Virologic response and characterisation of HCV genotype 2–6 in patients receiving TMC435 monotherapy (study TMC435-C202)

• DOI: 10.1016/j.jhep.2012.10.028
• Publication Date: 2012-11-07T09:35:56Z
• Authors: Oliver Lenz; Leen Vijgen; Jan Martin Berke; Maxwell D. Cummings; Bart Fevery; Monika Peeters; Goedele De Smedt; Christophe Moreno; Gaston Picchio
• Keywords: Hepacivirus -- classification -- drug effects -- genetics; Genotype; Viral Nonstructural Proteins -- antagonists & inhibitors -- genetics; Sulfonamides -- pharmacology -- therapeutic use; Hepacivirus; Viral Nonstructural Proteins; Antiviral Agents; 3-Ring -- pharmacology -- therapeutic use; 03 medical and health sciences; Antiviral Agents -- therapeutic use; Genetic; Heterocyclic Compounds; Simeprevir; Hepatitis C -- drug therapy -- virology; Humans; Polymorphism; Sulfonamides; 0303 health sciences; Polymorphism, Genetic; Viral -- blood; Sciences bio-médicales et agricoles; Hepatitis C; 3. Good health; Mutation; RNA; RNA, Viral; Heterocyclic Compounds, 3-Ring

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.Thirty-seven patients received TMC435 monotherapy (200 mg once daily) for 7 days. HCV RNA, NS3 protease sequences and the corresponding phenotypes were evaluated.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.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.