title: Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial.
abstract: Direct-acting antiviral agents have improved treatment outcomes for patients with hepatitis C virus (HCV) infection; however, head-to-head comparisons are limited. The C-EDGE Head-2-Head Study compared the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) with sofosbuvir plus pegylated interferon/ribavirin (SOF/PR) in patients with HCV infection.
  
  
  
  This was a randomized, open-label, phase III trial. Two hundred fifty-seven patients with HCV genotype (GT)1 or 4 infection and baseline viral load >10,000IU/ml were randomized to receive 12weeks of EBR/GZR 50mg/100mg once daily (n=129) or sofosbuvir (400mg once daily) plus PR (n=128). Primary efficacy objective was sustained virologic response 12weeks after the end of therapy (SVR12, HCV RNA <15IU/ml). The primary safety objective was the proportion of patients experiencing a tier 1 safety event.
  
  
  
  The majority of patients were non-cirrhotic (83.1%), treatment-naïve (74.9%) and had HCV GT1b infection (82.0%). SVR12 rates were 99.2% (128/129) and 90.5% (114/126) in the EBR/GZR and SOF/PR groups, respectively. The estimated adjusted difference in SVR12 was 8.8% (95% confidence interval [CI], 3.6-15.3%). Because the lower bound of the 1-sided 1-sample exact test was greater than -10% and greater than zero, both non-inferiority and superiority of EBR/GZR vs. SOF/PR were established. The frequency of tier 1 safety events was lower among patients receiving EBR/GZR than SOF/PR (0.8% vs. 27.8%, between group difference, 27.0% [95% CI, -35.5% to -19.6%; p<0.001]).
  
  
  
  EBR/GZR has a superior efficacy and safety profile in patients with HCV GT1 or 4 infection compared with SOF/PR.
  
  
  
  The combination of elbasvir/grazoprevir for 12weeks was highly effective in treating patients with chronic hepatitis C, genotypes 1 or 4 infection. This regimen was more effective than sofosbuvir/pegylated interferon/ribavirin for 12weeks, and was notably superior in patients regarded as difficult to treat, including those with previous treatment failure, cirrhosis, or a high baseline viral load. The combination of elbasvir/grazoprevir also demonstrated a superior safety and tolerability profile based on fewer serious adverse events, no serious drug-related adverse events, and no treatment discontinuations.
  
  
  
  Clinical trials.gov Identifier: NCT02358044.
authors.affiliation: Institut Klinické a Experimentální Medicíny (IKEM), Prague, Czech Republic. Electronic address: jase@medicon.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Sperl
authors.affiliation: Budai Hepatólogiai Centrum, Budapest, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Horvath
authors.affiliation: Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Halota
authors.affiliation: Hospital Universitario Donostia, Gipuzkoa, Spain.
authors.forename: Juan Arenas
authors.initials: JA
authors.lastname: Ruiz-Tapiador
authors.affiliation: Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases "Prof. Dr. Matei Balș", Bucharest, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Streinu-Cercel
authors.affiliation: Vilnius University, Department of Infectious and Chest Diseases, Dermatovenerology and Alergology, Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania.
authors.forename: Ligita
authors.initials: L
authors.lastname: Jancoriene
authors.affiliation: Semmelweis Egyetem, Budapest, Hungary.
authors.forename: Klara
authors.initials: K
authors.lastname: Werling
authors.affiliation: UNN Universitetssykehuset Nord Norge, Tromsø, Norway.
authors.forename: Hege
authors.initials: H
authors.lastname: Kileng
authors.affiliation: Hacettepe University Medical Faculty, Ankara, Turkey.
authors.forename: Seyfettin
authors.initials: S
authors.lastname: Koklu
authors.affiliation: Klinik for Infektionsmedicin, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.affiliation: Department of Internal Medicine, 1st Medical Faculty Charles University and Central Military Hospital, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Urbanek
authors.affiliation: Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Flisiak
authors.affiliation: Haukeland University Hospital, Bergen, Norway.
authors.forename: Rafael
authors.initials: R
authors.lastname: Leiva
authors.affiliation: Vilnius University, Faculty of Medicine, Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania.
authors.forename: Edita
authors.initials: E
authors.lastname: Kazenaite
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Renate
authors.initials: R
authors.lastname: Prinzing
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Sushma
authors.initials: S
authors.lastname: Patel
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Jingjun
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Asante-Appiah
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Janice
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Bach-Yen
authors.initials: BY
authors.lastname: Nguyen
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Eliav
authors.initials: E
authors.lastname: Barr
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Platt
mesh_terms: D000998:Antiviral Agents; D001572:Benzofurans; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D007372:Interferons; D011810:Quinoxalines; D012367:RNA, Viral; D012254:Ribavirin; D000069474:Sofosbuvir
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D007093:Imidazoles; D011810:Quinoxalines; D012367:RNA, Viral; D012254:Ribavirin; D007372:Interferons; D000069474:Sofosbuvir
keywords: Hepatitis; Randomized; Therapy