Molnupiravir 預防 COVID-19 相關住院或死亡的成效：一項包含1,592,214名患者的隨機對照試驗和真實世界研究的系統性回顧與統合分析

Abstract

背景 由於現有隨機分派試驗和納入隨機分派試驗的統合分析結果不一致，molnupiravir用於治療新型冠狀病毒疾病的角色仍不明確。本研究目的是透過納入隨機分派試驗和真實世界研究數據進行系統回顧和統合分析，以評估molnupiravir在不同患者群體中的有效性。

方法 本研究檢索了Medline、Embase、Cochrane Register of Clinical Trials和 ClinicalTrials.gov等資料庫，截至2024年6月9日，納入molnupiravir用於治療輕度至中度新冠肺炎且具重症風險非住院成年人的研究，研究類型包含隨機分派試驗及觀察性研究。分析使用隨機效應模型進行統合分析，研究終點為28天住院率、死亡率、不良事件，以及3個月和6個月的有效性結果，估計值使用校正風險比 (adjusted risk ratio, aRRs)。本研究已在PROSPERO (CRD42023477918) 註冊。

結果 本研究共納入33篇研究 (包含1,592,214名參與者)，其中11篇為隨機分派試驗、22篇為世代研究。隨機分派試驗的統合分析結果顯示，molnupiravir有效降低平均年齡<45歲患者的住院風險，但並未顯著降低平均年齡45-57歲患者的住院風險 (RR 0·55; 95% CI 0·36–0·84 vs 1·06; 95% CI 0·81–1·39，次組差異檢定P=0.01)；世代研究的統合分析結果顯示，molnupiravir有效降低平均年齡≥73歲患者的住院風險，但並未顯著降低平均年齡62-72歲患者的住院風險 (RR 0·62; 95% CI 0·49–0·78 vs 0·90; 95% CI 0·76–1·05，次組差異檢定P=0·01)。然而，molnupiravir在隨機分派試驗 (RR 0·35; 95% CI 0·12–0·98) 和世代研究 (RR 0·39; 95% CI 0·30–0·51) 中均有效降低28天死亡風險，且未增加不良反應事件。死亡率降低的效果在追蹤3個月 (RR 0·47; 95% CI 0·23–0·95) 和6個月 (RR 0·62; 95% CI 0·52–0·74) 仍然顯著。

結論 Molnupiravir不能有效降低平均年齡45至72歲輕度至中度新冠肺炎患者的住院風險，但可以降低28天、3個月和6個月的死亡風險。

Background The role of molnupiravir in the treatment of coronavirus disease 2019 (COVID-19) remains unclear, as randomised controlled trials (RCTs) and RCT-based meta-analyses have yielded conflicting results.

Methods We conducted a systematic review and meta-analysis of data from both RCTs and real-world studies to evaluate the effectiveness of molnupiravir in preventing COVID-19-related hospitalisation or death (PROSPERO #CRD42023477918). The search included studies up to 9 June 2024. Random effects models were used to estimate the pooled effect size.

Findings A total of 33 studies were included, comprising 30,345 participants from 11 RCTs and 1,561,869 participants from 22 cohort studies. In RCTs, molnupiravir was effective in preventing 28-day hospitalisation in younger patients (mean age 35-45 years) but not in older patients (mean age 45-57 years) (RR 0·55; 95% CI 0·36–0·84 vs 1·06; 95% CI 0·81–1·39, test for subgroup difference P=0.01). In contrast, cohort studies showed a benefit in older patients (mean age 73-83 years) but not in those aged 62-72 years (RR 0·62; 95% CI 0·49–0·78 vs 0·90; 95% CI 0·76–1·05, test for subgroup difference P=0·01). However, molnupiravir significantly decreased 28-day mortality risk in both RCTs (RR 0·35; 95% CI 0·12–0·98, I2 0%) and cohort studies (RR 0·39; 95% CI 0·30–0·51, I2 90%), without increasing adverse events. This mortality risk reduction persisted at 3 months (RR 0·47; 95% CI 0·23–0·95, I2 93%) and 6 months (RR 0·62; 95% CI 0·52–0·74, I2 0%).

Interpretation The synthesis of evidence from RCTs and real-world studies indicates that while molnupiravir may not be effective in preventing hospitalisation in patient groups with a mean age of 45-72 years, it significantly decreases COVID-19-related mortality risk at 28 days, 3 months, and 6 months.