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.

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients / C. Alteri, V. Fox, R. Scutari, G.J. Burastero, S. Volpi, M. Faltoni, V. Fini, A. Granaglia, S. Esperti, A. Gallerani, V. Costabile, B. Fontana, E. Franceschini, M. Meschiari, A. Campana, S. Bernardi, A. Villani, P. Bernaschi, C. Russo, G. Guaraldi, C. Mussini, C.F. Perno. - In: COMMUNICATIONS BIOLOGY. - ISSN 2399-3642. - 5:1(2022 Dec 15), pp. 1376.1-1376.12. [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

C. Alteri
Primo
;
V. Fox
Secondo
;
R. Scutari;V. Costabile;C.F. Perno
Ultimo
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-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.
Settore MED/07 - Microbiologia e Microbiologia Clinica
Article (author)
File in questo prodotto:
File Dimensione Formato  
s42003-022-04322-8.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.21 MB
Formato Adobe PDF
2.21 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/949093
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact