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SINGLE ROMIDEPSIN INFUSIONS DO NOT INCREASE HIV EXPRESSION IN PERSONS ON ART (A5315)
Deborah McMahon1, Lu Zheng2, Joshua C. Cyktor1, Evgenia Aga2, Bernard J. Macatangay1, Catherine Godfrey3, Michael Para4, Ronald T. Mitsuyasu5, Evelyn Hogg6, Joseph Hesselgesser7, Edward P. Acosta8, Rajesh T. Gandhi2, John W. Mellors1
1University of Pittsburgh, Pittsburgh, PA, USA,2Harvard University, Cambridge, MA, USA,3NIH, Bethesda, MD, USA,4The Ohio State University, Columbus, OH, USA,5University of California Los Angeles, Los Angeles, CA, USA,6Social & Scientific Systems, Silver Spring, MD, USA,7Gilead Sciences, Inc, Foster City, CA, USA,8University of Alabama at Birmingham, Birmingham, AL, USA
Romidepsin (RMD) is a potent histone deacetylase inhibitor reported to increase HIV RNA in plasma and cells after single or multiple infusions of 5 mg/m2. We sought to determine the safest, lowest effective dose of RMD for induction of HIV expression.
Three single-dose cohorts (0.5 mg/m2, 2 mg/m2, 5 mg/m2) of HIV-infected participants were sequentially enrolled in a double-blind, randomized, placebo-controlled (3:1 active/placebo per cohort) study, target 15/cohort. Enrollees were virally suppressed on EFV, RAL, or DTG-containing ART with plasma HIV RNA ≥0.4 but <50 cps/mL. Viremia was measured by single copy assay (SCA) before and after RMD/placebo 4 hr infusion at hrs 6, 12, 24, 48 and days 7, 14, 28. Cell-associated HIV DNA (CAD) and unspliced RNA (CAR) were measured by qPCR in resting CD4+ cells pre- and post-infusion (hr 24; day 14). Histone-3 acetylation (H3-Ac) was measured by flow in total CD3+ T-cells pre-infusion and at hrs 12, 24, 48 and days 7, 14, 28. RMD was measured pre- and post-infusion at hrs 4, 6, 12, 24. Pre-specified primary comparisons were between the pooled RMD and pooled placebo groups using the Wilcoxon test.
43 participants enrolled (36 RMD; 7 placebo); 40 male; 27 white, 14 black; median screening SCA 1.5 cps/mL; median CD4 667 cells/mm3. All completed the infusions; all but one completed 28-day follow-up. No Grade 3 events were deemed treatment-related. Median RMD levels at hr 4 were 12.0, 75.2, 89.0 ng/mL in the 0.5, 2.5 and 5 mg/m2 cohorts, respectively, and declined rapidly. The primary efficacy measure of SCA change from pre-infusion to the average of 24 and 48 hr post was similar between the pooled RMD and placebos (median: 0.12 vs. 0.12 log10 cps/mL, p=0.88, [95% CI on difference: -0.48, 0.33]). There was no significant difference in change in CAR from pre-infusion to 24 hr post (-0.09 vs. 0 log10 cps/106 resting CD4+ cells, p=0.37, [-0.54, 0.23]) or in CAD (-0.04 vs. 0.05 log10 cps/106 resting CD4+ cells, p=0.73, [-0.33, 0.32]). No significant increases in any virologic measure or in H3-Ac were observed in any of the RMD dose arms compared to pooled placebos or from pre-infusion to other timepoints (all p > 0.05).
In contrast to prior uncontrolled studies, in this placebo-controlled, dose-escalation study, single RMD doses that achieved a range (>5-fold) of systemic exposures were well-tolerated but did not increase HIV expression OR H3-Ac. Multiple or higher RMD doses may be needed to induce HIV expression.