L159F and V321A Sofosbuvir-Associated Hepatitis C Virus NS5B Substitutions

Evguenia S. Svarovskaia, Edward Gane, Hadas Dvory-Sobol, Ross Martin, Brian Doehle, Charlotte Hedskog, Ira M. Jacobson, David R. Nelson, Eric Lawitz, Diana M. Brainard, John G. McHutchison, Michael D. Miller, Hongmei Mo

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Background. Sofosbuvir (SOF) exhibits a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in phase 3 registration studies. Methods. Here, emergence of the NS5B variants L159F and V321A and possible association with resistance was evaluated in 8 studies of SOF (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1, PHOTON-2, and P7977-2025) and 5 studies of combination ledipasvir (LDV) and SOF (LDV/SOF; LONESTAR, ELECTRON [LDV/SOF arms], ION1, ION2, and ION3), using deep sequencing. Results. Deep sequencing detected L159F in 15% (53 of 353) and V321A in 5% (17 of 353) of patients with virologic failure in the SOF studies. Intensification of SOF treatment with LDV reduced the emergence of L159F or V321A to 2% (1 of 50 each) at virologic failure. L159F and V321A did not influence the outcome of retreatment with SOF, ribavirin, and pegylated interferon. At baseline, L159F was detected only in genotype 1-infected patients (1%) and was only associated with increased virologic failure in patients treated for short durations with SOF and ribavirin. Conclusions. Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of patients treated with SOF at virologic failure. These variants had no impact on retreatment outcome with SOF, ribavirin, and pegylated interferon. Baseline L159F in genotype 1 did not affect the treatment outcome with LDV/SOF.

Original languageEnglish (US)
Pages (from-to)1240-1247
Number of pages8
JournalJournal of Infectious Diseases
Issue number8
StatePublished - Apr 15 2016


  • HCV NS5B sofosbuvir resistance-associated variants
  • L159F
  • V321A
  • direct-acting antivirals
  • resistance
  • sofosbuvir

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy


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