title: Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202).
abstract: OBJECTIVE
  TMC435 is a potent, once-daily, investigational hepatitis C virus (HCV) NS3/4A protease inhibitor in phase III clinical development. In the phase II trial TMC435-C202 (NCT00812331), TMC435 displayed potent activity in genotype 4, 5 and 6 patients and in 3/6 genotype 2 patients, whereas no activity was observed with genotype 3.
  
  
  METHODS
  Thirty-seven patients received TMC435 monotherapy (200 mg once daily) for 7 days. HCV RNA, NS3 protease sequences and the corresponding phenotypes were evaluated.
  
  
  RESULTS
  Genotype and isolate-specific baseline polymorphisms at NS3 positions known to affect HCV protease inhibitor activity were present in all genotypes. Consistent with the antiviral activity observed in genotypes 4 and 6, TMC435 was active in vitro against all genotype 4 isolates, and against most genotype 6 polymorphisms when tested as single or double mutants. In contrast, in genotype 3 where no HCV RNA decline was observed, isolates displayed >700-fold increases in EC(50) attributed to the D168Q polymorphism. In genotypes 2 and 5, HCV RNA changes from baseline to Day 3 ranged between -0.3 to -3.6 and -1.5 to -4.0 log(10)IU/ml, respectively, and isolates or site-directed mutants displayed intermediate in vitro susceptibility to TMC435 with fold changes in EC(50) between 15 and 78. Viral breakthrough in genotypes 4-6 was associated with emerging mutations including Q80R, R155K and/or D168E/V.
  
  
  CONCLUSIONS
  Sequence and phenotypic analyses of baseline isolates identified polymorphisms which could explain the differences in antiviral activity between genotypes. Pathways of TMC435 resistance in genotypes 2-6 were similar to those identified in genotype 1.
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium. olenz@its.jnj.com
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.forename: Jan Martin
authors.initials: JM
authors.lastname: Berke
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Bart
authors.initials: B
authors.lastname: Fevery
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.forename: Goedele
authors.initials: G
authors.lastname: De Smedt
authors.forename: Christophe
authors.initials: C
authors.lastname: Moreno
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood; D000069616:Simeprevir; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; 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; D006575:Heterocyclic Compounds, 3-Ring; D012367:RNA, Viral; D000069616:Simeprevir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases