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-naive 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 & PLUSMN;Standard error: 18.7 x 10(-4) & PLUSMN; 2.1 x 10(-4) vs. 3.3 x 10(-4) & PLUSMN; 0.8 x 10(-4) vs. 3.1 x 10(-4) & PLUSMN; 0.8 x 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.

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients / Alteri, Claudia; Fox, Valeria; Scutari, Rossana; Burastero, Giulia Jole; Volpi, Sara; Faltoni, Matteo; Fini, Vanessa; Granaglia, Annarita; Esperti, Sara; Gallerani, Altea; Costabile, Valentino; Fontana, Beatrice; Franceschini, Erica; Meschiari, Marianna; Campana, Andrea; Bernardi, Stefania; Villani, Alberto; Bernaschi, Paola; Russo, Cristina; Guaraldi, Giovanni; Mussini, Cristina; Perno, Carlo Federico. - In: COMMUNICATIONS BIOLOGY. - ISSN 2399-3642. - 5:1(2022), pp. 1-12. [10.1038/s42003-022-04322-8]

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients

Volpi, Sara;Faltoni, Matteo;Esperti, Sara;Gallerani, Altea;Fontana, Beatrice;Franceschini, Erica;Meschiari, Marianna;Guaraldi, Giovanni;Mussini, Cristina;
2022

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-naive 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 & PLUSMN;Standard error: 18.7 x 10(-4) & PLUSMN; 2.1 x 10(-4) vs. 3.3 x 10(-4) & PLUSMN; 0.8 x 10(-4) vs. 3.1 x 10(-4) & PLUSMN; 0.8 x 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.
2022
5
1
1
12
A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients / Alteri, Claudia; Fox, Valeria; Scutari, Rossana; Burastero, Giulia Jole; Volpi, Sara; Faltoni, Matteo; Fini, Vanessa; Granaglia, Annarita; Esperti, Sara; Gallerani, Altea; Costabile, Valentino; Fontana, Beatrice; Franceschini, Erica; Meschiari, Marianna; Campana, Andrea; Bernardi, Stefania; Villani, Alberto; Bernaschi, Paola; Russo, Cristina; Guaraldi, Giovanni; Mussini, Cristina; Perno, Carlo Federico. - In: COMMUNICATIONS BIOLOGY. - ISSN 2399-3642. - 5:1(2022), pp. 1-12. [10.1038/s42003-022-04322-8]
Alteri, Claudia; Fox, Valeria; Scutari, Rossana; Burastero, Giulia Jole; Volpi, Sara; Faltoni, Matteo; Fini, Vanessa; Granaglia, Annarita; Esperti, Sa...espandi
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