Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Abstract Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

摘要：现有研究证实，2019冠状病毒病（coronavirus disease 2019，COVID-19）患者可出现肝损伤。然而，鉴于诸多未被证实可用于治疗2019冠状病毒病的药物具有已知的肝毒性潜能，药物治疗往往会对患者肝脏状态造成不良影响。本研究旨在评估疑似因2019冠状病毒病治疗药物引发的肝脏不良反应报告，对比此类药物在2019冠状病毒病患者中的其他临床应用指征，并评估药物间潜在的相互作用。本研究从美国食品药品监督管理局（Food and Drug Administration，FDA）不良事件报告系统（Adverse Event Reporting System，FAERS）公共平台获取了截至2020年6月30日登记的、用于治疗2019冠状病毒病的药物（托珠单抗（tocilizumab）、瑞德西韦（remdesivir）、羟氯喹（hydroxychloroquine）以及/或洛匹那韦/利托那韦（lopinavir/ritonavir））的相关报告。随后通过计算报告比值比（reported odds ratios，ROR），分析此类药物引发肝脏不良事件的风险。本研究共检索到与托珠单抗（tocilizumab）、洛匹那韦/利托那韦（lopinavir/ritonavir）及羟氯喹（hydroxychloroquine）相关的报告分别为662份、744份及1381份。三类药物的报告比值比（95%置信区间）分别为6.32（5.28~7.56）、6.12（5.22~7.17）及9.07（8.00~10.29），结果显示，与未感染人群相比，2019冠状病毒病患者使用此类药物时发生肝脏不良事件的风险显著升高。2019冠状病毒病患者单用或联用此类药物时，肝脏不良事件报告风险升高，这提示临床需谨慎选择药物，并致力于减少无明确获益的药物联用方案。与其他疾病诊疗原则一致，应避免使用未被证实有效的药物。