title: Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir.
abstract: OBJECTIVE
  The resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies.
  
  
  METHODS
  HCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan-Meier analysis.
  
  
  RESULTS
  Faldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (<1%) at baseline. Virologic response to faldaprevir/deleobuvir/ribavirin was not compromised by common baseline NS3 polymorphisms (e.g. Q80K in 17.5% of GT-1a) or by NS5B A421V, present in 20% of GT-1a. In GT-1b, alanine at NS5B codon 499 (present in 15% of baseline sequences) was associated with reduced response. Treatment-emergent RAVs consolidated previous findings: NS3 R155 and D168 were key faldaprevir RAVs; NS5B A421 and P495 were key deleobuvir RAVs. Among on-treatment virologic breakthroughs, RAVs emerged in both NS3 and NS5B (>90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post-treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months).
  
  
  CONCLUSIONS
  Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen.
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.|Boehringer Ingelheim Ltd/Ltée, R&D, Laval, QC, Canada.
authors: Kristi L
authors: KL
authors: Berger
authors: J.W. Goethe University Hospital, Frankfurt, Germany.
authors: Christoph
authors: C
authors: Sarrazin
authors: Clinical and Translational Science Institute, University of Florida, Gainesville, FL, United States of America.
authors: David R
authors: DR
authors: Nelson
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.
authors: Joseph
authors: J
authors: Scherer
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.
authors: Nanshi
authors: N
authors: Sha
authors: Boehringer Ingelheim Ltd/Ltée, R&D, Laval, QC, Canada.
authors: Martin
authors: M
authors: Marquis
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.|Boehringer Ingelheim Ltd/Ltée, R&D, Laval, QC, Canada.
authors: Alexandra
authors: A
authors: Côté-Martin
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.
authors: Richard
authors: R
authors: Vinisko
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.
authors: Jerry O
authors: JO
authors: Stern
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States of America.
authors: Federico J
authors: FJ
authors: Mensa
authors: Boehringer Ingelheim Ltd/Ltée, R&D, Laval, QC, Canada.|Boehringer Ingelheim Ltd/Ltée, Burlington, ON, Canada.
authors: George
authors: G
authors: Kukolj
mesh_terms: D000179:Acrylates / Q000627:therapeutic use*; D019943:Amino Acid Substitution; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000031:analogs & derivatives; D009154:Mutation / Q000235:genetics*; D009842:Oligopeptides / Q000627:therapeutic use*; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000627:therapeutic use; D011804:Quinolines; 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: D000179:Acrylates; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D001562:Benzimidazoles; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; 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; C000592437:deleobuvir; C552340:faldaprevir