A phase I/II randomized, placebo-controlled trial of romidepsin in persons with HIV-1 on suppressive antiretroviral therapy to assess safety and activation of HIV-1 expression (A5315)

Background Romidepsin (RMD) is a histone deacetylase inhibitor reported to reverse HIV-1 latency. We sought to identify doses of RMD that were safe and induced HIV-1 expression. Methods Enrollees had HIV-1 RNA <40 copies/ml on ART. Measurements included RMD levels, plasma viremia by single copy HIV-1 RNA assay, HIV-1 DNA, cell-associated unspliced HIV-1 RNA (CA-RNA), acetylation of histone H3-lysine-9 (H3K9ac+) and phosphorylation of transcription factor P-TEFb. Wilcoxon tests were used for comparison. Results 43 participants enrolled in the single dose Cohorts 1-3 of 0.5, 2, and 5 mg/m 2 (36 RMD; 7 placebo) and 16 enrolled in the multi-dose Cohort 4 of 5 mg/m 2 (13 RMD; 3 placebo). One grade 3 event (neutropenia) was possibly treatment-related. No significant changes in viremia were observed in Cohorts 1-4 compared to placebo. In Cohort 4, observed pharmacodynamic effects of RMD were reduced proportions of CD4+ T cells 24 hours after infusions 2, 3, and 4 (median -3.5% to -4.5%) vs. placebo (+0.5% to 1%; p≤0.022) and increases in H3K9ac+ and phosphorylated P-TEFb in CD4 + T cells compared to placebo (p≤0.02). Conclusions RMD infusions were safe but did not increase plasma viremia or unspliced CA-RNA despite pharmacodynamic effects on CD4 + T cells. The trial is registered with ClinicalTrials.gov, number NCT01933594.