title: The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis.
abstract: OBJECTIVE
  MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis.
  
  
  METHODS
  We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular.
  
  
  RESULTS
  At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups.
  
  
  CONCLUSIONS
  Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.
authors.affiliation: Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany. Electronic address: manns.michael@mh-hannover.de.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Baylor College of Medicine, Houston, Texas.
authors.forename: John M
authors.initials: JM
authors.lastname: Vierling
authors.affiliation: Saint Louis University, Saint Louis, Missouri.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bacon
authors.affiliation: A. O. Fatebenefratelli and Oftalmico, Milan, Italy.
authors.forename: Savino
authors.initials: S
authors.lastname: Bruno
authors.affiliation: Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Shibolet
authors.affiliation: Liver Unit, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Baruch
authors.affiliation: University Paris-Diderot, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Howe
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gress
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Gilbert
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Shaw
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooreman
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Peggy
authors.initials: P
authors.lastname: Hwang
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dutko
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Janice
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Merck & Co, Inc, Whitehouse Station, New Jersey.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002219:Carbamates; D003521:Cyclopropanes; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011810:Quinoxalines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D047029:Lactams, Macrocyclic
chemical_list: D000577:Amides; D000998:Antiviral Agents; D015415:Biomarkers; D002219:Carbamates; D003521:Cyclopropanes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011392:Proline; D011810:Quinoxalines; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D013449:Sulfonamides; C578009:grazoprevir; D047029:Lactams, Macrocyclic; 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
keywords: Chronic HCV; Protease Inhibitor; Response-Guided Therapy; Sustained Virologic Response