A Randomized Comparison of Antiretroviral Therapy Alone Versus Antiretroviral Therapy with a 'Kick-and-Kill' Approach, on Measures of the HIV Reservoir Amongst Participants with Recent HIV Infection: The RIVER Trial

Abstract

Background: Antiretroviral therapy (ART) alone cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from latently infected cells, making them susceptible to targeted killing - termed "kick and kill" -have the capacity to eliminate cells that comprise the reservoir, and have been explored as a strategy towards an HIV cure. RIVER is the first randomized trial to determine the impact of ART alone versus ART plus 'kick-and-kill' on markers of the HIV reservoir. Methods: RIVER was an open-label, multicenter, 1:1 randomized controlled trial of ART-only (control) versus ART plus the histone deacetylase inhibitor vorinostat (the 'kick') and replication-deficient viral vector vaccines encoding conserved HIV sequences ChAdV63.HIVconsv-prime, MVA.HIVconsv-boost T-cell vaccination (the 'kill') (ART+V+V; intervention) in HIV-positive adults treated in recent HIV-infection. The primary endpoint was total HIV DNA in peripheral blood CD4+ T-cells at weeks 16 and 18 post-randomization. Secondary endpoints included safety, quantitative viral outgrowth, HIV-specific T-cell frequencies, CD8+ T-cell mediated viral inhibition, and histone acetylation. Findings: Sixty HIV-positive male participants were randomized and completed the study interventions, with no loss-to-follow-up. There were no intervention-related serious adverse events. Histone acetylation increased 3.2-fold two hours post-vorinostat dosing (p<0.001). Significantly higher HIV-specific T-cell responses were observed in the ART+V+V than the ART-only arm. Overall mean total HIV DNA was 3.04 log10 copies HIV DNA/106 CD4+ T-cells with no statistically significant difference between the arms in the primary endpoint (mean difference (intervention - control) of 0.04 (95%CI -0.03, 0.11) log10 total HIV DNA copies/106 CD4+ T-cells (p=0.256)), or in the proportion of participants with undetectable viral outgrowth (Odds Ratio 0.41 (95%CI 0.13,1.35) (p=0.145)). Interpretations: Despite significantly enhanced vaccine-induced HIV-specific T-cell immunity and vorinostat-induced histone acetylation, this 'kick-and-kill' approach conferred no significant benefit compared to ART alone on measures of the HIV reservoir. Trial Registration: NCT02336074 Funding Statement: The trial was funded by grant MR/L00528X/1 MRC DPFS; The vaccine GMP manufacture was jointly funded by the UK Medical Research Council and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreements (MRC G0701669) by award to Tomas Hanke (TH) and Lucy Dorrell (LD), and by EC FP7 award 305632 to LD, TH and others. TH and LD are the Jenner Institute, University of Oxford Investigators. Sarah Fidler is partly funded through the Imperial College NIHR BRC. John Frater is funded by the Medical Research Council (MR/L006588/1). The MRC Clinical Trials Unit at University College London is supported by grants from the MRC (MC-UU-12023/23 and MC-UU-12023/26).This work is supported by the CHERUB Collaboration. Declaration of Interests: No competing interests to disclose. Ethics Approval Statement: Ethics committee approval was obtained from all participating centres, (14/SC/1372) in accordance with the principles of the Declaration of Helsinki.