{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:18:20Z","timestamp":1778635100311,"version":"3.51.4"},"reference-count":23,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"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":[[2014,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Treatment with GS-9669, a novel nonnucleoside inhibitor (site II) of hepatitis C virus (HCV) nonstructural 5B (NS5B) polymerase, resulted in significant antiviral activity in HCV genotype (GT) 1 patients dosed at 50 and 500 mg once daily (QD) and at 50, 100, and 500 mg twice daily (BID) for 3 days. This report characterizes the virologic resistance to GS-9669\n            <jats:italic>in vitro<\/jats:italic>\n            and in GT1 HCV-infected patients from a phase I clinical study. An\n            <jats:italic>in vitro<\/jats:italic>\n            resistance selection study with GS-9669 revealed substitutions at several NS5B residues that conferred resistance. The M423 variants were selected at low drug concentrations (5\u00d7 the 50% effective concentration [EC\n            <jats:sub>50<\/jats:sub>\n            ]), and the L419, R422, and I482 variants were selected at higher drug concentrations (20\u00d7 the EC\n            <jats:sub>50<\/jats:sub>\n            ). During the phase I clinical study, substitutions at NS5B residues 419, 422, and 486 were the predominant changes associated with GS-9669 monotherapy. Substitutions at position 423 were observed only in GT1a patients in the low-dose groups (50 and 100 mg BID). Interestingly, four HCV patients had substitutions at position 423 at baseline. Consistent with the low resistance level at this position, three patients with M423I or M423V at baseline achieved &gt;2-log\n            <jats:sub>10<\/jats:sub>\n            reductions of HCV RNA when treated with 100 mg BID or with 500 mg QD or BID of GS-9669. The fourth patient, who had the M423V substitution at baseline, had a 4.4-log\n            <jats:sub>10<\/jats:sub>\n            reduction of HCV RNA with 500 mg BID of GS-9669. Phenotypic analyses demonstrated that the viral isolates with multiple GS-9669 resistance-associated variants have reduced susceptibility to GS-9669 and lomibuvir (VX-222) but are not cross-resistant to other classes of HCV inhibitors. (This study has been registered at\n            <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n            under registration no. NCT01431898.)\n          <\/jats:p>","DOI":"10.1128\/aac.02815-14","type":"journal-article","created":{"date-parts":[[2014,8,26]],"date-time":"2014-08-26T06:40:17Z","timestamp":1409035217000},"page":"6599-6606","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Clinical and\n            <i>In Vitro<\/i>\n            Resistance to GS-9669, a Thumb Site II Nonnucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase"],"prefix":"10.1128","volume":"58","author":[{"given":"Hadas","family":"Dvory-Sobol","sequence":"first","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Voitenleitner","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Mabery","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor","family":"Skurnac","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric J.","family":"Lawitz","sequence":"additional","affiliation":[{"name":"The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"McHutchison","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evguenia S.","family":"Svarovskaia","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Delaney","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2010.03432.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22759"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.30531"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2005.076646"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020047"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(01)06102-5"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0807650"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60934-8"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24172"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.05.046"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02052-12"},{"key":"e_1_3_3_13_2","volume-title":"47th Ann. Meet. Eur. Assoc. Study Liver (EASL)","author":"Lawitz E","year":"2012","unstructured":"LawitzEHazanLGruenerDHackHBackonjaMHillJGermanPDvory-SobolHJainAArterburnSWatkinsWRossiSMcHutchinsonJRodriguez-TorresM. 2012. GS-9669, a novel NS5B non-nucleoside thumb site II inhibitor, demonstrates potent antiviral activity, favorable safety profile and potential for once-daily dosing; poster 1189. 47th Ann. Meet. Eur. Assoc. Study Liver (EASL), Barcelona, Spain, 18 to 22 April 2012."},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05611-11"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00307-11"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00289-10"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5424.110"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(10)60768-4"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3410\/B4-5"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.03.015"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00834-07"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01599-08"},{"key":"e_1_3_3_23_2","volume-title":"6th International Workshop on Clinical Pharmacology of Hepatitis Therapy","author":"Dvory-Sobol H","year":"2011","unstructured":"Dvory-SobolHXuSGoodwinHGoodmanDSvarovskaiaESMillerMDMoH. 2011. Replication fitness and drug susceptibility of HCV triple class drug-resistant mutants; abstr. R_13. 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, Cambridge, MA, 22 to 23 June 2011."},{"key":"e_1_3_3_24_2","doi-asserted-by":"crossref","unstructured":"Dvory-SobolHGontcharovaVMartinRLawitzEJMcHutchisonJGSvarovskaiaESMillerMDMoH. 2014. Low persistence of resistance-associated variants after 3 days of monotherapy with NS5B NNI site II inhibitor GS-9669 in genotype 1 HCV patients. Abstr. 49th Ann. Meet. Eur. Assoc. Study Liver. http:\/\/www.natap.org\/2014\/EASL\/EASL_74.htm.","DOI":"10.1016\/S0168-8278(14)61389-1"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02815-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02815-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:47:43Z","timestamp":1645483663000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02815-14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11]]},"references-count":23,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2014,11]]}},"alternative-id":["10.1128\/AAC.02815-14"],"URL":"https:\/\/doi.org\/10.1128\/aac.02815-14","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11]]},"assertion":[{"value":"2014-03-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-08-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-10-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}