title: Combination of vaniprevir with peginterferon and ribavirin significantly increases the rate of SVR in treatment-experienced patients with chronic HCV genotype 1 infection and cirrhosis.
abstract: OBJECTIVE
  The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin.
  
  
  METHODS
  Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin.
  
  
  RESULTS
  In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene.
  
  
  CONCLUSIONS
  In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.
authors.affiliation: Fundación de Investigación, San Juan, Puerto Rico.
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: Institut für Interdisziplinäre Medizin, Hamburg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stoehr
authors.affiliation: Auckland Clinical Studies, Ltd, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Service d'Hépatologie, Université Pierre et Marie Curie, Paris, France.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Amy
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Bourque
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Sanhita
authors.initials: S
authors.lastname: Bhanja
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Julie
authors.initials: J
authors.lastname: Strizki
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Richard J O
authors.initials: RJ
authors.lastname: Barnard
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Peggy M T
authors.initials: PM
authors.lastname: Hwang
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: DiNubile
authors.affiliation: Merck Sharp and Dohme, Whitehouse Station, New Jersey. Electronic address: nilou_mobashery@merck.com.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D003521:Cyclopropanes; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000627:therapeutic use*; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000627:therapeutic use*; D013449:Sulfonamides; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D016898:Interferon-alpha; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D010919:Placebos; D013449:Sulfonamides; D012254:Ribavirin; D011392:Proline; C540393:vaniprevir; D007930:Leucine
keywords: Clinical Trial; Direct-Acting Antiviral Agent; Fibrosis