title: Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies.
abstract: BACKGROUND
  We investigated the frequency of RAVs among patients failing to achieve SVR in two clinical trials. We also investigated the impact of interferon responsiveness on RAVs and specific baseline RAVs relationship with boceprevir treatment failure.
  
  
  METHODS
  Data are from 1020 patients enrolled into either SPRINT-2 or RESPOND-2; patients received a 4-week PR lead-in prior to receiving boceprevir or placebo. RAVs were analyzed via population-based sequence analysis of the NS3 protease gene (success rate of >90% at a virus level of ≥ 10,000IU/mL) RESULTS: The high SVR rate in patients who received boceprevir resulted in a low rate of RAVs; 7% was detected at baseline in all patients, which rose to 15% after treatment. However, RAVs were detected in 53% of patients that failed to achieve SVR, which declined to 22.8% 6-14 months following cessation of boceprevir therapy. Baseline RAVs alone were not predictive of virologic outcome; poor interferon responsiveness was highly predictive of non-SVR. RAVs were more frequently detected in poor interferon responders.
  
  
  CONCLUSIONS
  We detected no association between the presence of baseline amino acid variants at boceprevir resistance-associated loci and outcome in the context of good IFN response.
authors.affiliation: Merck, & Co., Inc. Whitehouse Station, NJ, USA. richard_barnard@merck.com
authors.forename: Richard J O
authors.initials: RJ
authors.lastname: Barnard
authors.forename: John A
authors.initials: JA
authors.lastname: Howe
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ogert
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Fred
authors.initials: F
authors.lastname: Poordad
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.forename: Robert
authors.initials: R
authors.lastname: Ralston
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: Vilma
authors.initials: V
authors.lastname: Sniukiene
authors.forename: Julie
authors.initials: J
authors.lastname: Strizki
authors.forename: Desmond
authors.initials: D
authors.lastname: Ryan
authors.forename: Jianmin
authors.initials: J
authors.lastname: Long
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Brass
authors.forename: Janice
authors.initials: J
authors.lastname: Albrecht
authors.forename: Margaret
authors.initials: M
authors.lastname: Burroughs
authors.forename: Scott
authors.initials: S
authors.lastname: Vuocolo
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D020125:Mutation, Missense; D011392:Proline / Q000031:analogs & derivatives* / 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; D011392:Proline; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; 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
keywords: Boceprevir; HCV; RAV; Resistance; Variants