Analysis of Hepatitis C Virus Resistance-Associated Substitutions in Direct-Acting Antiviral Failure in South Korea Using Next-Generation Sequencing

Background/aims: We analyzed resistance-associated substitutions (RAS) and retreatment outcomes in patients with chronic hepatitis C virus (HCV) infection who failed direct-acting antiviral agent (DAA) treatment in South Korea using next-generation sequencing (NGS).

Methods: Using prospectively collected data from the Korea HCV cohort study, 36 patients who failed DAA treatment were recruited from 10 centers between 2007 and 2020; 29 blood samples were available from 24 patients. RASs were analyzed using NGS.

Results: RAS was analyzed for 13 patients with genotype 1b, ten with genotype 2, and one with genotype 3a. The unsuccessful DAA regimens were daclatasvir+asunaprevir (n=11), sofosbuvir+ribavirin (n=9), ledipasvir/sofosbuvir (n=3), and glecaprevir/pibrentasvir (n=1). In patients with genotype 1b, NS3, NS5A, and NS5B RASs were detected in eight, seven, and seven out of ten patients at baseline and in four, six, and two out of six patients after DAA failure, respectively. Among ten patients with genotype 2, the only baseline RAS was NS3 Y56F, detected in one patient. NS5A F28C was detected after DAA failure in a patient with genotype 2 infection erroneously treated with daclatasvir+asunaprevir. After retreatment 16 patients had a 100% sustained virological response rate.

Conclusions: NS3 and NS5A RASs were commonly present at baseline, and there was an increasing trend of NS5A RAS after failed DAA treatment in genotype 1b. However, RAS was rarely present in patients with genotype 2 treated with sofosbuvir plus ribavirin. Despite baseline or treatment-emergent RAS, retreatment with pan-genotypic DAA was highly successful in Korea, encouraging active retreatment for unsuccessful DAA treatment.

Comments：

This study analyzed resistance-associated substitutions (RAS) and retreatment outcomes in 36 South Korean patients with chronic hepatitis C virus (HCV) infection who failed direct-acting antiviral agent (DAA) treatment. The researchers used next-generation sequencing (NGS) to analyze RAS in blood samples from 24 patients. The patients had received unsuccessful DAA regimens such as daclatasvir+asunaprevir, sofosbuvir+ribavirin, ledipasvir/sofosbuvir, and glecaprevir/pibrentasvir.

The study found that NS3 and NS5A RAS were commonly present at baseline in patients with genotype 1b, and there was an increasing trend of NS5A RAS after failed DAA treatment. However, RAS was rarely present in patients with genotype 2 treated with sofosbuvir plus ribavirin. Despite baseline or treatment-emergent RAS, retreatment with pan-genotypic DAA was highly successful in Korea, with a 100% sustained virological response rate observed in 16 patients after retreatment.

The findings of this study suggest that active retreatment with pan-genotypic DAA may be a viable option for patients who fail initial DAA treatment, even in the presence of RAS. The use of NGS for RAS analysis may also provide valuable information for selecting appropriate retreatment options.

Related Products

Cat.No.	Product Name	Information
S4935	Asunaprevir	Asunaprevir is an orally bioavailable inhibitor of the hepatitis C virus enzyme serine protease NS3 that is necessary for protein processing required for viral replication.

Related Targets

HCV Protease