In Vitro Assessment of Re-treatment Options for Patients with Hepatitis C Virus Genotype 1b Infection Resistant to Daclatasvir Plus Asunaprevir

被引：18

作者：

Friborg J. ^{[1
]}

Zhou N. ^{[1
]}

Han Z. ^{[1
]}

Yang X. ^{[1
]}

Falk P. ^{[1
]}

Mendez P. ^{[2
]}

McPhee F. ^{[1
]}

机构：

[1] Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, 06492, CT

[2] Bristol Myers-Squibb Research and Development, Lawrenceville, NJ

来源：

Infectious Diseases and Therapy | 2015年 / 4卷 / 1期

关键词：

Asunaprevir; Beclabuvir; Daclatasvir; Hepatitis C virus; Ledipasvir; Re-Treatment; Replicon; Resistance; Simeprevir; Sofosbuvir;

D O I：

10.1007/s40121-014-0052-8

中图分类号：

学科分类号：

摘要：

Introduction: Daclatasvir is a non-structural protein 5A (NS5A) inhibitor with activity against hepatitis C virus (HCV) genotypes 1–6 in vitro, and asunaprevir is a non-structural protein 3 (NS3) protease inhibitor with activity against genotypes 1, 4, 5, and 6. This study evaluates potential options for the re-treatment of HCV genotype 1b-infected patients who have failed combination therapy with daclatasvir plus asunaprevir. Methods: The antiviral activity of drug combination regimens in HCV subgenomic replicon cell lines representing genotype 1b (Con1 strain) wild-type or a variant with specific NS5A and NS3 amino acid substitutions conferring resistance to daclatasvir and asunaprevir were compared using replicon elimination assays. Drug concentrations representing multiple 50% effective concentrations (EC50) derived in vitro and trough plasma concentrations observed in a clinical setting were utilized. Results: At multiple EC50 values of each drug (3×, 10×, and 30× EC50), combinations of daclatasvir plus sofosbuvir, sofosbuvir plus ledipasvir, sofosbuvir plus simeprevir, and sofosbuvir plus either a next-generation NS3 or NS5A inhibitor demonstrated comparable activity in wild-type and daclatasvir/asunaprevir-resistant cell lines. At clinically relevant drug trough concentrations, combination regimens of daclatasvir plus asunaprevir plus beclabuvir (±ribavirin), and daclatasvir plus asunaprevir plus beclabuvir plus sofosbuvir efficiently cleared daclatasvir + asunaprevir-resistant replicons from cells within 5 days of treatment. Conclusion: Our in vitro results highlight a number of potential all-oral treatment options for patients who do not achieve a sustained virologic response following therapy with daclatasvir plus asunaprevir. These results require further evaluation in clinical studies. © 2014, The Author(s).

引用

页码：137 / 144

页数：7

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