Baseline and Breakthrough Resistance Mutations in HCV Patients Failing DAAs

Area of Science:

• Hepatology and Virology
• Infectious Diseases
• Pharmacogenomics

Background:

• Direct-acting antiviral (DAA) therapies have significantly improved sustained virologic response (SVR) rates in chronic hepatitis C virus (HCV) infection.
• However, treatment failure can occur due to resistance-associated substitutions (RASs), which may be present before or emerge after DAA exposure.

Purpose of the Study:

• To determine the prevalence of RASs in patients experiencing treatment failure with DAAs for chronic HCV infection.
• To investigate the role of pre-existing and emergent RASs in DAA treatment failure.
• To evaluate the utility of resistance testing in optimizing retreatment regimens.

Main Methods:

• Direct sequencing of HCV genes was performed on 31 DAA treatment-failing patients at breakthrough and 19 patients at baseline.
• Deep sequencing analysis was conducted on 15 of the baseline patients.
• RASs were identified and compared between baseline and breakthrough samples, as well as between sequencing methods.

Main Results:

• RASs were detected at breakthrough in 17/31 patients and at baseline in 11/19 patients.
• Deep sequencing identified RASs in 10/15 baseline treatment-failing patients, with no significant difference compared to Sanger sequencing.
• Treatment failure in patients without detectable RASs was linked to suboptimal treatment; RASs were implicated as a cause of failure in 54.8% of cases, often present at baseline.

Conclusions:

• Resistance-associated substitutions are a significant factor contributing to DAA treatment failure in chronic HCV infection.
• A majority of RASs implicated in treatment failure are present at baseline, highlighting the importance of pre-treatment screening.
• Direct resistance testing before initiating DAA therapy and at the time of treatment breakthrough is recommended to guide effective retreatment strategies.