单独抗逆转录病毒疗法与抗逆转录病毒疗法联合“踢杀”策略对近期感染 HIV 参与者的 HIV 储存库测量的影响（RIVER 试验）：一项 2 期随机试验。

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.

机构信息

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.

出版信息

Lancet. 2020 Mar 14;395(10227):888-898. doi: 10.1016/S0140-6736(19)32990-3. Epub 2020 Feb 19.

DOI:10.1016/S0140-6736(19)32990-3

PMID:32085823

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 log copies HIV DNA per 10 CD4 T-cells in the ART-only group versus 3·06 log copies HIV DNA per 10 CD4 T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log copies HIV DNA per 10 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).

摘要

背景

由于潜伏感染细胞的持续存在，抗逆转录病毒疗法（ART）无法治愈 HIV 感染。从这些细胞中强制转录 HIV 的方法，使它们容易受到杀伤，即所谓的“踢杀”方案，已被探索作为 HIV 治愈的一种策略。 RIVER 是第一个确定仅接受 ART 与 ART 加踢杀和杀伤对 HIV 储存库标志物影响的随机试验。

方法

这是一项在英国六家临床中心进行的 2 期、开放性标签、多中心、随机、对照试验。年龄在 18-60 岁之间的患者，在过去 6 个月内被确诊为 HIV 阳性，在确诊后 1 个月内开始接受 ART，通过计算机生成的随机分组列表随机分配接受仅接受 ART（对照组）或 ART 加组蛋白去乙酰化酶抑制剂伏立诺他（踢）和复制缺陷的 T 细胞诱导疫苗，编码保守的 HIV 序列 ChAdV63。 HIVconsv-prime 和 MVA.HIVconsv-boost（杀伤；ART+V+V；干预）。主要终点是随机分组后 16 和 18 周时从外周血 CD4 T 细胞中分离的总 HIV DNA。分析采用意向治疗。该试验在 ClinicalTrials.gov 注册，NCT02336074。

结果

2015 年 6 月 14 日至 2017 年 7 月 11 日，60 名 HIV 男性患者被随机分配接受仅接受 ART（n=30）或接受 ART+V+V（n=30）方案；所有 60 名参与者均完成了研究，无失访。随机分组后 16 和 18 周时，ART 组的总 HIV DNA 平均为每 10 个 CD4 T 细胞 3.02 对数拷贝 HIV DNA，而 ART+V+V 组为每 10 个 CD4 T 细胞 3.06 对数拷贝 HIV DNA，两组间无统计学差异（每 10 个 CD4 T 细胞相差 0.04 对数拷贝 HIV DNA[95%CI-0.03 至 0.11;p=0.26]）。无与干预相关的严重不良事件。