Susceptibility of Treatment-Naive Hepatitis C Virus (HCV) Clinical Isolates to HCV Protease Inhibitors

被引：72

作者：

Bae, Andrew ^{[1
]}

Sun, Siu-Chi ^{[1
]}

Qi, Xiaoping ^{[1
]}

Chen, Xiaowu ^{[1
]}

Ku, Karin ^{[1
]}

Worth, Angela ^{[1
]}

Wong, Kelly A. ^{[1
]}

Harris, Jeanette ^{[1
]}

Miller, Michael D. ^{[1
]}

Mo, Hongmei ^{[1
]}

机构：

[1] Gilead Sci Inc, Dept Clin Virol, Foster City, CA 94404 USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2010年 / 54卷 / 12期

关键词：

NS3; PROTEASE; RNA REPLICATION; RESISTANCE MUTATIONS; ANTIVIRAL ACTIVITY; SERINE-PROTEASE; TELAPREVIR; SCH-503034; HETEROGENEITY; GENOTYPE-1; ITMN-191;

D O I：

10.1128/AAC.00777-10

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two alpha-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the alpha-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the alpha-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.

引用

页码：5288 / 5297

页数：10

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