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Published on: June 9, 2022
Selection dynamics of HCV genotype 3 resistance-associated substitutions under direct-acting antiviral therapy
João Paulo Vilela Rodrigues1, Guilherme Rodrigues Fernandes Campos2, Cintia Bittar2
1Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
Insights
Direct-acting antivirals (DAAs) are used for chronic hepatitis C (CHC) but are less effective in genotype 3 (GT3) patients. Resistance-associated substitutions (RASs) in NS5A impact treatment outcomes, with cirrhosis and prior interferon treatment increasing failure risk.
Area of Science:
- Hepatology
- Virology
- Genetics
Background:
- Direct-acting antivirals (DAAs) are standard for chronic hepatitis C (CHC).
- Hepatitis C virus genotype 3 (GT3) presents treatment challenges.
- Resistance-associated substitutions (RASs) can reduce DAA efficacy.
Purpose of the Study:
- To investigate the impact of NS5A and NS5B RASs on DAA treatment effectiveness in GT3 CHC patients.
- To identify clinical factors associated with treatment failure in GT3 CHC.
- To analyze the dynamics of RASs during treatment.
Main Methods:
- Prospective cohort study in a Brazilian university hospital.
- Inclusion of patients aged over 18 with GT3 CHC treated with SOF + DCV ± RBV or SOF + PEG + RBV.
- Baseline and post-treatment blood sample analysis for RASs.
Main Results:
- Sustained virological response rates were 87.6% for SOF + DCV ± RBV and 80.0% for SOF + PEG + RBV.
- Cirrhosis, prior interferon/PEG + RBV treatment, and baseline NS5A RASs were linked to treatment failure.
- Specific NS5A RASs (A30K, Y93H, site 62) and their interactions were associated with treatment failure.
Conclusions:
- Understanding RAS dynamics is crucial for optimizing GT3 CHC treatment.
- Baseline NS5A RASs and clinical factors predict treatment failure.
- Further research into RASs can guide personalized DAA regimens for difficult-to-cure GT3 CHC patients.
Abstract:
The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF + DCV ± ribavirin (RBV) or SOF + peginterferon (PEG) + RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF + DCV ± RBV group and 80.0% for the SOF + PEG + RBV arm. Cirrhosis, prior treatment with interferon/PEG + RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.
