title: Factors that predict response of patients with hepatitis C virus infection to boceprevir.
abstract: OBJECTIVE
  Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors.
  
  
  METHODS
  Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a ≥ 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a <1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed.
  
  
  RESULTS
  In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥ 1 log(10) decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR.
  
  
  CONCLUSIONS
  The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥ 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B.
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: poordad@txliver.com.
authors.forename: Fred
authors.initials: F
authors.lastname: Poordad
authors.affiliation: INSERM 954, Centre Hospitalier Universitaire de Nancy, Université Henri Poincaré, Vandoeuvre les Nancy, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: Henry Ford Hospital, Detroit, Michigan.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.affiliation: J.W. Goethe University Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.affiliation: Assistance Publique Hôpitaux de Paris-University Pierre et Marie Curie Liver Center, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.affiliation: VA Long Beach Healthcare System, Long Beach, California.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Cliona
authors.initials: C
authors.lastname: Molony
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Pedicone
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Sings
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Burroughs
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Vilma
authors.initials: V
authors.lastname: Sniukiene
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Boparai
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Goteti
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Brass
authors.affiliation: Merck Sharp & Dohme, Corp, Whitehouse Station, New Jersey.
authors.forename: Janice K
authors.initials: JK
authors.lastname: Albrecht
authors.affiliation: Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bacon
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002170:Canada; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011392:Proline; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; 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; C417083:peginterferon alfa-2b