title: Viral resistance in hepatitis C virus genotype 1-infected patients receiving the NS3 protease inhibitor Faldaprevir (BI 201335) in a phase 1b multiple-rising-dose study.
abstract: Faldaprevir (BI 201335) is a selective NS3/4A protease inhibitor under development for the treatment of chronic hepatitis C virus (HCV) infection. NS3/4A genotyping and NS3 protease phenotyping analyses were performed to monitor the emergence of resistance in patients with HCV genotype 1 infection receiving faldaprevir alone or combined with pegylated interferon alfa 2a and ribavirin (PegIFN-RBV) during a phase 1b study. Among all baseline variants, a maximum 7-fold reduction in in vitro sensitivity to faldaprevir was observed for a rare NS3 (V/I)170T polymorphism. During faldaprevir monotherapy in treatment-naive patients, virologic breakthrough was common (77%, 20/26) and was associated with the emergence of resistance mutations predominantly carrying NS3 substitutions R155K in GT1a and D168V in GT1b. D168V conferred a greater reduction in faldaprevir sensitivity (1,800-fold) than R155K (330-fold); however, D168V was generally less fit than R155K in the absence of selective drug pressure. Treatment-experienced patients treated with faldaprevir-PegIFN-RBV triple therapy showed higher viral load reductions, lower rates of breakthrough (8%, 5/62), and less frequent emergence of resistance-associated variants compared with faldaprevir monotherapy. (This study has been registered at ClinicalTrials.gov under registration no. NCT00793793.).
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Berger
authors.forename: Lisette
authors.initials: L
authors.lastname: Lagacé
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Triki
authors.forename: Mireille
authors.initials: M
authors.lastname: Cartier
authors.forename: Martin
authors.initials: M
authors.lastname: Marquis
authors.forename: Carol
authors.initials: C
authors.lastname: Lawetz
authors.forename: Richard
authors.initials: R
authors.lastname: Bethell
authors.forename: Joseph
authors.initials: J
authors.lastname: Scherer
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D005838:Genotype; D060005:Genotyping Techniques / Q000379:methods; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D009842:Oligopeptides / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000627:therapeutic use; D011804:Quinolines; D013844:Thiazoles / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; 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; C552340:faldaprevir