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.
abstract: 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 = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<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 (P < 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 = 507 GT-1a; 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 in vitro). 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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA kristi.berger@boehringer-ingelheim.com george.kukolj@gmail.com.
authors.forename: K L
authors.initials: KL
authors.lastname: Berger
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: Scherer
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ranga
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sha
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: J O
authors.initials: JO
authors.lastname: Stern
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: A-M
authors.initials: AM
authors.lastname: Quinson
authors.affiliation: Boehringer Ingelheim Ltd./Ltée, Burlington, Ontario, Canada kristi.berger@boehringer-ingelheim.com george.kukolj@gmail.com.
authors.forename: G
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D019943:Amino Acid Substitution; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000031:analogs & derivatives; D009154:Mutation; D009842:Oligopeptides / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D002352:Carrier Proteins; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011804:Quinolines; D011994:Recombinant Proteins; D012254:Ribavirin; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C552340:faldaprevir; C100416:peginterferon alfa-2a