title: Mericitabine and ritonavir-boosted danoprevir with or without ribavirin in treatment-naive HCV genotype 1 patients: INFORM-SVR study.
abstract: OBJECTIVE
  Safety and tolerability of peginterferon-based hepatitis C virus (HCV) infection therapy remains suboptimal, even when direct-acting antiviral agents are added. This study assessed the efficacy, safety and tolerability of mericitabine combined with ritonavir-boosted danoprevir (danoprevir/r) ± ribavirin for up to 24 weeks in treatment-naïve HCV genotype (G)1 infected patients.
  
  
  METHODS
  Patients received twice daily mericitabine (1000 mg) and danoprevir/r (100 mg/100 mg) plus either ribavirin (1000/1200 mg/day; Arm A) or placebo (Arm B) for 12 or 24 weeks. Patients with HCV RNA <43 IU/ml between Weeks 2 and 8 and HCV RNA <15 IU/ml at Week 10 were rerandomized (1:1) at Week 12 to discontinue/continue assigned regimens until Week 24. Because of unacceptable relapse rates in both 12-week arms and in ribavirin-free Arm B, treatment was extended to 24 weeks and patients in Arm B received peginterferon alfa-2a/ribavirin. The primary outcome was sustained virological response 24 weeks after end of treatment (SVR24).
  
  
  RESULTS
  In Arm A, the SVR24 rate in patients receiving 24 weeks of therapy was 37.9% (25/66); 63.6% (14/22) in G1b and 25.0% (11/44) in G1a patients. Virologic breakthrough and relapse were associated with danoprevir-resistant virus in most cases. The mericitabine-resistance mutation (NS5BS282T) was detected in two patients bearing dual resistant virus NS3 R155K/NS5B S282T and dual resistance mutation L159F/L320F in one patient. Treatment was safe and well tolerated.
  
  
  CONCLUSIONS
  Mericitabine, danoprevir/r plus ribavirin for 24 weeks were safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients.
authors.affiliation: Auckland Clinical Studies, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Pockros
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Anna
authors.initials: A
authors.lastname: Shikhman
authors.forename: Coen
authors.initials: C
authors.lastname: Bernaards
authors.forename: Julian
authors.initials: J
authors.lastname: Zhou
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Yetzer
authors.forename: Rosa
authors.initials: R
authors.lastname: Ballester
authors.forename: Cindy
authors.initials: C
authors.lastname: Dwyer
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.forename: Anne
authors.initials: A
authors.lastname: Bertasso
authors.forename: Janet
authors.initials: J
authors.lastname: Hammond
authors.forename: Amy
authors.initials: A
authors.lastname: Kindrick
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Saray
authors.initials: S
authors.lastname: Stancic
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Shulman
mesh_terms: D000328:Adult; D000368:Aged; D003521:Cyclopropanes; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D013449:Sulfonamides; D003841:Deoxycytidine; D012254:Ribavirin; C553752:danoprevir; D011392:Proline; D019438:Ritonavir
keywords: chronic hepatitis C; danoprevir; direct-acting antiviral; interferon-free; mericitabine; response-guided; sustained virological response