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 naive patients, received telaprevir + pegylated-interferon-alpha + 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] log IU/ml within 48h. Second-phase decay was slower, especially in failing patients: 313 showed <1 log IU/ml decay between 48h and 2 weeks, and HCV-RNA >100 IU/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 24 h, but only in patients with sustained response afterwards. Indeed, 212 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. (C) 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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

Cento, Valeria;
2015

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 naive patients, received telaprevir + pegylated-interferon-alpha + 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] log IU/ml within 48h. Second-phase decay was slower, especially in failing patients: 313 showed <1 log IU/ml decay between 48h and 2 weeks, and HCV-RNA >100 IU/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 24 h, but only in patients with sustained response afterwards. Indeed, 212 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. (C) 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Drug-resistance
Mathematical modelling
Protease inhibitors
Viral kinetic
Aged
Antiviral Agents
Drug Resistance, Viral
Drug Therapy, Combination
Female
Genotype
Hepacivirus
Hepatitis C, Chronic
Humans
Interferon-alpha
Linear Models
Male
Middle Aged
Mutation
Oligopeptides
Protease Inhibitors
RNA Stability
RNA, Viral
Ribavirin
Treatment Outcome
Viral Load
Virus Replication
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11699/65794
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