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SAFETY, TOLERABILITY AND IMMUNOLOGIC ACTIVITY OF RUXOLITINIB ADDED TO SUPPRESSIVE ART
Vincent C. Marconi1, Carlee Moser2, Christina Gavegnano1, Athe Tsibris3, Amy Kantor2, Edgar T. Overton4, Charles W. Flexner5, Peter W. Hunt6, Rafick-Pierre Sekaly7, Carlos del Rio1, Michael M. Lederman7, Randall Tressler8, Steven G. Deeks6, Jeffrey J. Lennox1, Raymond F. Schinazi1
1Emory University, Atlanta, GA, USA,2Harvard T.H. Chan School of Public Health, Boston, MA, USA,3Harvard Medical School, Boston, MA, USA,4University of Alabama at Birmingham, Birmingham, AL, USA,5Johns Hopkins University School of Medicine, Baltimore, MD,6University of California San Francisco, San Francisco, CA, USA,7Case Western Reserve University, Cleveland, OH, USA,8NIH, Bethesda, MD, USA
Chronic inflammation is associated with end-organ disease and mortality for people living with HIV (PLWH). Ruxolitinib (RUX) is a Janus kinase (Jak) 1/2 inhibitor that reduced biomarkers of systemic inflammation in HIV-uninfected individuals, and HIV reservoir and persistence markers ex vivo. The goal of this trial was to determine the safety and efficacy of RUX in treated HIV disease.
ACTG 5336 was an open-label, multi-site, randomized controlled trial of RUX (10 mg BID) for 5 weeks plus continuing ART versus ART alone. Eligible participants were suppressed on ART for > 2 years, CD4+ T cells >350 cells/µL, and had no current diagnosis or history of significant medical comorbidities. Primary tolerability and safety outcomes were premature RUX discontinuation and occurrence of any pre-defined safety event. Mean changes in plasma levels of IL6 (primary efficacy outcome), sCD14, and circulating CD4 and CD8 counts were compared between arms with t-tests. Plasma HIV-1 RNA levels were measured by integrase single copy assay (iSCA) with a limit of detection of 0.4 cpm. GEE models for binary data compared changes between arms.
Sixty participants enrolled (80% men, median age 44 yrs and CD4 count 737 cells/ µL; n=40 RUX and n=20 ART alone). Primary safety events occurred in 2.5% in RUX arm and 0% in control arm (Fisher's, p=0.67). Three participants prematurely discontinued RUX due to participant request, unrelated syncope, and a grade 3 increased AST. At week 4/5, there was a non-significant decrease in IL6 in the RUX arm compared to control arm (mean fold change (FC) 0.93 vs 1.10, p=0.18), but a significant decrease in sCD14 in the RUX vs control arm (mean FC 0.97 vs 1.10, p=0.03). Those on RUX had a similar likelihood of iSCA < 0.4 cpm compared to control (relative risk = 0.98, p=0.94). In the RUX arm, CD4 and CD8 cell counts increased significantly at week 2 (mean Δ 131 and 162 cells/µL) and compared to control arm (p=0.01); at week 5, CD8 counts returned to baseline while CD4 counts remained elevated in the RUX arm.
In a highly selected cohort of HIV-positive adults on suppressive ART, RUX was safe and well tolerated but did not significantly reduce IL6 levels. On RUX treatment there was a modest decrease in sCD14 with an increase in circulating T cells through mechanisms undefined. This proof-of-concept trial provides a rationale for future studies of Jak inhibitors in PLWH who have residual inflammation or immune dysfunction despite long-term suppressive ART.