Introduction

Understanding the clinical potency of latency-reversing agents (LRAs) on the HIV-1 reservoir is useful to deploy future strategies. This systematic review evaluated the effects of LRAs in human intervention studies.

Methods

A literature search was performed using medical databases focusing on studies with adults living with HIV-1 receiving LRAs. Eligibility criteria required participants from prospective clinical studies, a studied compound hypothesised as LRA, and reactivation or tolerability assessments. Relevant demographical data, LRA reactivation capacity, reservoir size, and adverse events were extracted. A study quality assessment with analysis of bias was performed by RoB 2 and ROBINS-I tools. The primary endpoints were HIV-1 reservoir reactivation after LRA treatment quantified by cell-associated unspliced HIV-1 RNA, and LRA tolerability defined by adverse events. Secondary outcomes were reservoir size and the effect of LRAs on analytical treatment interruption (ATI) duration.

Results

After excluding duplicates, 5182 publications were screened. In total 45 publications fulfilled eligibility criteria including 26 intervention studies and 16 randomised trials. The risk of bias was evaluated as high. Chromatin modulators were the main investigated LRA class in 24 studies. Participants were mostly males (90.1%). Where reported, HIV-1 subtype B was most frequently observed. Reactivation after LRA treatment occurred in 78% of studies and was observed with nearly all chromatin modulators. When measured, reactivation mostly occurred within 24 h after treatment initiation. Combination LRA strategies have been infrequently studied and were without synergistic reactivation. Adverse events, where reported, were mostly low grade, yet occurred frequently. Seven studies had individuals who discontinued LRAs for related adverse events. The reservoir size was assessed by HIV-1 DNA in 80% of studies. A small decrease in reservoir was observed in three studies on immune checkpoint inhibitors and the histone deacetylase inhibitors romidepsin and chidamide. No clear effect of LRAs on ATI duration was observed.

Conclusion

This systematic review provides a summary of the reactivation of LRAs used in current clinical trials whilst highlighting the importance of pharmacovigilance. Highly heterogeneous study designs and underrepresentation of relevant patient groups are to be considered when interpreting these results. The observed reactivation did not lead to cure or a significant reduction in the size of the reservoir. Finding more effective LRAs by including well-designed studies are needed to define the required reactivation level to reduce the HIV-1 reservoir.

中文翻译：

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临床研究中潜伏期逆转剂重新激活 HIV-1 储存库的功效和耐受性：系统评价

介绍

了解潜伏期逆转剂 (LRA) 对 HIV-1 储存库的临床效力有助于部署未来的策略。本系统综述评估了上帝抵抗军在人类干预研究中的影响。

方法

使用医学数据库进行了文献检索，重点关注对接受 LRA 的 HIV-1 成人感染者的研究。资格标准要求参与者参与前瞻性临床研究、假设为 LRA 的研究化合物以及重新激活或耐受性评估。提取了相关人口统计数据、LRA 再激活能力、储存库大小和不良事件。通过 RoB 2 和 ROBINS-I 工具进行研究质量评估和偏倚分析。主要终点是通过细胞相关未剪接的 HIV-1 RNA 量化 LRA 治疗后 HIV-1 储存库的重新激活，以及通过不良事件定义的 LRA 耐受性。次要结果是储存库大小以及 LRA 对分析处理中断 (ATI) 持续时间的影响。

结果

排除重复后，筛选了 5182 篇出版物。共有 45 篇出版物符合资格标准，其中包括 26 项干预研究和 16 项随机试验。偏倚风险被评估为高。染色质调节剂是 24 项研究中主要研究的 LRA 类别。参与者大部分为男性（90.1%）。据报道，最常见的是 HIV-1 B 亚型。78% 的研究发生了 LRA 治疗后的重新激活，并且几乎所有染色质调节剂都观察到了这种情况。测量时，再激活大多发生在治疗开始后 24 小时内。组合 LRA 策略很少被研究，并且没有协同重新激活。据报道，不良事件大多是低级别的，但发生频率很高。七项研究的受试者因相关不良事件而停用 LRA。80% 的研究通过 HIV-1 DNA 评估病毒库大小。在关于免疫检查点抑制剂和组蛋白脱乙酰酶抑制剂罗米地辛和西达本胺的三项研究中观察到储存库略有减少。没有观察到 LRA 对 ATI 持续时间的明显影响。

结论

本系统综述总结了当前临床试验中使用的 LRA 的重新激活，同时强调了药物警戒的重要性。在解释这些结果时，应考虑高度异质性的研究设计和相关患者群体的代表性不足。观察到的重新激活并未导致治愈或储库尺寸显着减小。需要通过精心设计的研究来寻找更有效的 LRA，以确定减少 HIV-1 储存库所需的重新激活水平。