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


ABSTRACT: 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. 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. 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. 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.

SUBMITTER: Friborg J 

PROVIDER: S-EPMC4363215 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Friborg Jacques J   Zhou Nannan N   Han Zhou Z   Yang Xiaoyan X   Falk Paul P   Mendez Patricia P   McPhee Fiona F  

Infectious diseases and therapy 20141217


<h4>Introduction</h4>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.<h4>Methods</h4>The antiviral activity of drug combination regi  ...[more]

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