No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients

Christoph Sarrazin, Curtis L. Cooper, Michael P. Manns, K. Rajender Reddy, Kris V. Kowdley, Stuart K. Roberts, Hadas Dvory-Sobol*, Evguenia Svarovskia, Ross Martin, Gregory Camus, Brian P. Doehle, Luisa M. Stamm, Robert H. Hyland, Diana M. Brainard, Hongmei Mo, Stuart C. Gordon, Marc Bourliere, Stefan Zeuzem, Steven L. Flamm

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Background & Aims: In phase III studies, the fixed dose combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) administered for 12 weeks led to a sustained virologic response at 12 weeks (SVR12) in 96% of NS5A inhibitor-experienced patients, and an SVR12 rate of 98% in DAA-experienced patients who had not previously received an NS5A inhibitor. Herein, we evaluate the relationship between the presence of detectable resistance-associated substitutions (RASs) at baseline and treatment outcome, and whether RASs were selected for in cases of virologic failure. Methods: NS3, NS5A, and NS5B deep sequencing analyses were performed at baseline for all patients and at the time of virologic failure. Results are reported using a 15% cut-off. Results: A total of 82.7% of NS5A inhibitor-experienced patients (205/248) had baseline NS3 and/or NS5A RASs; 79% had baseline NS5A RASs. SVR12 rates were similar in patients with or without NS3 and/or NS5A RASs, and with or without VOX- or VEL-specific RASs. RASs at NS5A position Y93 were present in 37.3% of patients and 95% achieved SVR12. All patients with ≥2 NS5A RASs achieved SVR12. Baseline NS3 and/or NS5A RASs were present in 46.6% (83/178) of non-NS5A inhibitor DAA-experienced patients, all of whom achieved SVR12. All patients with baseline NS5B nucleoside inhibitor RASs, including two patients with S282T, achieved SVR12. Treatment-selected resistance was seen in one of seven patients who relapsed. Conclusions: Baseline RASs had no impact on virologic response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Selection of viral resistance with virologic relapse was uncommon. Lay summary: In phase III studies, 12 weeks of treatment with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) cured 97% of patients with hepatitis C virus who failed prior treatment with direct-acting antiviral drugs. Herein, we show that the presence of pretreatment drug resistance did not affect treatment outcome in these patients who had previously received direct-acting antivirals. We also showed that new drug resistance was rare in patients who failed treatment with SOF/VEL/VOX for 12 weeks. This has important implications for the selection of best retreatment strategies for these patients.

Original languageEnglish (US)
Pages (from-to)1221-1230
Number of pages10
JournalJournal of Hepatology
Volume69
Issue number6
DOIs
StatePublished - Dec 2018

Keywords

  • Direct-acting antivirals
  • NS5A
  • Pan-genotypic
  • Resistance-associated substitutions
  • SOF
  • VEL
  • VOX

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients'. Together they form a unique fingerprint.

  • Cite this

    Sarrazin, C., Cooper, C. L., Manns, M. P., Reddy, K. R., Kowdley, K. V., Roberts, S. K., Dvory-Sobol, H., Svarovskia, E., Martin, R., Camus, G., Doehle, B. P., Stamm, L. M., Hyland, R. H., Brainard, D. M., Mo, H., Gordon, S. C., Bourliere, M., Zeuzem, S., & Flamm, S. L. (2018). No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients. Journal of Hepatology, 69(6), 1221-1230. https://doi.org/10.1016/j.jhep.2018.07.023