title: Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs.
abstract: OBJECTIVE
  Chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among haemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants.
  
  
  METHODS
  Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation.
  
  
  RESULTS
  No dominant RAVs were identified at baseline, but low-level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (Ɛ) for lead-in ranged from 0 to 0.9745 (mean = 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. A total of 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only one patient. Adverse event profiles were similar to that observed in non-haemophilia cohorts. There was no evidence of factor inhibitor formation. There was no evidence that lead-in provided benefit in terms of response efficacy.
  
  
  CONCLUSIONS
  These data support DAA-based therapy in those with inherited bleeding disorders.
authors.affiliation: Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Sherman
authors.affiliation: Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ke
authors.affiliation: Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Rouster
authors.affiliation: Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Abdel-Hameed
authors.affiliation: Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.affiliation: Division of Hematology & Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Palascak
authors.affiliation: Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005838:Genotype; D006467:Hemophilia A / Q000150:complications*; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008954:Models, Biological; D009842:Oligopeptides / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D012367:RNA, Viral; C486464:telaprevir
keywords: HCV; direct-acting antivirals; haemophilia; resistance-associated variants; treatment response; viral dynamic models