Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders

Hepatology ◽  
2012 ◽  
Vol 55 (3) ◽  
pp. 742-748 ◽  
Author(s):  
Kazuaki Chayama ◽  
Shoichi Takahashi ◽  
Joji Toyota ◽  
Yoshiyasu Karino ◽  
Kenji Ikeda ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Nonstructural Protein ◽  
Dual Therapy ◽  
Virus Genotype ◽  
Genotype 1B ◽  
Nonstructural Protein 3 ◽  
Nonstructural Protein 5A

Nonstructural protein 5A/P32 deletion after failure of ledipasvir/sofosbuvir in hepatitis C virus genotype 1b infection

Hepatology ◽  
2018 ◽  
Vol 68 (1) ◽  
pp. 380-383 ◽  
Author(s):  
Akira Doi ◽  
Hayato Hikita ◽  
Ryotaro Sakamori ◽  
Yuki Tahata ◽  
Yugo Kai ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Virus Genotype ◽  
Genotype 1B ◽  
Nonstructural Protein 5A

scholarly journals Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

Hepatology ◽  
1999 ◽  
Vol 30 (4) ◽  
pp. 1045-1053 ◽  
Author(s):  
Takeshi Murakami ◽  
Nobuyuki Enomoto ◽  
Masayuki Kurosaki ◽  
Namiki Izumi ◽  
Fumiaki Marumo ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Virus Genotype ◽  
Genotype 2 ◽  
Nonstructural Protein 5A

scholarly journals Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir

2012 ◽  
Vol 56 (7) ◽  
pp. 3670-3681 ◽  
Author(s):  
Fiona McPhee ◽  
Jacques Friborg ◽  
Steven Levine ◽  
Chaoqun Chen ◽  
Paul Falk ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Clinical Studies ◽  
Replication Capacity ◽  
Replication Complex ◽  
Hcv Genotype ◽  
Genotype 1A ◽  
Genotype 1B ◽  
Ns3 Protease

ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

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