{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:20:42Z","timestamp":1790076042954,"version":"4.0.1"},"reference-count":23,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2013,12,1]],"date-time":"2013-12-01T00:00:00Z","timestamp":1385856000000},"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":[[2013,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            GS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naive genotype 1a (GT1a) and GT1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log\n            <jats:sub>10<\/jats:sub>\n            HCV RNA IU\/ml across dosing cohorts (1, 3, 10, 30, or 90 mg once daily). Here, we report viral sequencing and phenotypic analysis of clinical isolates from this study. Detection of baseline NS5A amino acid substitutions at positions 28, 30, 31, or 93 in GT1a was associated with a reduced treatment response. In the GT1b cohort, Y93H was detected in 100% of subjects at day 4 or 14. In the Gt1a cohort, population sequencing detected NS5A resistance-associated mutations at day 4 or 14 for 3\/10 subjects at the 1-mg dose and for all subjects dosed at \u22653 mg. A subset of mutants that confer a low level of reduced susceptibility to GS-5885 was not detected by population sequencing at the 30- and 90-mg doses. Subject-derived M28T, Q30R, L31M, and Y93C mutations all conferred &gt;30-fold reductions in GS-5885 and daclatasvir susceptibilities\n            <jats:italic>in vitro<\/jats:italic>\n            . Site-directed NS5A mutants also showed reduced susceptibility to GS-5885. However, all NS5A mutants tested remained fully susceptible to other classes of direct-acting antivirals (DAAs), interferon alpha, and ribavirin. Importantly, the nonoverlapping resistance profile and high potency of GS-5885 support its further development with other direct-acting antivirals for the treatment of chronic HCV. (This study has been registered at ClinicalTrials.gov under registration number NCT01193478.)\n          <\/jats:p>","DOI":"10.1128\/aac.02193-12","type":"journal-article","created":{"date-parts":[[2013,7,23]],"date-time":"2013-07-23T02:15:44Z","timestamp":1374545744000},"page":"6333-6340","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":89,"title":["Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885"],"prefix":"10.1128","volume":"57","author":[{"given":"Kelly A.","family":"Wong","sequence":"first","affiliation":[{"name":"Department of Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Worth","sequence":"additional","affiliation":[{"name":"Department of Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evguenia","family":"Svarovskaia","sequence":"additional","affiliation":[{"name":"Department of Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M.","family":"Brainard","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Lawitz","sequence":"additional","affiliation":[{"name":"Alamo Medical Research, Camden Medical Center, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Clinical Virology, Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70216-4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1012912"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1010494"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00328-07"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08960"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24594"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.12.029"},{"key":"e_1_3_3_9_2","first-page":"536A","article-title":"Resistance monitoring of HCV patients treated for three days with the NS5A inhibitor PPI-461 reveals rapid emergence of resistant HCV variants","volume":"54","author":"Huang Q","year":"2011","unstructured":"HuangQ HuangN LauM BencsikM HuqA PengE AgarwalK LalezariJ VigP BrownN ColonnoR. 2011. Resistance monitoring of HCV patients treated for three days with the NS5A inhibitor PPI-461 reveals rapid emergence of resistant HCV variants. Hepatology 54(Suppl 1):536A.","journal-title":"Hepatology"},{"key":"e_1_3_3_10_2","first-page":"400","article-title":"GSK2336805 HCV NS5A inhibitor demonstrates potent antiviral activity in chronic genotype 1 infection; results from a first time in human (FTIH) single and repeat dose study","volume":"54","author":"Spreen W","year":"2011","unstructured":"SpreenW WilfretDA BechtelJ AdkinsonKK LouY JonesL WillsieSK GlassSJ RobertsCD. 2011. GSK2336805 HCV NS5A inhibitor demonstrates potent antiviral activity in chronic genotype 1 infection; results from a first time in human (FTIH) single and repeat dose study. Hepatology 54(Suppl 1):400\u2013401A.","journal-title":"Hepatology"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(11)61206-3"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(11)61215-4"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(11)60817-9"},{"key":"e_1_3_3_14_2","first-page":"531A","article-title":"Discovery of MK-4882, a novel inhibitor of HCV NS5A with an attractive pre-clinical profile","volume":"54","author":"Ludmerer S","year":"2011","unstructured":"LudmererS FandozziCM HuangQ KargmanS LiuR MeinkeP OlsenDB CoburnC. 2011. Discovery of MK-4882, a novel inhibitor of HCV NS5A with an attractive pre-clinical profile. Hepatology 54(Suppl 1):531A\u2013532A.","journal-title":"Hepatology"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(11)61230-0"},{"key":"e_1_3_3_16_2","first-page":"537A","article-title":"Novel hepatitis C virus NS5A inhibitors with improved potency against genotype-1a replicons and replicons carrying mutations associated with viral resistance to 1st generation NS5A inhibitors","volume":"54","author":"Yang G","year":"2011","unstructured":"YangG ZhaoY PatelD FabryckiJL MarlorC RiveraJ StauberK WilesJ GadhachandaV HashimotoA ChenD WangQ PaisG WangX DeshpandeA HuangM. 2011. Novel hepatitis C virus NS5A inhibitors with improved potency against genotype-1a replicons and replicons carrying mutations associated with viral resistance to 1st generation NS5A inhibitors. 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