Background:
Ruxolitinib is FDA approved for myelofibrosis, polycythemia vera, atopic dermatitis and chronic graft-versus-host disease. We evaluated ruxolitinib’s impact on the peripheral HIV-1 reservoir and key immunomodulatory events driving HIV-1 persistence in people with HIV-1 (PWH) in an AIDS Clinical Trial (ACTG) sponsored open-label randomized Phase 2a multi-site trial (n=60).
Methods:
Inclusion criteria: ≥18 age ≤75, background ART regimen (NNRTI or INSTI without cobicistat for ≥2 years), continuously virologically suppressed, CD4+ T-cell count >350 cells/mm3; no significant medical condition besides HIV or hypertension. Participants were randomized to ruxolitinib 10 mg bid plus ART (n=40) or ART alone (n=20) from week 0 through 5. Both groups were observed through week 12. Cellular markers, integrated DNA, and IPDA were measured on peripheral blood from weeks 0, 5, and 12. A sequential series of Mann-Whitney U tests were performed to understand how biomarker changes across weeks impact reservoir decay. We evaluated 1) biomarkers within the ruxolitinib-treated (RUX) group which were altered from baseline, 2) which markers determined in round 1 were differential versus control (CNT) group, and 3) which of these were associated with participants who experienced reservoir growth or decay independent of treatment. Significance was further confirmed through Benjamini-Hochberg testing to minimize the false discovery rate (15%).
Results:
Integrated DNA and IPDA reservoir measurements were highly correlated to one another throughout trial. HIV-1 reservoir significantly decayed in the RUX group by week 12 versus CNT (p=0.0471). Cellular markers altered by ruxolitinib, possessing a different expression profile from CNT, and associated with reservoir decay were determined: pSTAT5+ monocytes in low baseline reservoir and total RUX groups at week 12, pSTAT3+ monocytes in low baseline reservoir at week 12, BCL-2+KI67+ CD4+ TN cells in the total RUX group at week 5, CD127+ CD8+ TTD cells in the total RUX group at week 5, and CD25+ CD8+ TTM cells in the total RUX group at week 5.
Conclusions:
Ruxolitinib decays the HIV-1 reservoir and resets immune balance in PWH on ART. Based on observed reservoir decay (week 5 to 12), our model predicts a 99.99% decay in 2.83 years, should rate of decay remain constant. These data are foundational for further human trials with Jak 1/2 inhibitors such as ruxolitinib towards HIV-1 elimination.