{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T16:41:27Z","timestamp":1770482487765,"version":"3.49.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Direct-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering-Plough) (PEG-IFN\/RBV) therapy, were treated with DCV combined with PEG-IFN alpha-2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV\/PEG-IFN\/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT01016912.)<\/jats:p>","DOI":"10.1128\/aac.02068-13","type":"journal-article","created":{"date-parts":[[2014,1,28]],"date-time":"2014-01-28T05:28:10Z","timestamp":1390886890000},"page":"2105-2112","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Ultradeep Sequencing Study of Chronic Hepatitis C Virus Genotype 1 Infection in Patients Treated with Daclatasvir, Peginterferon, and Ribavirin"],"prefix":"10.1128","volume":"58","author":[{"given":"Eisuke","family":"Murakami","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical &amp; Health Science, Hiroshima University, Hiroshima, Japan"},{"name":"Liver Research Project Center, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michio","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical &amp; Health Science, Hiroshima University, Hiroshima, Japan"},{"name":"Liver Research Project Center, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. 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