Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: A population and clonal analysis

被引：18

作者：

Barnard, Richard J. O. ^{[1
]}

McHale, Carolyn M. ^{[1
]}

Newhard, William ^{[1
]}

Cheney, Carol A. ^{[1
]}

Graham, Donald J. ^{[1
]}

Himmelberger, Amy L. ^{[1
]}

Strizki, Julie ^{[1
]}

Hwang, Peggy M. T. ^{[1
]}

Rivera, Amber A. ^{[2
]}

Reeves, Jacqueline D. ^{[2
]}

Nickle, David ^{[1
]}

DiNubile, Mark J. ^{[1
]}

Hazuda, Dania J. ^{[1
]}

Mobashery, Niloufar ^{[1
]}

机构：

[1] Merck Sharp & Dohme Ltd, Whitehouse Stn, NJ USA

[2] Monogram Biosci Inc, San Francisco, CA USA

来源：

VIROLOGY | 2013年 / 443卷 / 02期

关键词：

Vaniprevir; Hepatitis C-genotype 1; Resistance-associated variants; TELAPREVIR COMBINATION TREATMENT; VIRUS-INFECTION; PLUS RIBAVIRIN; HCV; PROTEASE; BOCEPREVIR; INHIBITOR; RULES;

D O I：

10.1016/j.virol.2013.05.013

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Background: Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy. Methods: Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia. Results: Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing. Conclusions: RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure. (C) 2013 Elsevier Inc. All rights reserved.

引用

页码：278 / 284

页数：7

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