The co-existence of NS5A and NS5B resistance-associated substitutions is associated with virologic failure in Hepatitis C Virus genotype 1 patients treated with sofosbuvir and ledipasvir

PLoS One. 2018 Jun 1;13(6):e0198642. doi: 10.1371/journal.pone.0198642. eCollection 2018.

Abstract

Objective: The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs).

Methods: Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed.

Results: Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%).

Conclusions: Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Cohort Studies
  • Drug Resistance, Multiple, Viral / genetics*
  • Female
  • Fluorenes / pharmacology*
  • Fluorenes / therapeutic use
  • Genotype
  • Hepacivirus / genetics*
  • Hepacivirus / isolation & purification
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Humans
  • Male
  • Middle Aged
  • Sofosbuvir
  • Sustained Virologic Response
  • Treatment Failure
  • Uridine Monophosphate / analogs & derivatives*
  • Uridine Monophosphate / pharmacology
  • Uridine Monophosphate / therapeutic use
  • Viral Nonstructural Proteins / genetics*

Substances

  • Benzimidazoles
  • Fluorenes
  • Viral Nonstructural Proteins
  • ledipasvir, sofosbuvir drug combination
  • Uridine Monophosphate
  • NS-5 protein, hepatitis C virus
  • Sofosbuvir

Grants and funding

This work was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare of Japan. There was no additional external funding received for this study. K.O. and A.I. belong to donated fund laboratory funded by Eisai Co., Ltd, and Minophagen Pharmaceutical Co., Ltd. A.I. received honoraria from Bristol-Myers Squibb Co., Ltd., MSD Co., Ltd., Gilead Sciences Co., Ltd., and Abbvie Inc., and received research funding from Eisai Co., Ltd., Bristol-Myers Squibb Co., Ltd, and MSD Co., Ltd.. None of the other authors has a conflict of interest to disclose. The funders (Eisai Co., Ltd, and Minophagen Pharmaceutical Co., Ltd.) provided support in the form of salaries for authors [K.O. and A.I.], but the all funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.