title: Nationwide experience of treatment with protease inhibitors in chronic hepatitis C patients in Denmark: identification of viral resistance mutations.
abstract: OBJECTIVE
  The first standard of care in treatment of chronic HCV genotype 1 infection involving directly acting antivirals was protease inhibitors telaprevir or boceprevir combined with pegylated-interferon and ribavirin (triple therapy). Phase III studies include highly selected patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1 infection in a routine clinical setting.
  
  
  METHODS
  80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis of the RT-PCR amplified NS3 protease were performed in patients without cure following triple therapy.
  
  
  RESULTS
  38 (47%) of the patients achieved cure, 15 (19%) discontinued treatment due to adverse events and remained infected, and 27 (34%) experienced relapse or treatment failure of whom 15 of 21 analyzed patients had well-described protease inhibitor resistance variants detected. Most frequently detected protease variants were V36M and/or R155K, and V36M, in patients with genotype 1a and 1b infection, respectively.
  
  
  CONCLUSIONS
  The cure rate after triple therapy in a routine clinical setting was 47%, which is substantially lower than in clinical trials. Resistance variants towards protease inhibitors were seen in 71% of patients failing therapy indicating that resistance could have an important role in treatment response.
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark; and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Sølund
authors.affiliation: Section of Molecular Diagnostics, Clinical Biochemistry and Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Krarup
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark; and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Santseharay
authors.initials: S
authors.lastname: Ramirez
authors.affiliation: Department of Gastroenterology, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Thielsen
authors.affiliation: Department of Medicine, Kolding Hospital, Kolding, Denmark.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Røge
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hillerød, Denmark.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lunding
authors.affiliation: Department of Infectious Diseases, Roskilde Hospital, Roskilde, Denmark.
authors.forename: Toke S
authors.initials: TS
authors.lastname: Barfod
authors.affiliation: Department of Gastroenterology, Køge Hospital, Køge, Denmark.
authors.forename: Lone G
authors.initials: LG
authors.lastname: Madsen
authors.affiliation: Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark.
authors.forename: Britta
authors.initials: B
authors.lastname: Tarp
authors.affiliation: Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.
authors.forename: Peer B
authors.initials: PB
authors.lastname: Christensen
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, Skejby, Aarhus, Denmark.
authors.forename: Alex L
authors.initials: AL
authors.lastname: Laursen
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark; and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Bukh
authors.affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Weis
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003718:Denmark / Q000453:epidemiology; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases