title: Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: a population and clonal analysis.
abstract: BACKGROUND
  Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy.
  
  
  METHODS
  Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia.
  
  
  RESULTS
  Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing.
  
  
  CONCLUSIONS
  RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure.
authors.affiliation: Merck Sharp & Dohme, Whitehouse Station, NJ, USA. richard_barnard@merck.com
authors.forename: Richard J O
authors.initials: RJ
authors.lastname: Barnard
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: McHale
authors.forename: William
authors.initials: W
authors.lastname: Newhard
authors.forename: Carol A
authors.initials: CA
authors.lastname: Cheney
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Graham
authors.forename: Amy L
authors.initials: AL
authors.lastname: Himmelberger
authors.forename: Julie
authors.initials: J
authors.lastname: Strizki
authors.forename: Peggy M T
authors.initials: PM
authors.lastname: Hwang
authors.forename: Amber A
authors.initials: AA
authors.lastname: Rivera
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Reeves
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dinubile
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003521:Cyclopropanes; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000235:genetics; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides; D017211:Treatment Failure; D016896:Treatment Outcome; D014766:Viremia / Q000188:drug therapy / Q000821:virology; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; D011392:Proline; C540393:vaniprevir; D010447:Peptide Hydrolases; D007930:Leucine
keywords: DAA; HCV; Hepatitis C-genotype 1; IC50; IU/mL; LLD; LLQ; P/R; Resistance-associated variants; SVR; Vaniprevir; directly acting antiviral agent; hepatitis C virus; inhibitory concentration 50%; international units per milliliter; lower limit of detection; lower limit of quantification; peginterferon alfa/ribavirin; sustained virologic response