Nguyen Bach Tran, Bertrand Julie, Agyeman Akosua A, Zhang Shengyuan, Yu Ly-Mee, Harris Victoria, Little Paul, Butler Christopher C, Breuer Judith, Lowe David M, Standing Joseph F, Guedj Jérémie
Université Paris Cité and Université Sorbonne Paris Nord, Inserm, IAME, France.
Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London.
J Infect Dis. 2025 Jul 11;231(6):e1080-e1090. doi: 10.1093/infdis/jiaf158.
The antiviral efficacy of molnupiravir against SARS-CoV-2 is controversial. Here, we develop a model integrating viral and immune dynamics to characterize the mechanism of action of molnupiravir in vivo and its impact on viral dynamics during and after treatment.
We analyzed data from the PANORAMIC trial, where 577 outpatients were randomized shortly after symptom onset to receive usual care or molnupiravir for 5 days, with viral and immunologic data collected within 2 weeks. We developed a mathematical model that characterized virus-host interaction, accounting for the impact of molnupiravir on viral replication and mutagenesis. The model was used to explore the impact of longer treatment duration.
Molnupiravir reduced RNA replication with an efficacy that reached 93% at the end of a 5-day treatment. This effect was mediated through 2 pathways: 1 that increased transition mutation frequency and 1 that directly inhibited viral production. Accordingly, 5-day treatment shortened the median time to clearance of RNA and infectious virus by approximately 2 days. Ten-day treatment could reduce the time to RNA clearance by 5 days and the occurrence of viral rebounds. Longer treatment durations might be needed for postexposure prophylaxis.
Our model suggests that molnupiravir acts primarily on viral replication, and not specifically on viral infectivity. Longer administration of molnupiravir may reduce the rebound rate, shortening the time to viral clearance.
莫努匹拉韦对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的抗病毒疗效存在争议。在此，我们开发了一个整合病毒和免疫动力学的模型，以描述莫努匹拉韦在体内的作用机制及其对治疗期间和治疗后病毒动力学的影响。
我们分析了来自全景试验的数据，577名门诊患者在症状出现后不久被随机分组，接受常规治疗或莫努匹拉韦治疗5天，并在2周内收集病毒和免疫学数据。我们开发了一个数学模型来描述病毒与宿主的相互作用，考虑了莫努匹拉韦对病毒复制和诱变的影响。该模型用于探索更长治疗时间的影响。
莫努匹拉韦降低了RNA复制，在5天治疗结束时疗效达到93%。这种作用通过两条途径介导：一条途径增加转换突变频率，另一条途径直接抑制病毒产生。因此，5天治疗使RNA和传染性病毒清除的中位时间缩短了约2天。10天治疗可使RNA清除时间缩短5天，并减少病毒反弹的发生。暴露后预防可能需要更长的治疗时间。
我们的模型表明，莫努匹拉韦主要作用于病毒复制，而非特异性作用于病毒感染性。延长莫努匹拉韦的给药时间可能会降低反弹率，缩短病毒清除时间。
