{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:42:25Z","timestamp":1788871345005,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,6,19]],"date-time":"2014-06-19T00:00:00Z","timestamp":1403136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Grant-in-Aid for Scientific Research"},{"name":"Japanese Ministry of Labor, Health and Welfare"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Viral Hepatitis"],"published-print":{"date-parts":[[2015,2]]},"abstract":"Summary<\/jats:title>\n \n Daclatasvir (\n DCV<\/jats:styled-content>\n ) and asunaprevir (\n ASV<\/jats:styled-content>\n ) are\n NS<\/jats:styled-content>\n 5A and\n NS<\/jats:styled-content>\n 3 protease\u2010targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (\n HCV<\/jats:styled-content>\n ) infection. We analysed the relationship between pre\u2010existing drug\u2010resistant variants and clinical outcome of the combination treatment with\n DCV<\/jats:styled-content>\n and\n ASV<\/jats:styled-content>\n . Ten patients with\n HCV<\/jats:styled-content>\n genotype 1b were orally treated with a combination of\n ASV<\/jats:styled-content>\n and\n DCV<\/jats:styled-content>\n for 24\u00a0weeks. The frequencies of amino acid (aa) variants at\n NS<\/jats:styled-content>\n 3 aa positions 155, 156 and 168 and at\n NS<\/jats:styled-content>\n 5A aa31 and 93 before and after treatment were analysed by ultra\u2010deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (\n SVR<\/jats:styled-content>\n ) was achieved in 8 out of 10 patients (80%), and relapse of\n HCV RNA<\/jats:styled-content>\n after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre\u2010existing\n DCV<\/jats:styled-content>\n \u2010resistant variants (\n L<\/jats:styled-content>\n 31\n V<\/jats:styled-content>\n \/\n M<\/jats:styled-content>\n and\/or\n Y<\/jats:styled-content>\n 93\n H<\/jats:styled-content>\n ; 0.9\u201399.4%) were detected in three out of eight patients who achieved\n SVR<\/jats:styled-content>\n . Pre\u2010existing\n DCV<\/jats:styled-content>\n \u2010resistant variants were detected in a relapsed patient (\n L<\/jats:styled-content>\n 31\n M<\/jats:styled-content>\n ,\n Y<\/jats:styled-content>\n 93\n H<\/jats:styled-content>\n ) and in a patient with viral breakthrough (\n Y<\/jats:styled-content>\n 93\n H<\/jats:styled-content>\n ); however, no\n ASV<\/jats:styled-content>\n \u2010resistant variants were detected. In these patients,\n HCV RNA<\/jats:styled-content>\n rebounded with\n ASV<\/jats:styled-content>\n \u2010 and\n DCV<\/jats:styled-content>\n \u2010 double resistant variants (\n NS<\/jats:styled-content>\n 3\n D<\/jats:styled-content>\n 168\n A<\/jats:styled-content>\n \/\n V<\/jats:styled-content>\n plus\n NS<\/jats:styled-content>\n 5\n A L<\/jats:styled-content>\n 31\n M<\/jats:styled-content>\n and\n Y<\/jats:styled-content>\n 93\n H<\/jats:styled-content>\n ). While pre\u2010existing\n DCV<\/jats:styled-content>\n \u2010resistant variants might contribute to viral breakthrough in\n DCV<\/jats:styled-content>\n and\n ASV<\/jats:styled-content>\n combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra\u2010deep sequence analysis of pre\u2010existing resistant variants appears limited.\n <\/jats:p>","DOI":"10.1111\/jvh.12271","type":"journal-article","created":{"date-parts":[[2014,6,19]],"date-time":"2014-06-19T01:34:06Z","timestamp":1403141646000},"page":"158-165","source":"Crossref","is-referenced-by-count":29,"title":["Emergence of resistant variants detected by ultra\u2010deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis\n C<\/scp>\n virus genotype 1"],"prefix":"10.1111","volume":"22","author":[{"given":"K.","family":"Kosaka","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. N.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Hiraga","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Yoshimi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Kawaoka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Tsuge","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Aikata","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Miki","sequence":"additional","affiliation":[{"name":"Laboratory for Digestive Diseases Center for Genomic Medicine The Institute of Physical and Chemical Research (RIKEN) Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Ochi","sequence":"additional","affiliation":[{"name":"Laboratory for Digestive Diseases Center for Genomic Medicine The Institute of Physical and Chemical Research (RIKEN) Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology and Leukemia Program Project Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Kanai","sequence":"additional","affiliation":[{"name":"Radiation Research Center for Frontier Science Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Inaba","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology and Leukemia Program Project Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Chayama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Metabolism Applied Life Science Institute of Biomedical & Health Science Hiroshima University Hiroshima Japan"},{"name":"Laboratory for Digestive Diseases Center for Genomic Medicine The Institute of Physical and Chemical Research (RIKEN) Hiroshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,6,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840120409"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510280632"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0806104"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1013086"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020047"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2003.50258"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1012912"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0807650"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.07.016"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2893.2011.01528.x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08960"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008329200"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01186-12"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1086\/595848"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24724"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.09.037"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.11.012"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024907"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.05715-11"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06627-11"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.23579"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(11)61197-5"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.21438"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.03.022"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24460"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22549"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01004-06"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2012.04.024"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26388"}],"container-title":["Journal of Viral Hepatitis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjvh.12271","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjvh.12271","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvh.12271","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T19:02:10Z","timestamp":1696273330000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jvh.12271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,19]]},"references-count":30,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015,2]]}},"alternative-id":["10.1111\/jvh.12271"],"URL":"https:\/\/doi.org\/10.1111\/jvh.12271","archive":["Portico"],"relation":{},"ISSN":["1352-0504","1365-2893"],"issn-type":[{"value":"1352-0504","type":"print"},{"value":"1365-2893","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,19]]}}}