GENOMIC EVOLUTION OF SARS-COV-2 IN MOLNUPIRAVIR-TREATED PATIENTS COMPARED TO PAXLOVID-TREATED AND DRUG-NAÏVE PATIENTS: A PROOF-OF-CONCEPT STUDY

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 was found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site 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), peaking between Day 2 and 5. Molnupiravir drove the emergence of more G-A and C-T transitions than other mutations (P=0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure did not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN>dS,P=0.001); few amino acid mutations were enriched at specific sites. No RdRp or Mpro mutations conferring resistance to Molnupiravir or Paxlovid were 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