[Direct-acting antiviral-resistant variant].

Area of Science:

• Hepatology
• Virology
• Pharmacogenomics

Background:

• Interferon-free direct-acting antiviral (DAA) regimens, including NS5A inhibitors like daclatasvir and protease inhibitors like asunaprevir, are approved for Hepatitis C Virus (HCV) genotype 1b.
• Pre-existing resistance-associated variants (RAVs) to NS5A inhibitors can occur even in treatment-naïve patients.

Purpose of the Study:

• To evaluate the impact of pre-existing NS5A inhibitor resistance variants on the efficacy of daclatasvir and asunaprevir combination therapy in Japanese patients with genotype 1b HCV.
• To determine the frequency of NS5A RAVs in this patient population.

Main Methods:

• Analysis of baseline NS5A sequences from patients treated with daclatasvir and asunaprevir.
• Correlation of the presence of specific NS5A RAVs (e.g., at positions 31 and 93) with virological failure in a phase 3 clinical study.

Main Results:

• The frequency of NS5A RAVs in Japanese genotype 1b HCV patients was found to be approximately 11-23%.
• Patients harboring pre-existing NS5A RAVs at positions 31 and/or 93 were significantly more likely to experience virological failure during combination therapy.

Conclusions:

• Pre-existing NS5A resistance variants pose a significant challenge to the effectiveness of daclatasvir and asunaprevir therapy in genotype 1b HCV.
• Genotypic resistance testing for NS5A RAVs should be considered prior to initiating treatment to optimize therapeutic outcomes.