{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T10:51:14Z","timestamp":1761562274064},"reference-count":30,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,10,4]],"date-time":"2017-10-04T00:00:00Z","timestamp":1507075200000},"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":[[2018,2]]},"abstract":"Summary<\/jats:title>The study aimed to evaluate the effects of baseline hepatitis C virus (HCV<\/jats:styled-content>) nonstructural protein 5A (NS5A) resistance\u2010associated substitutions (RAS<\/jats:styled-content>s) on sustained virologic response to ledipasvir (LDV<\/jats:styled-content>)\u2010containing regimens in the absence of sofosbuvir (SOF<\/jats:styled-content>) in patients with HCV<\/jats:styled-content> genotype (GT<\/jats:styled-content>) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV<\/jats:styled-content>\u00a0+\u00a0vedroprevir (NS<\/jats:styled-content>3 protease inhibitor<\/jats:styled-content>)\u00a0+\u00a0tegobuvir (NS<\/jats:styled-content>5B inhibitor)\u00a0\u00b1\u00a0ribavirin or LDV<\/jats:styled-content>\u00a0+\u00a0ribavirin\u00a0+\u00a0pegylated interferon. Population sequencing of HCV NS<\/jats:styled-content>5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT<\/jats:styled-content>1a, and 298 (26.9%) had GT<\/jats:styled-content>1b infection. The overall prevalence of NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s at baseline was 9.4%; 7.6% (57\/747) and 13.8% (41\/298) of patients with GT<\/jats:styled-content>1a and GT<\/jats:styled-content>1b infection, respectively. The majority of GT<\/jats:styled-content>1a\u2010infected patients with NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s at baseline had a single NS<\/jats:styled-content>5A RAS<\/jats:styled-content> (78.9%) at NS<\/jats:styled-content>5A positions K24R, M28T, Q30H\/L, L31M and Y93H\/N\/C\/S. The spectrum of NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s detected in GT<\/jats:styled-content>1b patients was much less diverse compared to GT<\/jats:styled-content>1a patients, with all patients harbouring a single NS<\/jats:styled-content>5A RAS<\/jats:styled-content> either L31M or Y93H\/C. For patients treated with LDV<\/jats:styled-content>\u2010containing regimens in the absence of SOF<\/jats:styled-content>, the presence of baseline NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s was associated with low SVR<\/jats:styled-content> rates. In patients with virologic failure, nearly all had either pre\u2010existing and\/or emergent NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s: 287\/287 (100%) and 40\/42 (95.2%) patients with GT<\/jats:styled-content>1a and GT<\/jats:styled-content>1b infection, respectively. Three novel NS<\/jats:styled-content>5A substitutions were identified as emergent NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s: K26E and S38F in GT<\/jats:styled-content>1a; and L31I in GT<\/jats:styled-content>1b. In conclusion, the presence of NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s at baseline reduced the SVR<\/jats:styled-content> rate in patients treated with LDV<\/jats:styled-content> in combination vedroprevir\u00a0+\u00a0tegobuvir\u00a0\u00b1\u00a0ribavirin or ribavirin\u00a0+\u00a0pegylated interferon. Virologic failure was associated with the detection of NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV<\/jats:styled-content> drug combination and may be more important than that of the individual DAA<\/jats:styled-content>s.<\/jats:p>","DOI":"10.1111\/jvh.12783","type":"journal-article","created":{"date-parts":[[2017,8,20]],"date-time":"2017-08-20T09:46:36Z","timestamp":1503222396000},"page":"126-133","source":"Crossref","is-referenced-by-count":5,"title":["Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir\u2010containing regimens without sofosbuvir"],"prefix":"10.1111","volume":"25","author":[{"given":"K. M.","family":"Kitrinos","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. C.","family":"Corsa","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Worth","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Hedskog","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. M.","family":"Brainard","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Mo","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26141"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199908193410802"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.12.029"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02524-15"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02193-12"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402454"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1316366"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402355"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62121-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.06.002"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27053"},{"key":"e_1_2_8_13_1","doi-asserted-by":"crossref","unstructured":"ThompsonAH ShiffmanS RossaroML et\u00a0al.GS\u20105885\u00a0+\u00a0GS\u20109451\u00a0+\u00a0peginterferon and ribavirin (PR) for six or twelve weeks achieves high SVR12 rates in treatment\u2010naive genotype 1 IL28B CC patients. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). 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