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MULTIDOSE IV ROMIDEPSIN: NO INCREASED HIV-1 EXPRESSION IN PERSONS ON ART, ACTG A5315
Deborah McMahon1, Lu Zheng2, Joshua C. Cyktor1, Evgenia Aga2, Bernard J. Macatangay1, Catherine Godfrey3, Michael Para4, Ronald T. Mitsuyasu5, Joseph Hesselgesser6, Curtis Dobrowolski7, Jonathan Karn7, Edward P. Acosta8, Rajesh T. Gandhi9, John W. Mellors1
1University of Pittsburgh, Pittsburgh, PA, USA,2Harvard University, Boston, MA, USA,3NIH, Bethesda, MD, USA,4The Ohio State University, Columbus, OH, USA,5University of California Los Angeles, Los Angeles, CA, USA,6Gilead Sciences, Inc, Foster City, CA, USA,7Case Western Reserve University, Cleveland, OH, USA,8University of Alabama at Birmingham, Birmingham, AL, USA,9Massachusetts General Hospital, Boston, MA, USA
Romidepsin (RMD) is a histone deacetylase inhibitor that has been reported to increase HIV-1 RNA expression in plasma and cells after single or multiple infusions of 5 mg/m2. We sought to determine if administering multiple doses of RMD would be safe and induce HIV-1 expression.
HIV-1-infected participants were enrolled in a double-blind, randomized, placebo-controlled (3:1 RMD/placebo) cohort to receive RMD 5 mg/m2 x 4 doses (at days 0, 14, 28, 42). Enrollees were receiving RAL- or DTG-containing ART with plasma HIV-1 RNA <50 cps/mL. Viremia was measured by integrase single copy assay (iSCA) before and 24hr after each RMD/placebo infusion and 72hr after the 2nd infusion. Cell-associated HIV-1 DNA (CAD) and cellular unspliced RNA (CAR) were measured by qPCR in PBMC at the same time points, as well as changes in CD4%, histone-3/4 acetylation and methylation (H3-Ac/Me), P-TEFb, and NFκb by flow. Other measures included changes in T cell activation and apoptosis from baseline to 24 hrs post 1st and 4th infusion. RMD levels were measured at hr 4 post-infusions 3 and 4. Comparisons between arms used Wilcoxon tests.
16 participants enrolled (13 RMD; 3 placebo); 11 male; median CD4 699 cells/mm3. All but two completed 4 infusions. One Grade 3 event (transient neutropenia) was deemed possibly treatment-related. Median RMD levels were 69 and 134 ng/mL, at hr 4 post-infusions 3 and 4, respectively. No significant increases in iSCA, CAR, or CAD were observed from baseline to post-baseline time points or from pre- to post-infusion for each infusion compared to placebo (Figure; all p>0.05). Evidence of host pharmacodynamic effects was demonstrated as significant decreases in CD4% at 24hr after infusions 2, 3, and 4 (median -3.5% to -4.5% vs. 1.5% to 1% in placebos, all p≤0.022). Significant increases were observed in H3-Ac/Me (pNFκB+)%, (pS175+)% on CD4+ T cells 24 and 72 hrs after 2nd infusion of RMD compared to placebo (Figure; all p≤0.02). No differences were detected in T cell activation/apoptosis changes between arms.
Multiple RMD doses were safe but did not induce HIV-1 expression in individuals on suppressive ART despite pharmacodynamic effects on host cells including reductions in % CD4+T-cells, increases in histone acetylation, and PTEFb activation. More effective strategies will be needed to reverse HIV-1 latency.