title: Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice.
abstract: BACKGROUND
  The used first generation protease inhibitors may be hampered by virological failure in partially interferon-sensitive patients.
  
  
  OBJECTIVE
  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.
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy. Electronic address: valeriacento@gmail.com.
authors: Valeria
authors: V
authors: Cento
authors: Infectious Disease Unit, Pescara General Hospital, Pescara, Italy; Infectious Disease Clinic, Chieti, Italy.
authors: Monica
authors: M
authors: Tontodonati
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors: Velia Chiara
authors: VC
authors: Di Maio
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors: Maria Concetta
authors: MC
authors: Bellocchi
authors: Department of Economics, Institutions and Law, University of Rome "Tor Vergata", Rome, Italy.
authors: Fabrizio
authors: F
authors: Valenti
authors: Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Italy.
authors: Alessandra
authors: A
authors: Manunta
authors: Pharmacology Unit, "A. Gemelli" Hospital, Rome, Italy.
authors: Serena
authors: S
authors: Fortuna
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors: Daniele
authors: D
authors: Armenia
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors: Luca
authors: L
authors: Carioti
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors: Francesco Paolo
authors: FP
authors: Antonucci
authors: Molecular Virology Unit, University Hospital of Rome "Tor Vergata", Rome, Italy.
authors: Ada
authors: A
authors: Bertoli
authors: Infectious Disease Unit, Pescara General Hospital, Pescara, Italy.
authors: Francesca
authors: F
authors: Trave
authors: Infectious Disease Unit, Pescara General Hospital, Pescara, Italy.
authors: Pierluigi
authors: P
authors: Cacciatore
authors: Hepatology Unit, University Hospital of Rome "Tor Vergata", Rome, Italy.
authors: Mario
authors: M
authors: Angelico
authors: Pharmacology Unit, "A. Gemelli" Hospital, Rome, Italy.
authors: Pierluigi
authors: P
authors: Navarra
authors: Goodman Faculty of Life Sciences, Bar-Ilan University, Israel.
authors: Avidan U
authors: AU
authors: Neumann
authors: Infectious Disease Clinic, Chieti, Italy.
authors: Jacopo
authors: J
authors: Vecchiet
authors: Infectious Disease Unit, Pescara General Hospital, Pescara, Italy.
authors: Giustino
authors: G
authors: Parruti
authors: Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Italy.
authors: Sergio
authors: S
authors: Babudieri
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy; Molecular Virology Unit, University Hospital of Rome "Tor Vergata", Rome, Italy.
authors: Carlo Federico
authors: CF
authors: Perno
authors: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors: Francesca
authors: F
authors: Ceccherini-Silberstein
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009842:Oligopeptides / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D020871:RNA Stability / Q000187:drug effects*; D012367:RNA, Viral / Q000235:genetics*; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011480:Protease Inhibitors; D012367:RNA, Viral; D012254:Ribavirin; C486464:telaprevir
keywords: Drug-resistance; Mathematical modelling; Protease inhibitors; Viral kinetic