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L159F and V321A Sofosbuvir-Associated Hepatitis C Virus NS5B Substitutions
Evguenia S Svarovskaia1, Edward Gane2, Hadas Dvory-Sobol1
1Gilead Sciences, Foster City, California.
The Journal of Infectious Diseases
|November 26, 2015
Summary
Sofosbuvir (SOF) can lead to NS5B variants L159F and V321A in some patients experiencing virologic failure. Adding ledipasvir (LDV) to SOF treatment significantly reduced the emergence of these resistance variants.
Area of Science:
- Hepatology and Virology
- Antiviral Drug Resistance
- Molecular Biology
Background:
- Sofosbuvir (SOF) is a key antiviral for Hepatitis C Virus (HCV) with a high barrier to resistance.
- Previous studies showed no S282T NS5B substitution or phenotypic resistance in phase 3 trials of SOF.
Purpose of the Study:
- To evaluate the emergence and potential association with resistance of NS5B variants L159F and V321A during SOF and ledipasvir/SOF (LDV/SOF) treatment.
- To assess the impact of these variants on retreatment outcomes.
Main Methods:
- Deep sequencing was employed to analyze NS5B variants in patients from 8 SOF studies and 5 LDV/SOF studies.
- Virologic failure and baseline samples were analyzed for the presence of L159F and V321A variants.
Main Results:
- NS5B variants L159F and V321A were detected in 15% and 5% of patients with virologic failure on SOF, respectively.
- Combination therapy with LDV/SOF reduced the emergence of these variants to 2% in patients with virologic failure.
- L159F and V321A did not impact retreatment outcomes with SOF, ribavirin, and pegylated interferon.
- Baseline L159F in genotype 1 patients was associated with increased virologic failure only in short-duration SOF/ribavirin regimens.
Conclusions:
- Deep sequencing confirmed NS5B variants L159F and V321A emerge in a subset of patients treated with SOF, but do not affect retreatment outcomes.
- Ledipasvir intensification with SOF significantly reduces the emergence of these resistance-associated variants.
- Baseline L159F in genotype 1 patients does not impact treatment outcomes with LDV/SOF.
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