Adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomized trials

Background: To summarize specific adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir in patients with COVID-19.

Methods: We searched 32 databases through 27 October 2020. We included randomized trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the GRADE approach.

Results: We included 16 randomized trials which enrolled 8226 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared to standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury or cognitive dysfunction/delirium. Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (and cognitive dysfunction/delirium, whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI: 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI: 23 more to 110 more) compared to standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting compared to standard care or placebo.

Discussion: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

Funding: This study was supported by the Canadian Institutes of Health Research (grant: VR4-172738)

Registration: Not registered in PROSPERO, protocol available in the supplementary material of BMJ 2020;370:m2980; http://dx.doi.org/10.1136/bmj.m2980.

背景：本研究旨在总结新型冠状病毒肺炎（COVID-19）患者使用瑞德西韦（remdesivir）、羟氯喹（hydroxychloroquine）以及洛匹那韦/利托那韦（lopinavir/ritonavir）的特异性不良反应。
方法：截至2020年10月27日，我们检索了32个数据库。纳入将上述任一研究药物与安慰剂或标准治疗进行对比，或各研究药物之间相互对比的随机对照试验。我们采用固定效应两两比较元分析，并使用推荐分级的评估、制定与评价（GRADE）方法评估证据质量。
结果：本研究共纳入16项随机对照试验，共计8226例患者。除羟氯喹所致胃肠道不良反应证据质量为中等外，绝大多数干预措施对应的结局指标证据质量均为极低至低水平。与标准治疗或安慰剂相比，低质量证据提示瑞德西韦对急性肾损伤或认知功能障碍/谵妄可能无显著影响。低质量证据提示羟氯喹可能增加心脏毒性（以及认知功能障碍/谵妄）的发生风险；而中等质量证据显示，相较于标准治疗或安慰剂，羟氯喹可升高腹泻发生风险（相对风险差RD=每1000例多出106例，95%置信区间CI：48~175），并增加恶心和/或呕吐的发生风险（RD=每1000例多出62例，95%CI：23~110）。低质量证据提示，相较于标准治疗或安慰剂，洛匹那韦/利托那韦可能升高腹泻及恶心和/或呕吐的发生风险。
讨论：羟氯喹大概率可升高腹泻与恶心和/或呕吐的发生风险，且可能增加心脏毒性及认知功能障碍/谵妄的发病风险。洛匹那韦/利托那韦可能升高腹泻与恶心和/或呕吐的发生风险。瑞德西韦对急性肾损伤或认知功能障碍/谵妄的发生风险可能无显著影响。本研究结果可为新型冠状病毒肺炎患者的循证管理策略制定提供重要参考依据。
资助：本研究由加拿大卫生研究院（Canadian Institutes of Health Research）资助（项目编号：VR4-172738）。
注册信息：本研究未在国际前瞻性系统评价注册平台（PROSPERO）进行注册，研究方案可参见《英国医学杂志》（BMJ）2020;370:m2980的补充材料：http://dx.doi.org/10.1136/bmj.m2980。