title: Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir.
abstract: BACKGROUND
  Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance.
  
  
  OBJECTIVE
  Potential persistence of resistance mutations during long-term follow-up should be analyzed.
  
  
  METHODS
  Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment.
  
  
  RESULTS
  After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S+R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up.
  
  
  CONCLUSIONS
  In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.
authors.affiliation: Klinikum der Goethe Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Susser
authors.forename: Johannes
authors.initials: J
authors.lastname: Vermehren
authors.forename: Nicole
authors.initials: N
authors.lastname: Forestier
authors.forename: Martin Walter
authors.initials: MW
authors.lastname: Welker
authors.forename: Natalia
authors.initials: N
authors.lastname: Grigorian
authors.forename: Caterina
authors.initials: C
authors.lastname: Füller
authors.forename: Dany
authors.initials: D
authors.lastname: Perner
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008137:Longitudinal Studies; D020125:Mutation, Missense; D009842:Oligopeptides / Q000008:administration & dosage*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives*; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; 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; D009842:Oligopeptides; D011392:Proline; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide