Genomic Evolution of Sars-Cov-2 in Molnupiravir-Treated Patients Compared to Paxlovid-Treated and Drug-Naïve Patients: A Proof-of-Concept Study
Claudia Alteri, Valeria Fox, Rossana Scutari, Giulia Jole Burastero, Sara Volpi, Matteo Faltoni, Vanessa Fini, Annarita Granaglia, Sara Esperti, Altea Gallerani, Valentino Costabile, Beatrice Fontana, Erica Franceschini, Marianna Meschiari, Andrea Campana, Stefania Bernardi, Alberto Villani, Paola Bernaschi, Cristina Russo, Giovanni Guaraldi, Cristina Mussini, Carlo Perno
doi:10.21203/rs.3.rs-2105569/v1
Molnupiravir and Paxlovid are the only antivirals approved for COVID-19 treatment. Previous studies have evaluated their e cacy, tolerability, and viral clearance, but little is known about SARS-CoV-2 evolution under their pressure. Here the dynamics of genomic evolution of SARS-CoV-2 in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Day 0, Day 2, Day 5 of treatment and Day 7) were in-depth investigated. SARS-CoV-2 strains under Molnupiravir pressure were characterized by a higher genetic diversity compared to Paxlovid and no-drug pressure (mean ± SE: 18.66x10 − 4 ±2.06x10 − 4 vs. 3.34x10 − 4 ±0.84x10 − 4 vs. 3.10x10 − 4 ±0.84x10 − 4 , P = 0.0003), with a peak between Day 2 and Day 5. Molnupiravir drove the emergence of more G-A and C-T transitions than other mutations (P = 0.031), regardless of SARS-CoV-2 genes. SARS-CoV-2 under Molnupiravir pressure did not show selective evolution different than that under Paxlovid or no-drug pressure, with the only exception of orf8 (dN > dS, P = 0.001); few amino acid mutations were enriched consistently at speci c sites. No evidence of RdRp or Mpro mutations conferring resistance to Molnupiravir or Paxlovid was found. This proof-of-concept study de nes the SARS-CoV-2 within-host evolution during antiviral treatment, con rming the higher in vivo variability induced by Molnupiravir respect to Paxlovid and controls, albeit not resulting in selection of resistance mutations.
COMPETING INTERESTS The authors have no nancial or non-nancial competing interests that might be perceived to in uence the results and/or discussion reported in this paper.
Supplementary Files This is a list of supplementary les associated with this preprint. Click to download. SupplementaryTable1v.2.0.docx
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