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Kinetics of hepatitis C virus RNA decay, quasispecies evolution andrisk of virological failure during telaprevir-based triple therapy inclinical practice

Cento, Valeria and Tontodonati, Monica and Di Maio, Velia Chiara and Bellocchi, Maria Concetta and Valenti, Fabrizio and Manunta, Alessandra and Fortuna, Serena and Armenia, Daniele and Carioti, Luca and Antonucci, Francesco Paolo and Bertoli, Ada and Trave, Francesca and Cacciatore, Pierluigi and Angelico, Mario and Navarra, Pierluigi and Neumann, Avidan U. and Vecchiet, Jacopo and Parruti, Giustino and Babudieri, Sergio and Perno, Carlo Federico and Ceccherini Silberstein, Francesca (2015) Kinetics of hepatitis C virus RNA decay, quasispecies evolution andrisk of virological failure during telaprevir-based triple therapy inclinical practice. Digestive and liver disease, Vol. 47 (3), p. 233-241. ISSN 1590-8658. eISSN 1878-3562. Article.

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DOI: 10.1016/j.dld.2014.12.004

Abstract

Background: The used first generation protease inhibitors may be hampered by virological failure inpartially interferon-sensitive patients.
Aim: To investigate early hepatitis C virus (HCV)-RNA decay and quasispecies modifications, and discloseviral dynamics underlying failure.
Methods: Viraemia decay at early time-points during telaprevir treatment was modelled according toNeumann 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- + 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 48 h. Second-phase decay wasslower, especially in failing patients: 3/3 showed <1 log IU/ml decay between 48 h and 2 weeks, andHCV-RNA >100 IU/ml at week 2. Only one patient experiencing sustained viral response showed similarkinetics. By pyrosequencing, mutational freeze was observed in all 15 patients within the first 24 h, but onlyin patients with sustained response afterwards. Indeed, 2/2 failing patients showed early resistance, asminor (V36A-T54A: prevalence <26% at 48 h) or major (V36M/A-R155K: prevalence, 99.8% at week 2)variants.
Conclusions: Following telaprevir administration, first-phase HCV-RNA decay is consistent with muta-tional 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.

Item Type:Article
ID Code:10671
Status:Published
Refereed:Yes
Uncontrolled Keywords:Drug-resistance, mathematical modelling, protease inhibitors, viral kinetic
Subjects:Area 06 - Scienze mediche > MED/17 Malattie infettive
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Medicina Clinica e Sperimentale
Publisher:Elsevier
ISSN:1590-8658
eISSN:1878-3562
Copyright Holders:© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved
Deposited On:22 Jan 2015 10:24

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