A Viroimmunologic Model to Characterize the Antiviral Effect of Molnupiravir in Outpatients Infected With SARS-CoV-2: Implication for Treatment Duration

Background 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. Methods 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. Results 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. Conclusions 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.