title: Protease inhibitor-based triple therapy is highly effective for hepatitis C recurrence after liver transplant: a multicenter experience.
abstract: BACKGROUND
  Hepatitis C (HCV) continues to be the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for recurrent HCV in Genotype 1 (G1) LT recipients have been disappointing (30-40%). Experience with triple therapy using protease inhibitors (PI) boceprevir (BOC), telaprevir (TVR) in these patients has been limited.
  
  
  METHODS
  This national multicenter retrospective study included 76 patients (64 male, mean age 57 ± 6 years), treated for G1 HCV recurrence with either BOC (n = 41) or TVR (n = 35), who were non-responders or relapsers (n = 54), treatment naïve (n = 22) or had fibrosing cholestatic HCV (n = 3). 53 patients were on cyclosporine, 22 on tacrolimus and one patient on prednisone alone.
  
  
  RESULTS
  On treatment virologic response was observed in 84% (64/76), 83% in BOC and 85% in TVR group. A higher week 4 response after starting triple therapy (RVR) was noted in TVR group 25/35 (81%) as compared to BOC group 26/41 (63%); p value = 0.02. The end of treatment response was 78% and 75% in BOC and TVR group, respectively. SVR 12 weeks after treatment discontinuation was observed in 59.5% (22/37); 58.3% in the BOC group and 61.5% in TVR group. Treatment was discontinued early in 23 patients (serious adverse effects n = 19, treatment failure n = 4). Infections occurred in 5 patients with 2 deaths (all in BOC). Anemia was the most common side effect (n = 55, 72%) requiring erythropoietin and RBV dose reduction. In the BOC group, cyclosporine dose reduction was 2.2 ± 1.0 fold and 8.6 ± 2.4 fold with tacrolimus. In TVR group, dose reduction was 3.0 ± 1.4 with cyclosporine and 12 ± 5.7 fold with tacrolimus.
  
  
  CONCLUSIONS
  PI-based triple therapy appears more effective in producing HCV-RNA clearance than dual therapy. Tolerability is a serious issue and drug-drug interactions are manageable with close monitoring.
authors.affiliation: Toronto General Hospital, University of Toronto. Ontario, Canada.
authors.forename: Nabiha
authors.initials: N
authors.lastname: Faisal
authors.affiliation: Eric M. Yoshida University of British Columbia and Vancouver General Hospital. Ontario, Canada.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Yoshida
authors.affiliation: Marc Bilodeau University of Montreal, Quebec. Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Bilodeau
authors.affiliation: Philip Wong McGill University, Quebec. Ontario, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Mang Ma University of Alberta. Ontario, Canada.
authors.forename: Mang
authors.initials: M
authors.lastname: Ma
authors.affiliation: University of Calgary. Ontario, Canada.
authors.forename: Kelly W
authors.initials: KW
authors.lastname: Burak
authors.affiliation: Western University, London. Ontario, Canada.
authors.forename: Bandar
authors.initials: B
authors.lastname: Al-Judaibi
authors.affiliation: Toronto General Hospital, University of Toronto. Ontario, Canada.
authors.forename: Eberhard L
authors.initials: EL
authors.lastname: Renner
authors.affiliation: Toronto General Hospital, University of Toronto. Ontario, Canada.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lilly
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002170:Canada; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D058625:End Stage Liver Disease / Q000601:surgery* / Q000821:virology; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use*; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014775:Virus Activation / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C486464:telaprevir; 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