Investigation of NS3 Protease Resistance-Associated Variants and Phenotypes for the Prediction of Treatment Response to HCV Triple Therapy

PLoS One. 2016 Jun 9;11(6):e0156731. doi: 10.1371/journal.pone.0156731. eCollection 2016.

Abstract

Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / pharmacology*
  • Drug Resistance, Viral / genetics*
  • Female
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / virology
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Treatment Outcome
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / genetics*

Substances

  • Antiviral Agents
  • NS3 protein, hepatitis C virus
  • Viral Nonstructural Proteins

Grants and funding

This study was funded by a DZIF (Deutsches Zentrum für Infektionsforschung, http://www.dzif.de/forschung/hepatitis/) grant entitled “Geno- & phenotypic NS3, NS5A and NS5B inhibitor resistance analysis” to Christoph Sarrazin and Stefan Zeuzem (TTU 05.902) and by Janssen-Cilag GmbH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.