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Title
A randomised controlled trial comparing the impact of antiretroviral therapy (ART) with a 'Kick-and-Kill' approach to ART alone on HIV reservoirs in individuals with primary HIV infection (PHI); RIVER trial
Presenter
Sarah Fidler
Authors
S. Fidler1, W. Stohr2, M. Pace3, L. Dorrell3, A. Lever4, S. Pett2, S. Kinloch5, J. Fox6, A. Clarke7, M. Nelson8, M. Khan9, A. Fun4, D. Kelly10, J. Kopycinski3, M. Johnson5, T. Hanke3, H. Yang3, B. Howell11, S. Kaye9, M. Wills4, R. Barnard11, A. Babiker2, J. Frater12, On Behalf of the RIVER trial investigators
Institutions
1Imperial College London, Medicine, London, United Kingdom, 2University College London, MRC CTU, London, United Kingdom, 3University of Oxford, NDM, Oxford, United Kingdom, 4University of Cambridge, Cambridge, United Kingdom, 5University College London, Royal Free Hospital, London, United Kingdom, 6Kings College London, Guys & St Thomas Kings, London, United Kingdom, 7Univeristy of Brighton, Medicine, Brighton, United Kingdom, 8Chelsea & Westminster Hospital, Medicine, London, United Kingdom, 9Imperial College London, London, United Kingdom, 10Patient advocacy Alliance CIC, Manchester, United Kingdom, 11Merck MSD, Pennsylvania, United States, 12University of Oxford, Peter Medwar, Oxford, United Kingdom

Background: ART alone is unable to cure HIV because of an inaccessible pool of latently infected cells, the HIV reservoir. In the first randomised controlled trial (RCT) of a ''kick-and-kill'' strategy, amongst participants with PHI on ART, we investigated the impact of HIV-specific T-cell vaccines and a latency reversing agent (vorinostat) on the HIV reservoir.
Methods: Individuals who started ART within 4 weeks of confirmed PHI diagnosis with suppressed plasma HIV-RNA were randomised to either ART plus vaccination with ChAdV63.HIVconsv prime < 1 week post-randomisation (PR) and MVA.HIVconsv boost (8 weeks later) followed by 10 doses of 400mg oral vorinostat taken every 3 days (intervention) or ART alone (control).
The two arms were compared for the primary outcome (log10 total HIV-DNA copies/million from CD4+ T-cells at weeks PR-16&18) using analysis of covariance adjusted for baseline level. Secondary endpoints included quantitative viral outgrowth measuring replication-competent HIV-1 reservoir at week PR-16, HIV-specific CD4+ and CD8+ T-cell responses by intracellular cytokine staining at weeks PR-9&12, histone acetylation pre&post vorinostat and adverse events.
Results: 60 male participants were randomised at 6 UK sites (30 intervention, 30 control), with median: age 32 years, 26 weeks since ART start and CD4+ count 708 cells/mm3. All participants completed follow-up. There was no difference between the arms in the primary outcome (intervention versus control: 0.041 (95%CI -0.031, 0.113) log10 HIV-DNA copies/million CD4+ T-cells p=0.256), or in the proportion with undetectable viral outgrowth (0.42 (95% CI 0.13, 1,37) p=0.151) Participants with undetectable viral outgrowth had significantly lower total HIV-DNA. Participants in the intervention arm showed significantly higher HIV-specific CD4+ (IFNg/IL2/TNFa/CD154) and CD8+ (IFNg/TNFa) T-cell responses post vaccination than control. Histone acetylation increased 3.2-fold two hours post-vorinostat (p< 0.001). There was no virological failure or intervention-related SAE. More clinical adverse events were reported in the intervention arm, all were mild/moderate.
Conclusions: In the first ''kick-and-kill'' RCT in PHI, despite evidence of robust vaccine-induced HIV-specific T-cell immunity and vorinostat activity, there was no impact on measures of HIV reservoir compared to ART alone. Vaccination and vorinostat did not raise any safety concerns. Further analyses are ongoing to explore mechanisms to explain these findings.


Figure of total HIV DNA by arm
[Figure of total HIV DNA by arm ]