A viro-immunological model to characterize the antiviral effect of molnupiravir in SARS-CoV-2-infected outpatients: implication for treatment duration.

Abstract

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 analysed data from the PANORAMIC trial, where 577 outpatients were randomised shortly after symptom onset to receive usual care or molnupiravir for 5 days, and where viral and immunological data were collected for two weeks. We developed a mathematical model that characterized virus/host interaction and accounted 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 five-day treatment. This effect was mediated through two different pathways, one that increased transition mutation frequency, and other that directly inhibited viral production. Accordingly five-day treatment shortened the median time to clearance of both RNA and infectious virus by approximately 2 days. Treatment duration of 10 days could reduce the time to RNA clearance by 5 days and reduce the occurrence of viral rebounds. Longer treatment durations might be needed in case of post-exposure prophylaxis.

Conclusions: Our model suggests that molnupiravir acts primarily on viral replication, and does not act specifically on viral infectivity. Longer administration of molnupiravir may reduce rebound rate and shorten time to viral clearance.