title: Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.
abstract: BACKGROUND
  Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease.
  
  
  METHODS
  In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350.
  
  
  RESULTS
  224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis.
  
  
  CONCLUSIONS
  Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease.
  
  
  BACKGROUND
  Merck Sharp & Dohme Corp.
authors.affiliation: Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: d.roth@med.miami.edu.
authors.forename: David
authors.initials: D
authors.lastname: Roth
authors.affiliation: Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.affiliation: Department of Renal Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Annette
authors.initials: A
authors.lastname: Bruchfeld
authors.affiliation: Yale University Digestive Disease, Yale New Haven Hospital Transplant Center, New Haven, CT, USA.
authors.forename: AnnMarie
authors.initials: A
authors.lastname: Liapakis
authors.affiliation: Hospital Universitario Austral, Pilar, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Silva
authors.affiliation: Hepatology & Transplant Medicine, Houston Methodist Hospital, Houston, TX, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Monsour
authors.affiliation: Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: Unité d'Hépatologie, Hôpital Cochin; Université Paris Descartes; and UMS20, Institut Pasteur; Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Maria-Carlota
authors.initials: MC
authors.lastname: Londoño
authors.affiliation: Southern California Research Center, Coronado, CA, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.affiliation: Division of Hepatology, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Zamor
authors.affiliation: Liver Unit, Carmel Medical Center Technion Faculty of Medicine, Haifa, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Zuckerman
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Wan
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Jackson
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Bach-Yen
authors.initials: BY
authors.lastname: Nguyen
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Robertson
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Eliav
authors.initials: E
authors.lastname: Barr
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Merck & Co, Inc, Kenilworth, NJ, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Greaves
mesh_terms: D000368:Aged; D000577:Amides; D001572:Benzofurans / Q000627:therapeutic use*; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D012367:RNA, Viral; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy*; D013449:Sulfonamides; D016896:Treatment Outcome; D047029:Lactams, Macrocyclic
chemical_list: D000577:Amides; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D007093:Imidazoles; D011480:Protease Inhibitors; D011810:Quinoxalines; D012367:RNA, Viral; D013449:Sulfonamides; C578009:grazoprevir; D047029:Lactams, Macrocyclic; C000589335:elbasvir