title: Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study.
abstract: Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses.
  
  
  CONCLUSIONS
  Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medical School of Hannover, Hannover, Germany. manns.michael@mh-hannover.de
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Edward
authors.initials: E
authors.lastname: Gane
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stoehr
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wiedmann
authors.forename: Peggy M
authors.initials: PM
authors.lastname: Hwang
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.forename: Richard J O
authors.initials: RJ
authors.lastname: Barnard
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D003521:Cyclopropanes; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage*; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011392:Proline / Q000031:analogs & derivatives; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage*; D013449:Sulfonamides; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D016898:Interferon-alpha; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; D011392:Proline; C540393:vaniprevir; D007930:Leucine; C100416:peginterferon alfa-2a