title: Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies.
abstract: OBJECTIVE
  Simeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of chronic HCV infection. Baseline NS3 polymorphisms in all patients and emerging mutations in patients who failed to achieve sustained virologic response (SVR) with simeprevir plus peginterferon/ribavirin (PR) in Phase IIb/III studies are described.
  
  
  METHODS
  Baseline sequencing data were available for 2007 genotype 1 (GT1)-infected patients. Post-baseline data were available for 197/245 simeprevir-treated patients who did not achieve SVR. In vitro simeprevir susceptibility was assessed in a transient replicon assay as site-directed mutants or in chimeric replicons with patient-derived NS3 protease sequences.
  
  
  RESULTS
  Baseline NS3 polymorphisms at positions associated with reduced in vitro susceptibility to simeprevir (43, 80, 122, 155, 156, and/or 168; EC50 fold change >2.0) were uncommon (1.3% [26/2007]), with the exception of Q80K, which confers ∼10-fold reduction in simeprevir activity in vitro (13.7% [274/2007]; GT1a 29.5% [269/911], GT1b 0.5% [5/1096]). Baseline Q80K had minor effect on initial response to simeprevir/PR, but resulted in lower SVR rates. Overall, 91.4% of simeprevir-treated patients [180/197] without SVR had emerging mutations at NS3 positions 80, 122, 155, and/or 168 at failure (mainly R155K in GT1a with and without Q80K, and D168V in GT1b), conferring high-level resistance in vitro (EC50 fold change >50). Emerging mutations were no longer detectable by population sequencing at study end in 50% [90/180] of patients (median follow-up 28.4weeks).
  
  
  CONCLUSIONS
  Simeprevir treatment failure was usually associated with emerging high-level resistance mutations, which became undetectable over time in half of the patients.
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium. Electronic address: olenz@its.jnj.com.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Verbinnen
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Fevery
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Lotke
authors.initials: L
authors.lastname: Tambuyzer
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Buelens
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Ceulemans
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ, USA.
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology*; D000069616:Simeprevir / Q000494:pharmacology*; D013997:Time Factors; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D000069616:Simeprevir; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C100416:peginterferon alfa-2a
keywords: Genotype 1; HCV NS3/4A protease inhibitor; Hepatitis C virus; Once-daily; Peginterferon; Polymorphism; Q80K; Ribavirin; Simeprevir