title: Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 trial.
abstract: BACKGROUND
  Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C.
  
  
  METHODS
  SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs).
  
  
  RESULTS
  A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm.
  
  
  CONCLUSIONS
  SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.
authors: Merck Sharp & Dohme Corporation, Whitehouse Station, NJ, USA. robert.ogert@merck.com
authors: Robert A
authors: RA
authors: Ogert
authors: John A
authors: JA
authors: Howe
authors: John M
authors: JM
authors: Vierling
authors: Paul Y
authors: PY
authors: Kwo
authors: Eric J
authors: EJ
authors: Lawitz
authors: Jonathan
authors: J
authors: McCone
authors: Eugene R
authors: ER
authors: Schiff
authors: David
authors: D
authors: Pound
authors: Mitchell N
authors: MN
authors: Davis
authors: Stuart C
authors: SC
authors: Gordon
authors: Natarajan
authors: N
authors: Ravendhran
authors: Lorenzo
authors: L
authors: Rossaro
authors: Ira M
authors: IM
authors: Jacobson
authors: Robert
authors: R
authors: Ralston
authors: Eirum
authors: E
authors: Chaudhri
authors: Ping
authors: P
authors: Qiu
authors: Lisa D
authors: LD
authors: Pedicone
authors: Clifford A
authors: CA
authors: Brass
authors: Janice K
authors: JK
authors: Albrecht
authors: Richard J O
authors: RJ
authors: Barnard
authors: Daria J
authors: DJ
authors: Hazuda
authors: Anita Y M
authors: AY
authors: Howe
mesh_terms: D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012367:RNA, Viral; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012008:Recurrence; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; 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; D011392:Proline; C417083:peginterferon alfa-2b