Sarah Fidler1, Wolfgang Stöhr2, Matt Pace3, Lucy Dorrell4, Andrew Lever5, Sarah Pett6, Sabine Kinloch-de Loes7, Julie Fox8, Amanda Clarke9, Mark Nelson10, John Thornhill11, Maryam Khan11, Axel Fun12, Mikaila Bandara13, Damian Kelly14, Jakub Kopycinski4, Tomáš Hanke15, Hongbing Yang4, Rachel Bennett2, Margaret Johnson16, Bonnie Howell17, Richard Barnard18, Guoxin Wu17, Steve Kaye19, Mark Wills12, Abdel Babiker2, John Frater20. 1. Department of Infectious Disease, Imperial College London, London, UK; NIHR Imperial Biomedical Research Centre, London, UK. Electronic address: s.fidler@imperial.ac.uk. 2. Medical Research Council Clinical Trials Unit, University College London, London, UK. 3. Nuffield Department of Medicine, Oxford University, UK; Nuffield Department of Medicine Oxford Martin School, Oxford, UK. 4. Nuffield Department of Medicine, Oxford University, UK; Nuffield Department of Medicine, Oxford NIHR Biomedical Research Centre, Oxford, UK. 5. Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 6. Medical Research Council Clinical Trials Unit, University College London, London, UK; Institute for Global Health, University College London, London, UK; Mortimer Market Centre, London, UK. 7. Department of Infection and Immunity, Royal Free Hospital, London, UK; University College London, London, UK. 8. Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas' NHS Trust, London, UK; Department of Genitourinary Medicine and Infectious Disease, NIHR Biomedical Research Centre, Kings College London, London, UK. 9. Elton John Centre, Brighton, UK; Department of HIV and Sexual Health, Sussex University Hospital, Brighton, UK; Brighton and Sussex Medical School, University of Sussex, Brighton, UK. 10. Chelsea and Westminster Hospital, Department of HIV Medicine, Imperial College London London, UK. 11. Department of Infectious Disease, Imperial College London, London, UK; NIHR Imperial Biomedical Research Centre, London, UK. 12. Department of Medicine, University of Cambridge, Cambridge, UK. 13. University of Cambridge, Cambridge, UK. 14. Patient Advocacy Alliance, Manchester, UK. 15. Nuffield Department of Medicine, Oxford University, UK; International Research Center for Medical Sciences, Kumamoto University, Japan. 16. Department of HIV Medicine, Royal Free Hospital, London, UK. 17. Department of Infectious Disease and Vaccines, Merck and Co, West Point, PA, USA. 18. Global Regulatory Affairs and Clinical Safety, Merck and Co, North Wales, PA, USA. 19. Department of Infectious Disease, Imperial College London, London, UK. 20. Nuffield Department of Medicine, Oxford University, UK; Nuffield Department of Medicine, Oxford NIHR Biomedical Research Centre, Oxford, UK. Electronic address: john.frater@ndm.ox.ac.uk.
Abstract
BACKGROUND:Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. METHODS: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. FINDINGS:Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. INTERPRETATION: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. FUNDING: Medical Research Council (MR/L00528X/1).
RCT Entities:
BACKGROUND: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. METHODS: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. FINDINGS: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. INTERPRETATION: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. FUNDING: Medical Research Council (MR/L00528X/1).
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