Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.
Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms).


CONCLUSIONS
These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).
Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
M
M
Lagging
Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
A
A
Brown
The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA.
P S
PS
Mantry
University of British Columbia, Vancouver, BC, Canada.
A
A
Ramji
Waikato District Health Board, Hamilton, New Zealand.
F
F
Weilert
Baylor College of Medicine, Houston, TX, USA.
J M
JM
Vierling
Merck & Co. Inc., Kenilworth, NJ, USA.
A
A
Howe
Merck & Co. Inc., Kenilworth, NJ, USA.
I N
IN
Gendrano
Merck & Co. Inc., Kenilworth, NJ, USA.
P
P
Hwang
Merck & Co. Inc., Kenilworth, NJ, USA.
B
B
Zhang
Merck & Co. Inc., Kenilworth, NJ, USA.
J
J
Wahl
Merck & Co. Inc., Kenilworth, NJ, USA.
M
M
Robertson
Merck & Co. Inc., Kenilworth, NJ, USA.
N
N
Mobashery
D000328:Adult; D000368:Aged; D000577:Amides; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011810:Quinoxalines / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D047029:Lactams, Macrocyclic
D000577:Amides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011810:Quinoxalines; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C578009:grazoprevir; D047029:Lactams, Macrocyclic; C100416:peginterferon alfa-2a
adverse event; clinical trial; direct-acting antiviral drugs; resistance; sustained virologic response