A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients
Claudia Alteri, Valeria Fox, Rossana Scutari, Giulia 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 Federico Perno
Abstract
Abstract Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean±Standard error: 18.7 × 10 −4 ± 2.1 × 10 −4 vs. 3.3 × 10 −4 ± 0.8 × 10 −4 vs. 3.1 × 10 −4 ± 0.8 × 10 −4 , P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations ( P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlovid are found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection.