title: Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus.
abstract: OBJECTIVE
  To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence.
  
  
  METHODS
  From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation.
  
  
  RESULTS
  The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L (P = 0.01), total bilirubin ≥ 1.5 mg/dL (P = 0.001) and creatinine ≥ 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis).
  
  
  CONCLUSIONS
  LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Kieron B L
authors.initials: KB
authors.lastname: Lim
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Sima
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Khaitova
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: John T
authors.initials: JT
authors.lastname: Doucette
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Chernyiak
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Jawad
authors.initials: J
authors.lastname: Ahmad
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bach
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Charissa
authors.initials: C
authors.lastname: Chang
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Priya
authors.initials: P
authors.lastname: Grewal
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Leona
authors.initials: L
authors.lastname: Kim-Schluger
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Liu
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Odin
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Ponni
authors.initials: P
authors.lastname: Perumalswami
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Sander S
authors.initials: SS
authors.lastname: Florman
authors.affiliation: Kieron BL Lim, Hamid R Sima, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Thomas D Schiano, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Schiano
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001706:Biopsy; D018450:Disease Progression; D004359:Drug Therapy, Combination; D058625:End Stage Liver Disease / Q000175:diagnosis / Q000601:surgery* / Q000821:virology; D005260:Female; D005838:Genotype; D006085:Graft Survival; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006526:Hepatitis C / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D016031:Liver Transplantation / Q000009:adverse effects* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009519:New York City; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D016016:Proportional Hazards Models; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012008:Recurrence; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a
keywords: Hepatitis C recurrence; IL28B; Liver transplant; Low accelerating dose regimen; Peginterferon α-2a