title: In Vitro Assessment of Re-treatment Options for Patients with Hepatitis C Virus Genotype 1b Infection Resistant to Daclatasvir Plus Asunaprevir.
abstract: BACKGROUND
  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 EC50values 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhou
authors.forename: Zhou
authors.initials: Z
authors.lastname: Han
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: Falk
authors.forename: Patricia
authors.initials: P
authors.lastname: Mendez
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee