Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3

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• 作者：Marcelo O. Silva¹ ; ^{msilva@cas.austral.edu.ar} ; Michelle Treitel² ; ^&dagger ; ; Donald J. Graham² ; Stephanie Curry² ; Maria J. Frontera¹ ; Patricia McMonagle² ; Samir Gupta² ; ^&dagger ; ; Eric Hughes² ; ^&dagger ; ; Robert Chase² ; Fred Lahser² ; Richard J.O. Barnard² ; Anita Y.M. Howe² ; John A. Howe²
• 关键词：AE ; adverse event ; ANOVA ; analysis of variance ; AUC ; area under the plasma concentration-time curve ; BMI ; body mass index ; Cmax ; maximum observed plasma concentration ; CHC ; chronic hepatitis C ; CLss/F ; apparent total body clearance at steady state ; DAA ; d
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：59
• 期：1
• 页码：31-37
• 全文大小：633 K

文摘

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Background & Aims

To examine the antiviral activity of boceprevir, a hepatitis C virus (HCV) protease inhibitor, in HCV genotype (G) 2/3-infected patients.

Methods

We assessed boceprevir and telaprevir activity against an HCV G2 and G3 isolates enzyme panel, in replicon, and in phenotypic cell-based assays. Additionally, a phase I study evaluated the antiviral activity of boceprevir monotherapy (200 mg BID, 400 mg BID, or 400 mg TID) vs. placebo for 14 days in HCV G2/3 treatment-naive patients.

Results

Boceprevir and telaprevir similarly inhibited G1 and G2 NS3/4A enzymes and replication in G1 and G2 replicon and cell-based assays. However, telaprevir demonstrated lower potency than boceprevir against HCV G3a enzyme (K_i = 75 nM vs. 17 nM), in the G3a replicon assay (EC₅₀ = 953 nM vs. 159 nM), and against HCV G3a NS3 isolates (IC₅₀ = 3312 nM vs. 803 nM) in the cell-based assay. In HCV G2/3-infected patients, boceprevir (400 mg TID) resulted in a maximum mean decrease in HCV RNA of ?1.60 log vs. ?0.21 log with placebo.

Conclusions

In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays. In HCV G2/3-infected treatment-naive patients, decreases in HCV RNA levels with boceprevir (400 mg TID) were comparable to those observed with the same dose in HCV treatment-experienced G1-infected patients.