{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:07:36Z","timestamp":1790698056040,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,9,4]],"date-time":"2020-09-04T00:00:00Z","timestamp":1599177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","award":["ECTZ73330"],"award-info":[{"award-number":["ECTZ73330"]}],"id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>In hepatitis C virus (HCV) infection, treatment failure is generally associated with the selection of resistance\u2010associated substitutions (RAS) conferring reduced susceptibility to direct\u2010acting antiviral (DAA) drugs. Resistant variants continue to replicate after the end of treatment with potential for transmission. This may result from the selection of \u201cfitness\u2010associated substitutions\u201d.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To characterise potential \u201cfitness\u2010associated substitutions\u201d in patients infected with genotype 3a failing DAA drugs<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>By means of shotgun metagenomics, we sequenced full\u2010length HCV genomes at treatment initiation and at virological relapse in eight patients infected with genotype 3a with cirrhosis failing sofosbuvir and an NS5A inhibitor. The impact of amino acid changes occurring outside of DAA target regions selected in at least two patients were assessed on the in vitro susceptibility to an NS5A inhibitor and replication capacity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At treatment failure, besides selection of known NS5A RASs, especially Y93H, a large number of amino acid changes was observed outside of DAA target regions. We identified four amino acid positions at which observed changes substantially improved in vitro replication capacity without affecting NS5A inhibitor susceptibility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first in vivo observation combined with in vitro confirmation of selection of phenotypically characterised \u201cfitness\u2010associated substitutions\u201d together with RASs at the time of sofosbuvir\u2010NS5A inhibitor treatment failure in patients infected with genotype 3a with cirrhosis. Our findings may explain the persistence of resistant HCV variants after treatment in patients who did not achieve sustained virological remission.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.16054","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T07:51:12Z","timestamp":1601452272000},"page":"1583-1591","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Fitness\u2010associated substitutions following failure of direct\u2010acting antivirals assessed by deep sequencing of full\u2010length hepatitis C virus genomes"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1236-5467","authenticated-orcid":false,"given":"Slim","family":"Fourati","sequence":"first","affiliation":[{"name":"Department of Virology National Reference Center for Viral Hepatitis B, C and D Henri Mondor Hospital University of Paris\u2010Est Cr\u00e9teil France"},{"name":"INSERM U955 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