Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients

Abstract: Article https://doi.org/10.1038/s41467-024-45641-0 Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients Received: 4 August 2023 A list of authors and their affiliations appears at the end of the paper 1234567890():,; 1234567890():,; Accepted: 26 January 2024 Check for updates Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031 Treatment of SARS-CoV-2 with the nucleoside analogue molnupiravir (MK4482, EIDD2801) was reported to reduce viral load, hospitalisation and mortality in unvaccinated participants with early COVID-19 in the MOVeOUT trial1,2. Based on these data, molnupiravir received emergency use authorisation in the UK in November 2021 for early treatment of SARS-CoV-2 in individuals deemed to be at higher risk of complications due to age or underlying comorbidities. Molnupiravir is metabolised intracellularly to NHC-triphosphate, which competes with natural cytidine and uridine for incorporation by the viral RNA-dependent RNA polymerase (RdRp) into the nascent viral RNA. This leads to abnormal, non-Watson-Crick pairing with guanosine and uridine in further rounds of replication, increasing the substitution of adenosine for guanosine and cytosine for uridine, so-called transition mutations, within the SARS-CoV-2 genome. Lethal mutagenesis resulting from treatment with RdRp inhibitors eventually leads to viral extinction3,4. A distinctive pattern of transition mutagenesis is evident in viral genomes recovered from animals and humans who have received molnupiravir3–5. The risk that, following molnupiravir treatment, some highly mutated viruses might remain viable and capable of onward transmission has been postulated6,7. To measure the impact of molnupiravir in a largely vaccinated population, the Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community (PANORAMIC) was established. The first drug tested in PANORAMIC was molnupiravir, and amongst 25,783 mostly vaccinated individuals, found that molnupiravir did not reduce hospitalisation or death8 (primary endpoint). Secondary outcomes showed those receiving molnupiravir experienced significantly reduced viral load during treatment and reported faster symptom recovery and fewer general..