{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T11:33:56Z","timestamp":1777203236128,"version":"3.51.4"},"reference-count":28,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T00:00:00Z","timestamp":1528848000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2016M3A9B6918984"],"award-info":[{"award-number":["2016M3A9B6918984"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2016R1A2B1009847"],"award-info":[{"award-number":["2016R1A2B1009847"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017M3A9G6068245"],"award-info":[{"award-number":["2017M3A9G6068245"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Viral Hepatitis"],"published-print":{"date-parts":[[2018,11]]},"abstract":"Summary<\/jats:title>Daclatasvir plus asunaprevir (DCV<\/jats:styled-content>+ASV<\/jats:styled-content>) treatment is an all\u2010oral direct\u2010acting antiviral (DAA<\/jats:styled-content>) therapy for the genotype 1b HCV<\/jats:styled-content>\u2010infected patients. In this study, we investigated how resistance\u2010associated substitutions (RAS<\/jats:styled-content>s) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS<\/jats:styled-content>5A and NS<\/jats:styled-content>3 revealed typical RAS<\/jats:styled-content>s after treatment failures. Interestingly, the RAS<\/jats:styled-content>s of NS<\/jats:styled-content>3 reverted to the wild\u2010type amino acid within 1\u00a0year after treatment failures. However, the RAS<\/jats:styled-content>s of NS<\/jats:styled-content>5A were stable and did not change. The effect of NS<\/jats:styled-content>5A and NS<\/jats:styled-content>3 RAS<\/jats:styled-content>s on viral RNA<\/jats:styled-content> replication was assessed after mutagenic substitution in the genotype 1b HCV RNA<\/jats:styled-content>. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS<\/jats:styled-content> at NS<\/jats:styled-content>5A Y93 affected both viral RNA<\/jats:styled-content> replication and virus production. Finally, the effect of trans<\/jats:italic>\u2010complementation of NS<\/jats:styled-content>5A was demonstrated in our co\u2010transfection experiments and these results suggest that such a trans<\/jats:italic>\u2010complementation effect of NS<\/jats:styled-content>5A may help maintain the NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s for a long time even after cessation of the DAA<\/jats:styled-content> treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RAS<\/jats:styled-content>s.<\/jats:p>","DOI":"10.1111\/jvh.12932","type":"journal-article","created":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T18:56:20Z","timestamp":1526496980000},"page":"1251-1259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Evolution and persistence of resistance\u2010associated substitutions of hepatitis C virus after direct\u2010acting antiviral treatment failures"],"prefix":"10.1111","volume":"25","author":[{"given":"Y.","family":"Jeong","sequence":"first","affiliation":[{"name":"Brain Korea 21 Plus Project for Medical Science Yonsei University College of Medicine Seoul Korea"},{"name":"Yonsei Liver Center Severance Hospital Seoul Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B.","family":"Jin","sequence":"additional","affiliation":[{"name":"Brain Korea 21 Plus Project for Medical Science Yonsei University College of Medicine Seoul Korea"},{"name":"Yonsei Liver Center Severance Hospital Seoul Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3552-3560","authenticated-orcid":false,"given":"H. W.","family":"Lee","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center Severance Hospital Seoul Korea"},{"name":"Department of Internal Medicine Institute of Gastroenterology Yonsei University College of Medicine Seoul Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. J.","family":"Park","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center Severance Hospital Seoul Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Y.","family":"Park","sequence":"additional","affiliation":[{"name":"Yonsei Liver Center Severance Hospital Seoul Korea"},{"name":"Department of Internal Medicine Institute of Gastroenterology Yonsei University College of Medicine Seoul Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. 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