A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons with HIV-1 on Suppressive Antiretroviral Therapy

Academic Article

Abstract

  • 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 antiretroviral therapy. 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: In the single-dose cohorts 1-3, 43 participants enrolled (36 participants 0.5, 2, 5 mg/m 2 RMD; 7 placebo) and 16 enrolled in the multidose cohort 4 (13 participants 5 mg/m 2 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, pharmacodynamic effects of RMD were reduced proportions of CD4+ T cells 24 hours after infusions 2-4 (median, -3.5% to -4.5%) vs placebo (median, 0.5% to 1%; P ≤. 022), and increased H3K9ac+ and phosphorylated P-TEFb in CD4 + T cells vs placebo (P ≤. 02). Conclusions: RMD infusions were safe but did not increase plasma viremia or unspliced CA-RNA despite pharmacodynamic effects on CD4 + T cells. Clinical Trials Registration: NCT01933594.
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    Author List

  • McMahon DK; Zheng L; Cyktor JC; Aga E; Macatangay BJ; Godfrey C; Para M; Mitsuyasu RT; Hesselgesser J; Dragavon J
  • Start Page

  • 648
  • End Page

  • 656
  • Volume

  • 224
  • Issue

  • 4