Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice

Dig Liver Dis. 2015 Mar;47(3):233-41. doi: 10.1016/j.dld.2014.12.004. Epub 2014 Dec 27.

Abstract

Background: The used first generation protease inhibitors may be hampered by virological failure in partially interferon-sensitive patients.

Aim: To investigate early hepatitis C virus (HCV)-RNA decay and quasispecies modifications, and disclose viral dynamics underlying failure.

Methods: Viraemia decay at early time-points during telaprevir treatment was modelled according to Neumann et al. (1998). NS3-sequences were obtained by population-sequencing and ultradeep-454-pyrosequencing.

Results: 13 treatment-experienced (8 non-responders, 5 relapsers), and two cirrhotic naïve patients, received telaprevir+pegylated-interferon-α+ribavirin. Viraemia decay was biphasic. In all patients, first-phase was rapid and consistent, with a median [interquartile-range] viraemia decay of 2.8 [2.6-3.2]logIU/ml within 48h. Second-phase decay was slower, especially in failing patients: 3/3 showed <1logIU/ml decay between 48h and 2 weeks, and HCV-RNA >100IU/ml at week 2. Only one patient experiencing sustained viral response showed similar kinetics. By pyrosequencing, mutational freeze was observed in all 15 patients within the first 24h, but only in patients with sustained response afterwards. Indeed, 2/2 failing patients showed early resistance, as minor (V36A-T54A: prevalence <26% at 48h) or major (V36M/A-R155K: prevalence, 99.8% at week 2) variants.

Conclusions: Following telaprevir administration, first-phase HCV-RNA decay is consistent with mutational freeze and limited/no viral replication, while second-phase is significantly slower in failing patients (with appearance of resistance), suggesting the usefulness of early HCV-RNA monitoring.

Keywords: Drug-resistance; Mathematical modelling; Protease inhibitors; Viral kinetic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antiviral Agents / therapeutic use*
  • Drug Resistance, Viral / genetics
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Hepacivirus / genetics
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Interferon-alpha / therapeutic use
  • Linear Models
  • Male
  • Middle Aged
  • Mutation
  • Oligopeptides / therapeutic use*
  • Protease Inhibitors / therapeutic use*
  • RNA Stability / drug effects*
  • RNA, Viral / genetics*
  • Ribavirin / therapeutic use
  • Treatment Outcome
  • Viral Load
  • Virus Replication

Substances

  • Antiviral Agents
  • Interferon-alpha
  • Oligopeptides
  • Protease Inhibitors
  • RNA, Viral
  • Ribavirin
  • telaprevir