Research Article| Volume 58, ISSUE 3, P445-451, March 2013

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

Published:November 08, 2012DOI:

      Background & Aims

      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 EC50 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 log10 IU/ml, respectively, and isolates or site-directed mutants displayed intermediate in vitro susceptibility to TMC435 with fold changes in EC50 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.


      HCV (hepatitis C virus), PegIFN (pegylated interferon), RBV (ribavirin), SVR (sustained virologic response), DAAs (direct-acting antiviral agents), PIs (protease inhibitors), BID (twice daily), QD (once daily), LLOQ (lower limit of quantification), RT-PCR (reverse transcriptase-polymerase chain reaction), BLAST (basic local alignment search tool), EC50 (half maximal effective concentration), FC (fold changes), Cmin (minimum plasma concentration (TMC435 plasma exposure))


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