Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial.,The Lancet

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Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial.
The Lancet ( IF 98.4 ) Pub Date : 2020-02-18 , DOI: 10.1016/s0140-6736(19)32990-3
Sarah Fidler ₁ , Wolfgang Stöhr ₂ , Matt Pace ₃ , Lucy Dorrell ₄ , Andrew Lever ₅ , Sarah Pett ₆ , Sabine Kinloch-de Loes ₇ , Julie Fox ₈ , Amanda Clarke ₉ , Mark Nelson ₁₀ , John Thornhill ₁ , Maryam Khan ₁ , Axel Fun ₁₁ , Mikaila Bandara ₁₂ , Damian Kelly ₁₃ , Jakub Kopycinski ₄ , Tomáš Hanke ₁₄ , Hongbing Yang ₄ , Rachel Bennett ₂ , Margaret Johnson ₁₅ , Bonnie Howell ₁₆ , Richard Barnard ₁₇ , Guoxin Wu ₁₆ , Steve Kaye ₁₈ , Mark Wills ₁₁ , Abdel Babiker ₂ , John Frater ₄ ,

Affiliation

Department of Infectious Disease, Imperial College London, London, UK; NIHR Imperial Biomedical Research Centre, London, UK.
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Nuffield Department of Medicine, Oxford University, UK; Nuffield Department of Medicine Oxford Martin School, Oxford, UK.
Nuffield Department of Medicine, Oxford University, UK; Nuffield Department of Medicine, Oxford NIHR Biomedical Research Centre, Oxford, UK.
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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.
Department of Infection and Immunity, Royal Free Hospital, London, UK; University College London, London, UK.
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.
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.
Chelsea and Westminster Hospital, Department of HIV Medicine, Imperial College London London, UK.
Department of Medicine, University of Cambridge, Cambridge, UK.
University of Cambridge, Cambridge, UK.
Patient Advocacy Alliance, Manchester, UK.
Nuffield Department of Medicine, Oxford University, UK; International Research Center for Medical Sciences, Kumamoto University, Japan.
Department of HIV Medicine, Royal Free Hospital, London, UK.
Department of Infectious Disease and Vaccines, Merck and Co, West Point, PA, USA.
Global Regulatory Affairs and Clinical Safety, Merck and Co, North Wales, PA, USA.
Department of Infectious Disease, Imperial College London, London, UK.

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).

中文翻译：

单独抗逆转录病毒治疗与采用踢杀方法的抗逆转录病毒治疗，对最近感染 HIV 的参与者的 HIV 储存库进行测量（RIVER 试验）：一项 2 期随机试验。

背景技术抗逆转录病毒疗法(ART)不能治愈HIV感染，因为潜伏感染细胞的持续储存。迫使这些细胞转录艾滋病毒，使它们容易受到杀伤的方法（称为“踢杀疗法”）已被探索作为治疗艾滋病毒的策略。RIVER 是第一个随机试验，旨在确定仅 ART 与 ART 加踢杀对 HIV 病毒库标记物的影响。方法这项 2 期、开放标签、多中心、随机、对照试验在英国的六个临床中心进行。过去 6 个月内被确诊为 HIV 阳性并在确诊后 1 个月内开始 ART 的 18-60 岁患者被计算机生成的随机化列表随机分配接受仅 ART（对照）或 ART 加治疗组蛋白脱乙酰酶抑制剂伏立诺他（Kick）和编码保守的 HIV 序列 ChAdV63 的复制缺陷病毒载体 T 细胞诱导疫苗。HIVconsv-prime 和 MVA.HIVconsv-boost（杀死；ART + V + V；干预）。主要终点是随机分组后第 16 周和第 18 周从外周血 CD4+ T 细胞中分离出的总 HIV DNA。分析是按意向治疗进行的。该试验已在 ClinicalTrials.gov 注册，NCT02336074。结果 2015 年 6 月 14 日至 2017 年 7 月 11 日期间，60 名 HIV 感染者被随机分配接受仅 ART (n=30) 或 ART + V + V (n=30) 治疗方案；所有 60 名参与者均完成了研究，无失访情况。随机化后第 16 周和第 18 周时，仅接受 ART 组的平均 HIV DNA 总量为每 106 个 CD4+ T 细胞 3·02 log10 拷贝 HIV DNA，而 ART + V + 组中每 106 个 CD4+ T 细胞为 3·06 log10 拷贝 HIV DNA V 组，两组之间无统计学显着差异（每 106 个 CD4+ T 细胞有 0·04 log10 拷贝 HIV DNA 的平均差异 [95% CI -0·03 至 0·11；p=0·26]）。没有发生与干预相关的严重不良事件。解释与单独的 ART 相比，这种踢杀方法在 HIV 储存库的测量方面没有带来显着的益处。尽管这并不能反驳踢杀策略的功效，但未来的试验将需要增强踢杀剂。资助医学研究委员会（MR/L00528X/1）。

更新日期：2020-03-16

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