Title

Ruxolitinib-mediated HIV-1 reservoir decay in A5336 phase 2a trial

Presenter

Monica D. Reece

Authors

M.D. Reece¹, Z. Zhang¹, S. Pereira-Ribeiro¹, R. Sekaly¹, D.A. Kulpa¹, J. Yoon¹, E. White¹, R.F. Schinazi^2,3,4, V.C. Marconi^5,6, C. Gavegnano^1,7,8,9,10

Institutions

¹Emory University, Department of Pathology and Laboratory Medicine, Atlanta, United States, ²Emory University, School of Medicine, Atlanta, United States, ³Emory University, Department of Pediatrics, Atlanta, United States, ⁴Center for ViroScience and Cure, Atlanta, United States, ⁵Emory University, Division of Infectious Diseases, Atlanta, United States, ⁶Emory University, Department of Global Health, Atlanta, United States, ⁷Emory University, Department of Pharmacology and Chemical Biology, Atlanta, United States, ⁸Emory University, Center for Human Health, Atlanta, United States, ⁹Atlanta Veterans Affairs Medical Center, Department of Pathology, Decatur, United States, ¹⁰Harvard University, Center for Bioethics, Boston, United States

BACKGROUND: Ruxolitinib is FDA approved for myelofibrosis, polycythemia vera, atopic dermatitis and chronic graft-versus-host disease. We evaluated the impact of ruxolitinib 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 (flow-cytometry), soluble cytokine (Mesoscale), intDNA and IPDA were measured on peripheral blood from weeks 0, 5, and 12. 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 group which were significantly (p<0.05) different between weeks 5 and 12, 2)which markers determined in test 1 were significantly (p<0.05) different versus control group, and 3) which of these were trending towards significance (p<0.1) between participants with high reservoir decay and those with no decay. Significance was further confirmed through Benjamini-Hochberg testing to minimize the false discovery rate.
RESULTS: IntDNA and IPDA reservoir measurements were highly correlated to one another (r²0.86). HIV-1 reservoir significantly decayed in the ruxolitinib group by week 12 versus control. Decay correlates included decrease in activation and expansion markers (week 5), leading to reservoir decay by week 12 (CD127⁺/CD4⁺ T_Nand CD127⁺/CD8⁺ T_TD, CD39⁺/CD4⁺ T_EM, and CD69⁺ in B cells). Reservoir decay by week 5 associated with change at week 5 (IL10), and change at week 12 (BCL2⁺/CD8⁺ T_CM).
CONCLUSIONS: Ruxolitinib decays the HIV-1 reservoir and resets immune balance in PWH on ART. Based on reservoir decay during treatment (week 0 to 5), our model predicts a 99.99% decay in 2.5 years, should rates of decay remain constant. These data are foundational for further human trials with Jak 1/2 inhibitors such as ruxolitinib towards HIV-1 elimination.

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