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

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• 作者：Oliver Lenz¹ ; ^{olenz@its.jnj.com} ; Leen Vijgen¹ ; Jan Martin Berke¹ ; Maxwell D. Cummings² ; Bart Fevery¹ ; Monika Peeters¹ ; Goedele De Smedt¹ ; Christophe Moreno³ ; Gaston Picchio⁴
• 关键词：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
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：58
• 期：3
• 页码：445-451
• 全文大小：1013 K

文摘

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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.

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 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.

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.