{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T03:27:39Z","timestamp":1772162859102,"version":"3.50.1"},"reference-count":36,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"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":[[2015,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3\/4A (NS3\/4A) protease inhibitor faldaprevir plus pegylated interferon alpha\/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3\/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (\n                    <jats:italic>n<\/jats:italic>\n                    = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (&lt;1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (\n                    <jats:italic>n<\/jats:italic>\n                    = 507 GT-1a;\n                    <jats:italic>n<\/jats:italic>\n                    = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference\n                    <jats:italic>in vitro<\/jats:italic>\n                    ). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.\n                  <\/jats:p>","DOI":"10.1128\/aac.00932-15","type":"journal-article","created":{"date-parts":[[2015,7,20]],"date-time":"2015-07-20T20:23:30Z","timestamp":1437423810000},"page":"6017-6025","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Baseline Polymorphisms and Emergence of Drug Resistance in the NS3\/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a\/Ribavirin in Phase 2 and Phase 3 Studies"],"prefix":"10.1128","volume":"59","author":[{"given":"K. 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