Genomic Evolution of Sars-Cov-2 in Molnupiravir-Treated Patients Compared to Paxlovid-Treated and Drug-Naïve Patients: A Proof-of-Concept Study

{ 'institution': [{'name': 'Research Square'}], 'indexed': {'date-parts': [[2022, 10, 6]], 'date-time': '2022-10-06T16:15:26Z', 'timestamp': 1665072926262}, 'posted': {'date-parts': [[2022, 10, 6]]}, 'group-title': 'In Review', 'reference-count': 48, 'publisher': 'Research Square Platform LLC', 'license': [ { 'start': { 'date-parts': [[2022, 10, 6]], 'date-time': '2022-10-06T00:00:00Z', 'timestamp': 1665014400000}, 'content-version': 'unspecified', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2022, 9, 26]]}, 'abstract': '<jats:title>Abstract</jats:title>\n' ' <jats:p>Molnupiravir and Paxlovid are the only antivirals approved for COVID-19 ' 'treatment. Previous studies have evaluated their efficacy, 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\u2009±\u2009SE: ' '18.66x10<jats:sup>−\u20094</jats:sup>±2.06x10<jats:sup>−\u20094</jats:sup> vs. ' '3.34x10<jats:sup>−\u20094</jats:sup>±0.84x10<jats:sup>−\u20094</jats:sup> vs. ' '3.10x10<jats:sup>−\u20094</jats:sup>±0.84x10<jats:sup>−\u20094</jats:sup>, P\u2009=\u2009' '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\u2009=\u20090.031), 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\u2009&gt;\u2009' 'dS, P\u2009=\u20090.001); few amino acid mutations were enriched consistently at specific ' 'sites. No evidence of RdRp or Mpro mutations conferring resistance to Molnupiravir or ' 'Paxlovid was found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution ' 'during antiviral treatment, confirming the higher in vivo variability induced by Molnupiravir ' 'respect to Paxlovid and controls, albeit not resulting in selection of resistance ' 'mutations.</jats:p>', 'DOI': '10.21203/rs.3.rs-2105569/v1', 'type': 'posted-content', 'created': {'date-parts': [[2022, 10, 6]], 'date-time': '2022-10-06T15:45:55Z', 'timestamp': 1665071155000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Genomic Evolution of Sars-Cov-2 in Molnupiravir-Treated Patients Compared to Paxlovid-Treated ' 'and Drug-Naïve Patients: A Proof-of-Concept Study', 'prefix': '10.21203', 'author': [ { 'given': 'Claudia', 'family': 'Alteri', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Oncology and Hemato-oncology, University of Milan, ' 'Milan, Italy and Multimodal Research Area, Bambino Gesù Children ' 'Hospital IRCCS, Rome, Italy'}]}, {'given': 'Valeria', 'family': 'Fox', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rossana', 'family': 'Scutari', 'sequence': 'additional', 'affiliation': []}, {'given': 'Giulia Jole', 'family': 'Burastero', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sara', 'family': 'Volpi', 'sequence': 'additional', 'affiliation': []}, {'given': 'Matteo', 'family': 'Faltoni', 'sequence': 'additional', 'affiliation': []}, {'given': 'Vanessa', 'family': 'Fini', 'sequence': 'additional', 'affiliation': []}, {'given': 'Annarita', 'family': 'Granaglia', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sara', 'family': 'Esperti', 'sequence': 'additional', 'affiliation': []}, {'given': 'Altea', 'family': 'Gallerani', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-5207-8147', 'authenticated-orcid': False, 'given': 'Valentino', 'family': 'Costabile', 'sequence': 'additional', 'affiliation': []}, {'given': 'Beatrice', 'family': 'Fontana', 'sequence': 'additional', 'affiliation': []}, {'given': 'Erica', 'family': 'Franceschini', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-1254-9995', 'authenticated-orcid': False, 'given': 'Marianna', 'family': 'Meschiari', 'sequence': 'additional', 'affiliation': [{'name': 'University of Modena and Reggio Emilia'}]}, {'given': 'Andrea', 'family': 'Campana', 'sequence': 'additional', 'affiliation': []}, {'given': 'Stefania', 'family': 'Bernardi', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alberto', 'family': 'Villani', 'sequence': 'additional', 'affiliation': []}, {'given': 'Paola', 'family': 'Bernaschi', 'sequence': 'additional', 'affiliation': []}, {'given': 'Cristina', 'family': 'Russo', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-5724-3914', 'authenticated-orcid': False, 'given': 'Giovanni', 'family': 'Guaraldi', 'sequence': 'additional', 'affiliation': [{'name': 'University of Modena'}]}, { 'given': 'Cristina', 'family': 'Mussini', 'sequence': 'additional', 'affiliation': [{'name': 'University of Modena'}]}, {'given': 'Carlo', 'family': 'Perno', 'sequence': 'additional', 'affiliation': []}], 'member': '8761', 'reference': [ { 'key': 'ref1', 'unstructured': 'https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain'}, { 'key': 'ref2', 'unstructured': 'https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19'}, { 'issue': '19', 'key': 'ref3', 'doi-asserted-by': 'crossref', 'first-page': '5795', 'DOI': '10.3390/molecules26195795', 'article-title': 'Discovery, Development, and Patent Trends on Molnupiravir: A ' 'Prospective Oral Treatment for COVID-19', 'volume': '24', 'author': 'Imran M', 'unstructured': 'Imran, M., Kumar Arora, M., Asdaq, S.M.B., et al.: Discovery, ' 'Development, and Patent Trends on Molnupiravir: A Prospective Oral ' 'Treatment for COVID-19. 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