cure-related research interventions that could potentially be tested in PWH at the EOL. More research will be necessary to determine practical and ethical considerations for testing specific interventions in the EOL translational research model (e.g., small-molecule repurposed agents such as JAK 1/2 inhibitors [51], CGT approaches such as CRISPR-Cas9 [52][53][54], long-acting slow effective reslease ART [55,56], etc.). Ethical research at the EOL will require robust and sustained engagement of diverse communities, patients, clinicians, and NOK/loved ones.…”

Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators

“…Tofacitinib is a Jak 3 selective inhibitor that is FDA approved for the indication of rheumatoid arthritis, however its utility in the space of HIV-1-1 in humans is diminished due to potential for Jak 3 mediated lymphopenia [Xeljanz package insert]. Ruxolitinib, a first generation Jak ½ selective inhibitor, has been evaluated in vitro, ex vivo and in humans for the indication of HIV-1-1 and has demonstrated a novel mechanism to block reservoir reseeding and maintenance (99,(108)(109)(110). The A5336 ACTG sponsored Phase 2a study demonstrated that ruxolitinib is safe and well tolerated in virally suppressed people living with HIV-1 and conferred a significant reduction in key markers of HIV-1-1 persistence including HLA-DR/CD38, sCD14, and reservoir lifespan marker Bcl-2.…”