Data_Sheet_2_Efficacy and Safety of Anti-malarial Drugs (Chloroquine and Hydroxy-Chloroquine) in Treatment of COVID-19 Infection: A Systematic Review and Meta-Analysis.docx

Background: Anti-malarial drugs inhibit coronaviruses in-vitro. Few published studies have evaluated the safety and efficacy of these drugs in the treatment of COVID-19 infection.Materials and Methods: This is a systematic review and meta-analysis of clinical trials and observational studies. Major database searches were carried out up until June 5, 2020. Participants admitted with RT-PCR-confirmed SARS Cov-2 (COVID-19) infection were included. The “Intervention group” received anti-malarial drugs with or without other drugs (Azithromycin) administered as an adjunct to the standard treatment/care. The “Control group” received treatment except anti-malarial drugs. The primary outcome is “all-cause mortality.” Secondary outcome measures were effects on clinical and laboratory parameters and adverse events.Results: Of 3,472 citations, 17 (six clinical trials and 11 observational studies) studies provided data of 8,071 participants. Compared to the control, Hydroxy-chloroquine (HCQ) has no significant effect on mortality [(OR 0.87; 95% CI 0.46–1.64); eight observational studies; N = 5,944]. Data from a single, small non-randomized trial (N = 42) also reached a similar conclusion (OR 1.94; 95% CI 0.07–50.57; p = 0.69). Compared to the control, HCQ plus Azithromycin (AZM) significantly increased mortality [(OR 2.84; 95% CI 2.19–3.69); four observational studies; N = 2,310]. Compared to the control, risk of any adverse event was significantly increased in HCQ group [(OR 3.35; 95% CI 1.58–7.13); four clinical trials; N = 263]. Compared to control, risk of adverse cardiac events (abnormal ECG, arrhythmia, or QT prolongation) were not significantly increased in HCQ group (but significantly increased in the HCQ plus AZM group). The GRADE evidence generated for all the outcomes was of “very low-quality.”Conclusions: As very low quality evidence suggests an increased risk of mortality and adverse event with HCQ plus Azithromycin combination (not HCQ alone), caution should be exercised while prescribing this combination for treatment of hospitalized adults with COVID-19 infection. Good quality, multi-centric RCTs (including both hospitalized and non-hospitalized patients) are required for any firm recommendation to be made during the ongoing pandemic.OSF Protocol Registration Link:https://osf.io/6zxsu.

背景：抗疟药物可在体外抑制冠状病毒。关于这些药物在治疗COVID-19感染中的安全性和有效性的研究发表数量有限。研究材料与方法：本研究为对临床试验和观察性研究的系统评价与荟萃分析。主要数据库的检索截止至2020年6月5日。纳入对象为经RT-PCR确诊的SARS Cov-2（COVID-19）感染患者。‘干预组’接受抗疟药物治疗，并可能联合其他药物（如阿奇霉素）作为标准治疗/护理的辅助。‘对照组’接受治疗，但不包括抗疟药物。主要研究结果是‘全因死亡率’。次要结果指标包括临床和实验室参数以及不良事件。结果：在3,472篇文献中，有17项研究（包括6项临床试验和11项观察性研究）提供了8,071名参与者的数据。与对照组相比，羟氯喹（HCQ）对死亡率无显著影响[(比值比OR 0.87；95%置信区间CI 0.46–1.64)；8项观察性研究；N = 5,944]。来自一项单一的小型非随机试验（N = 42）的数据也得出相似结论（OR 1.94；95%置信区间CI 0.07–50.57；p = 0.69）。与对照组相比，HCQ联合阿奇霉素（AZM）显著增加了死亡率[(OR 2.84；95%置信区间CI 2.19–3.69)；4项观察性研究；N = 2,310]。与对照组相比，HCQ组的任何不良事件的风险显著增加[(OR 3.35；95%置信区间CI 1.58–7.13)；4项临床试验；N = 263]。与对照组相比，HCQ组不良心脏事件（如心电图异常、心律失常或QT间期延长）的风险并未显著增加（但HCQ联合AZM组显著增加）。为所有结果生成的GRADE证据质量均为“非常低”。结论：鉴于非常低质量证据表明，HCQ联合阿奇霉素组合（而非单独HCQ）可能增加死亡和不良事件的风险，在为住院的COVID-19感染成人开具该组合药物时应谨慎。为了在持续的大流行期间做出任何明确的推荐，需要高质量、多中心的随机对照试验（包括住院和非住院患者）。OSF协议注册链接：https://osf.io/6zxsu。