{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:45:35Z","timestamp":1789908335182,"version":"4.0.1"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,11,7]],"date-time":"2017-11-07T00:00:00Z","timestamp":1510012800000},"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>HCV<\/jats:styled-content> genotype 4 (GT<\/jats:styled-content>4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir\/sofosbuvir and sofosbuvir\/velpatasvir were highly efficacious in GT<\/jats:styled-content>4 HCV<\/jats:styled-content>\u2010infected patients from GS<\/jats:styled-content>\u2010US<\/jats:styled-content>\u2010337\u20101119 and GS<\/jats:styled-content>\u2010US<\/jats:styled-content>\u2010342\u20101138. Here, we characterize the resistance profile of ledipasvir (LDV<\/jats:styled-content>) and velpatasvir (VEL<\/jats:styled-content>) in patients with GT<\/jats:styled-content>4 HCV<\/jats:styled-content> infection. NS<\/jats:styled-content>5A deep\u2010sequencing was performed for 454 patients infected with HCV GT<\/jats:styled-content>4 at baseline, including 44 patients enrolled in GS<\/jats:styled-content>\u2010US<\/jats:styled-content>\u2010337\u20101119 and 116 patients enrolled in GS<\/jats:styled-content>\u2010US<\/jats:styled-content>\u2010342\u20101138, and at relapse for patients with virologic failure. LDV<\/jats:styled-content> and VEL<\/jats:styled-content> susceptibilities of 56 patient isolates were determined. In GS<\/jats:styled-content>\u2010US<\/jats:styled-content>\u2010337\u20101119, SVR<\/jats:styled-content>12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS<\/jats:styled-content>5A patient isolates from various GT<\/jats:styled-content>4 subtypes indicated that LDV<\/jats:styled-content> had high potency for the common subtypes 4a\/d, and subtypes 4c\/f\/k\/l\/m\/n\/o\/p\/r\/t despite the presence of resistance\u2010associated substitutions (RAS<\/jats:styled-content>s). For the rare GT<\/jats:styled-content>4b, LDV<\/jats:styled-content> median EC<\/jats:styled-content>50<\/jats:sub> was higher, but with a broad range of individual values. Importantly, all GT<\/jats:styled-content>4b isolates tested had 2\u20104 NS<\/jats:styled-content>5A RAS<\/jats:styled-content>s, some including Y93H. Similarly, the 2 GT<\/jats:styled-content>4r infected patients who had virologic relapse had rare triple RAS<\/jats:styled-content>s. Reversion of these substitutions to the consensus residue significantly increased LDV<\/jats:styled-content> susceptibility. In GS<\/jats:styled-content>\u2010US<\/jats:styled-content>\u2010342\u20101138, all patients achieved SVR<\/jats:styled-content>12, regardless of their subtype or presence of RAS<\/jats:styled-content>s. In vitro data confirmed that VEL<\/jats:styled-content> is potent against all GT<\/jats:styled-content>4 isolates tested.<\/jats:p>LDV<\/jats:styled-content> and VEL<\/jats:styled-content> are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT<\/jats:styled-content>4 HCV<\/jats:styled-content> isolates.<\/jats:p>","DOI":"10.1111\/jvh.12795","type":"journal-article","created":{"date-parts":[[2017,10,6]],"date-time":"2017-10-06T07:52:37Z","timestamp":1507276357000},"page":"134-143","source":"Crossref","is-referenced-by-count":28,"title":["Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0018-6234","authenticated-orcid":false,"given":"G.","family":"Camus","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Han","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Asselah","sequence":"additional","affiliation":[{"name":"Department of Hepatology H\u00f4pital Beaujon, Assistance Publique\u2010H\u00f4pitaux de Paris Universit\u00e9 Paris\u2010Diderot and INSERM UMR1149 Clichy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Dvory\u2010Sobol","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Lu","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":"R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Parhy","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"}]},{"given":"D. M.","family":"Brainard","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Kersey","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Abergel","sequence":"additional","affiliation":[{"name":"UMR CNRS 6284 Department of Hepatology and Gastroenterology Centre Hospitalier Universitaire Estaing Universit\u00e9 d'Auvergne Clermont\u2010Ferrand France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Mo","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc. Foster City CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2010.03432.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199506013322202"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1542-3565(05)00711-1"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26744"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.03.014"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2014.07.006"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.21724"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0179064"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22759"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2005.076646"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-016-0396-4"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.09.008"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13027"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28706"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00157-7"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gtc.2015.07.013"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1512610"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01229-15"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v7.i28.2792"},{"key":"e_1_2_8_21_1","first-page":"1","article-title":"Clinically relevant HCV drug resistance mutations figure and tables (updated)","volume":"14","author":"Hddag HPWG","year":"2012","journal-title":"Ann Forum Collab HIV Res [Internet]"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5424.110"},{"key":"e_1_2_8_23_1","volume-title":"International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies","author":"Dong Han KS","year":"2011"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402454"},{"key":"e_1_2_8_25_1","unstructured":"Merck & Co. Inc.ZEPATIER\u2122(elbasvir and grazoprevir) tablets for oral use.http:\/\/www.merck.com\/product\/usa\/pi_circulars\/z\/zepatier\/zepatier_pi.pdf. 2016. Accessed on January 28 2016."},{"key":"e_1_2_8_26_1","doi-asserted-by":"crossref","first-page":"e00363\u201017","DOI":"10.1128\/AAC.00363-17","article-title":"Antiviral activity and resistance analysis of NS3\/4A protease inhibitor grazoprevir and NS5A inhibitor elbasvir in hepatitis C virus GT4 replicons","volume":"61","author":"Asante\u2010Appiah E","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28611"},{"key":"e_1_2_8_28_1","doi-asserted-by":"crossref","first-page":"S525","DOI":"10.1016\/S0168-8278(17)31452-6","article-title":"Resistance patterns in patients with chronic hepatitis C genotype 4 infection and treatment outcome","volume":"66","author":"Dietz J","year":"2017","journal-title":"EASL. 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