Retrospective Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2015; 21(20): 6236-6245
Published online May 28, 2015. doi: 10.3748/wjg.v21.i20.6236
Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus
Kieron BL Lim, Hamid R Sima, M Isabel Fiel, Viktoriya Khaitova, John T Doucette, Maria Chernyiak, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Sander S Florman, Thomas D Schiano
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
M Isabel Fiel, Lillian and Henry M Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Viktoriya Khaitova, Jawad Ahmad, Nancy Bach, Charissa Chang, Priya Grewal, Leona Kim-Schluger, Lawrence Liu, Joseph Odin, Ponni Perumalswami, Sander S Florman, Thomas D Schiano, Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
John T Doucette, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Kieron BL Lim, Division of Gastroenterology and Hepatology, National University Center for Organ Transplantation, National University Hospital, Singapore 119228, Singapore
Author contributions: Lim KBL and Schiano TD participated in research design, writing of the manuscript, performance of the research, data analysis; Sima HR, Fiel MI and Khaitova V participated in performance of the research, data analysis; Doucette JT participated in research design and data analysis manuscript revision; Chernyiak M, Ahmad J, Bach N, Chang C, Grewal P, Kim-Schluger L, Liu L, Odin J, Perumalswami P and Florman SS participated in research design/manuscript revision.
Supported by JTD (an employee of Mount Sinai Medical Center) in part was provided by Genentech Pharmaceuticals.
Ethics approval: On 4/23/2013, an Institutional Review Board of the Mount Sinai School of Medicine, in accordance with Mount Sinal’s Federal Wide Assurances (FWA#00005656, FWA#00005651) to the Department of Health and Human Services approved the following human subject from 5/14/2013 until 5/13/2014 inclusive.
Informed consent: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest: No potential conflicts of interest relevant to this article were reported.
Data sharing: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Kieron BL Lim, FRCP (Edin), Head, Division of Gastroenterology and Hepatology, National University Centre for Organ Transplantation, National University Hospital, 1E Kent Ridge Road, Tower Block Level 10, Singapore 119228, Singapore. kieron_lim@nuhs.edu.sg
Telephone: +65-67726258 Fax: +65-67751518
Received: December 20, 2014
Peer-review started: December 21, 2014
First decision: January 22, 2015
Revised: February 9, 2015
Accepted: March 12, 2015
Article in press: March 12, 2015
Published online: May 28, 2015
Abstract

AIM: 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).

CONCLUSION: 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.

Keywords: Hepatitis C recurrence, Liver transplant, Low accelerating dose regimen, Peginterferon α-2a, IL28B

Core tip: This study represents the largest single center experience in treating recurrent hepatitis C virus (HCV) in LT recipients utilizing a low-accelerating-dose regimen (LADR) protocol of PEG alpha-2a and RBV; achieving 38% SVR and superior five-year patient survival in patients with SVR (97% vs 82%, P = 0.001). A novel technique was used to ascertain recipient and donor IL28B (rs12979860) Gt data using archival FFPE tissue from explanted native livers and donor gallbladders. A comprehensive blinded review of available liver histology was performed. LADR strategy remains relevant in managing recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.