{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:27:24Z","timestamp":1791433644003,"version":"4.3.3"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,3,23]],"date-time":"2016-03-23T00:00:00Z","timestamp":1458691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Viral Hepatitis"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190 is a <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>5B non\u2010nucleoside analogue with demonstrated effectiveness in a Phase 1 monotherapy study and in combination with other <jats:styled-content style=\"fixed-case\">DAA<\/jats:styled-content>s for treatment of chronic <jats:styled-content style=\"fixed-case\">HCV<\/jats:styled-content> infection. Here, the resistance profile of <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190 monotherapy in a Phase 1b study was investigated. Resistance analysis was performed by population sequencing and allele\u2010specific <jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>) for Y448H with an assay cut\u2010off of 0.5%. Phenotypic susceptibility analyses were performed on patient isolates as well as site\u2010directed mutagenesis of mutations selected during monotherapy. No resistance\u2010associated variants were observed in patients before or after receiving single doses of <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190 by population sequencing. In contrast, in patients who received <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190 for 8 days, mutations Y448H and Y452H in <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>5B were observed by population sequencing in 21\/36 (58%) and 2\/36 (5.6%) patients, respectively, at Day 8 or Day 14. Among the remaining 15 patients who had no detectable Y448H at Day 8 or Day 14 by population sequencing, low frequencies of Y448H ranging from 1.3 to 9.7% were detected in 14 of 15 patients by <jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>. By <jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>, Y448H remained detectable at reduced frequency in the majority of patients analysed through 4\u20136 months of follow\u2010up. Chimeric <jats:styled-content style=\"fixed-case\">HCV<\/jats:styled-content> replicons constructed with the <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>5B sequence from patients with Y448H and Y448H + Y452H\/Y demonstrated 27\u2010fold and 78.5\u2010fold reduced susceptibility to <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190. In conclusion, Y448H was rapidly selected in the majority of patients receiving multiple doses of <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190 as monotherapy, despite undetectable levels in pretreatment samples. Y448H confers reduced susceptibility to <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>\u20109190 and other <jats:styled-content style=\"fixed-case\">NNI<\/jats:styled-content>s and persisted in most patients for months post\u2010treatment.<\/jats:p>","DOI":"10.1111\/jvh.12536","type":"journal-article","created":{"date-parts":[[2016,3,23]],"date-time":"2016-03-23T11:04:53Z","timestamp":1458731093000},"page":"644-651","source":"Crossref","is-referenced-by-count":5,"title":["Antiviral response and resistance analysis of treatment\u2010na\u00efve <scp>HCV<\/scp>\u2010infected patients receiving single and multiple doses of <scp>GS<\/scp>\u20109190"],"prefix":"10.1111","volume":"23","author":[{"given":"H.","family":"Mo","sequence":"first","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Hedskog","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Svarovskaia","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.\u2010C.","family":"Sun","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. M.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Mount Sinai Beth Israel Medical Center New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. M.","family":"Brainard","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. G.","family":"McHutchison","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70216-4"},{"issue":"5","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1128\/jvi.66.5.3225-3229.1992","article-title":"Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution","volume":"66","author":"Martell M","year":"1992","journal-title":"J Virol"},{"issue":"4","key":"e_1_2_9_4_1","first-page":"201","article-title":"RNA virus quasispecies: significance for viral disease and epidemiology","volume":"3","author":"Duarte EA","year":"1994","journal-title":"Infect Agents Dis"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00838-12"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24262"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1101515108"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02628-05"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/v2102169"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.11.018"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.109309"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60247-0"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1214853"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1214854"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402454"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1316366"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402355"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27053"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62121-2"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu697"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402338"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402869"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1315722"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1401561"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04619-14"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.1328"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00998-15"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00307-11"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24744"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00274-11"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0an00695e"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05438-11"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02052-12"},{"issue":"4","key":"e_1_2_9_34_1","first-page":"104","article-title":"Viral kinetics of the Y448H HCV NS5B polymerase mutant in patients treated with the HCV inhibitor tegobuvir (GS\u20109190)","volume":"5","author":"Ku KS","year":"2013","journal-title":"Antivir Antiretrovir"}],"container-title":["Journal of Viral Hepatitis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjvh.12536","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjvh.12536","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvh.12536","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T11:29:59Z","timestamp":1696246199000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jvh.12536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,23]]},"references-count":33,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1111\/jvh.12536"],"URL":"https:\/\/doi.org\/10.1111\/jvh.12536","archive":["Portico"],"relation":{},"ISSN":["1352-0504","1365-2893"],"issn-type":[{"value":"1352-0504","type":"print"},{"value":"1365-2893","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,23]]}}}