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Dooghaie Moghadam A, Eslami P, Dowlati Beirami A, Iravani S, Farokhi E, Mansour-Ghanaei A, Hashemi MR, Aghajanpoor Pasha M, Mehrvar A, Nassiri-Toosi M. An Overview of the Current Hepatitis B Treatment Strategies after Liver Transplantation. Middle East J Dig Dis 2021; 13:5-14. [PMID: 34712432 PMCID: PMC8531931 DOI: 10.34172/mejdd.2021.197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/11/2020] [Indexed: 12/15/2022] Open
Abstract
Currently, liver transplantation (LT) is considered as the only option for the treatment of patients with various causes of liver failure, including patients with chronic hepatitis B virus (HBV) infections. Overall, patients with HBV who undergo LT are at increased risk of hepatitis B infection recurrence. Although the current knowledge regarding the pathophysiology of this infection has been dramatically increased over the past few decades, it is still considered a complex disease process with varying degrees of clinical characteristics and changing patterns over time. There are various treatment strategies for preventing HBV recurrence in the LT setting. Generally, these regimens include oral nucleoside/ nucleotide analogues (NAs), hepatitis B immune globulin (HBIG), and vaccines or the combination of these drugs. The treatment strategy of choice should be based on cost-effectiveness, along with other patients underlying conditions. In this case, studies indicate that potent NAs are more cost-effective than HBIG in most case scenarios. In this article, we aimed to review the general medications used in the prophylaxis of the recurrence of HBV infection after LT.
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Affiliation(s)
- Arash Dooghaie Moghadam
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pegah Eslami
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirreza Dowlati Beirami
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahrokh Iravani
- Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
| | - Ermia Farokhi
- Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center (GLDRC), Guilan University of Medical Sciences, Guilan, Iran
| | - Mahmood Reza Hashemi
- Gastroenterology and Hepatobiliary Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Morteza Aghajanpoor Pasha
- Gastroenterology and Hepatobiliary Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Azim Mehrvar
- Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
| | - Mohssen Nassiri-Toosi
- Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Lai Q, Mennini G, Giovanardi F, Rossi M, Giannini EG. Immunoglobulin, nucleos(t)ide analogues and hepatitis B virus recurrence after liver transplant: A meta-analysis. Eur J Clin Invest 2021; 51:e13575. [PMID: 33866547 PMCID: PMC8365701 DOI: 10.1111/eci.13575] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/04/2021] [Accepted: 04/13/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Prophylaxis with hepatitis B immunoglobulin (HBIG) represents an efficient strategy for reducing the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). Unfortunately, the long-term use of HBIG presents high costs. Therefore, the use of prophylaxis based only on nucleos(t)ide analogues (NUC) has been recently postulated. The present meta-analysis aimed to evaluate the impact of HBIG ± NUC vs HBIG alone or NUC alone in post-LT HBV recurrence prophylaxis. MATERIALS AND METHODS A systematic literature search was performed using PubMed and Cochrane databases. The primary outcome investigated was the HBV recurrence after LT. Three analyses were done comparing the effect of (a) HBIG + NUC vs HBIG alone; (b) HBIG+NUC vs NUC alone; and (c) HBIG alone vs NUC alone. Sub-analyses were also performed investigating the effect of low and high genetic barrierto-recurrence NUC. RESULTS Fifty-one studies were included. The summary OR (95%CI) showed a decreased risk with the combination of HBIG + NUC vs HBIG alone for HBV recurrence, being 0.36 (95% CI = 0.22-0.61; P < .001). HBIG + NUC combined treatment reduced HBV reappearance respect to NUC alone (OR = 0.22; 95% CI = 0.16-0.30; P < .0001). Similarly, HBIG alone was significantly better than NUC alone in preventing HBV recurrence (OR = 0.20; 95% CI = 0.09-0.44; P < .0001). CONCLUSIONS Prophylaxis with HBIG is relevant in preventing post-LT HBV recurrence. Its combination with NUC gives the best results in terms of protection. The present results should be considered in light of the fact that also old studies based on lamivudine use were included. Studies exploring in detail high genetic barrier-to-recurrence NUC and protocols with definite use of HBIG are needed.
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Affiliation(s)
- Quirino Lai
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Gianluca Mennini
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Massimo Rossi
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Edoardo G. Giannini
- Gastroenterology UnitDepartment of Internal MedicineUniversity of GenoaIRCCS Ospedale Policlinico San MartinoGenoaItaly
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Park JS, Gayam V, Pan CQ. Review article: preventing hepatitis B graft infection in hepatitis B patients after liver transplantation: immunoglobulin vs anti-virals. Aliment Pharmacol Ther 2020; 52:944-954. [PMID: 32743822 DOI: 10.1111/apt.15999] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/10/2020] [Accepted: 07/05/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND A critical aspect of liver transplantation in hepatitis B patients is to prevent graft reinfection with hepatitis B virus. The use of hepatitis B immune globulin after transplant was a significant milestone, which allowed prolonged graft and patient survival by controlling hepatitis B reinfection in liver grafts. The development of anti-viral treatments with oral nucleos(t)ide analogues, led to a further reduction in graft reinfection and improvement in patient survival. The combination of the aforementioned two therapies has been widely used in hepatitis B-associated liver transplants. AIMS To address the post-transplant management of hepatitis B and provide updates on preventing graft reinfection. METHODS We performed a literature search on Ovid and PubMed for randomised controlled trials or cohort studies in English, which investigated the effectiveness of hepatitis B immune globulin and anti-viral therapy on hepatitis B-associated transplants (1/2000-1/2020). Studies that met pre-established criteria were reviewed. RESULTS Based on currently available evidence, an algorithm for post-transplant management with anti-viral therapy is proposed. Also, the management of recipients who received grafts from hepatitis B core antibody-positive donors is discussed. CONCLUSIONS The development of hepatitis B immune globulin and anti-viral treatments led to substantial improvement in graft and patient survival. The prevention of hepatitis B graft reinfection is complex and involves a broad interdisciplinary team.
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Affiliation(s)
- James S Park
- Division of Gastroenterology and Hepatology, Department of Medicine, NYU School of Medicine, NYU Langone Health, New York, NY, USA.,NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA
| | - Vijay Gayam
- Interfaith Medical Center, SUNY Downstate University Hospital, Brooklyn, NY, USA
| | - Calvin Q Pan
- Division of Gastroenterology and Hepatology, Department of Medicine, NYU School of Medicine, NYU Langone Health, New York, NY, USA.,Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Fernández I, Pascasio JM, Colmenero J. Prophylaxis and treatment in liver transplantation. VII Consensus Document of the Spanish Society of Liver Transplantation. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:169-177. [PMID: 32094045 DOI: 10.1016/j.gastrohep.2019.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 11/05/2019] [Accepted: 11/20/2019] [Indexed: 12/26/2022]
Abstract
Whilst prophylaxis of hepatitis B is universally accepted after liver transplantation (LT), national recommendations for the prophylaxis and treatment of hepatitis B virus (HBV) infection after LT are lacking in Spain. The aim of the VII consensus meeting organised by the Spanish Society of Liver Transplantation (SETH) was to set recommendations on the prophylaxis and treatment of hepatitis B after LT. The scientific evidence and strength of recommendations was evaluated by using the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) system. This document describes the recommendations and their level of evidence for: the definition and risk factors for hepatitis B recurrence after LT, monitoring and prophylaxis of hepatitis B recurrence at different periods after LT, treatment of hepatitis B before and after LT, and the prophylaxis of HBV infection by the recipients of LT with hepatitis B core antigen positive donors.
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Affiliation(s)
- Inmaculada Fernández
- Sociedad Española de Trasplante Hepático, Unidad de Hepatología y Trasplante Hepático, Hospital 12 de Octubre, Madrid, España
| | - Juan Manuel Pascasio
- Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Hospital Virgen del Rocío, Sevilla, España
| | - Jordi Colmenero
- Unidad de Trasplante Hepático, Hospital Clínic, IDIBAPS, CIBERehd, Univ. Barcelona, Barcelona, España.
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Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, Hu TH, Yang HI, Lu SN, Ni YH, Chuang WL, Lee CM, Wu JC, Chen PJ, Liaw YF. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc 2019; 118:7-38. [PMID: 30527436 DOI: 10.1016/j.jfma.2018.11.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 01/10/2023] Open
Abstract
The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Affiliation(s)
- Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan.
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hwa-I Yang
- Department of Genomic Research Center, Sinica Academia, Taipei, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Won-Long Chuang
- Division of Hepatobiliary and Pancreas, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jaw-Chin Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan
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Urabe A, Imamura M, Tsuge M, Kan H, Fujino H, Fukuhara T, Masaki K, Kobayashi T, Ono A, Nakahara T, Kawaoka T, Hiramatsu A, Kawakami Y, Aikata H, Hayes CN, Maki N, Ohdan H, Chayama K. The relationship between HBcrAg and HBV reinfection in HBV related post-liver transplantation patients. J Gastroenterol 2017; 52:366-375. [PMID: 27422771 DOI: 10.1007/s00535-016-1240-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 07/02/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Post-transplant hepatitis B virus (HBV) reinfection is one of the major problems facing patients who undergo HBV-related liver transplantation (LT). We analyzed the clinical impact of serum hepatitis B core-related antigen (HBcrAg) on HBV reinfection in post-LT patients with HBV-related liver diseases. METHODS Serum hepatitis B surface antigen (HBsAg), HBV DNA, and HBcrAg were measured over time in 32 post-LT patients. Twenty-one out of 32 patients had HCC at LT. The effects of HBcrAg, hepatocellular carcinoma (HCC) recurrence, and HBs gene mutation on HBV reinfection and withdrawal from hepatitis B immune globulin (HBIG) were analyzed. RESULTS Sixteen out of 32 patients (50 %) were positive for HBcrAg even though only six patients were thought to have experienced HBV reinfection based on reappearance of either HBV DNA or HBsAg during a median follow-up time of 75 months. Three of these six patients who became re-infected with HBV experienced HCC recurrence after LT. The HBV DNA reappearance rate was significantly higher in patients with HCC recurrence after LT (p < 0.001). Two HBV re-infected patients without HCC recurrence had HBs gene mutations G145R and G145A, respectively. Anti-HBs antibody development rate by HB vaccination was similar between HBcrAg-positive and negative patients (p = 0.325). CONCLUSIONS HBV reinfection is more common than is usually considered based on conventional measurement of HBsAg and HBV DNA. HCC recurrence and mutations in the HBV S gene were associated with HBV reinfection after LT.
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Affiliation(s)
- Ayako Urabe
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Noboru Maki
- Advanced Life Science Institute, Inc., Wako, Japan
| | - Hideaki Ohdan
- Division of Frontier Medical Science, Department of Surgery, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
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Burra P, Belli LS, Ginanni Corradini S, Volpes R, Marzioni M, Giannini E, Toniutto P. Common issues in the management of patients in the waiting list and after liver transplantation. Dig Liver Dis 2017; 49:241-253. [PMID: 28096056 DOI: 10.1016/j.dld.2016.12.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 02/06/2023]
Abstract
The present document contains the recommendations of an expert panel of transplant hepatologists, appointed by the Italian Association for the Study of the Liver (AISF), on how to manage the most common aspects of liver transplantation: the topics covered include: new treatments for HCV in patients on the waiting list for liver transplantation; antiviral treatments in patients with HCV recurrence after liver transplantation; prophylaxis for HBV recurrence after liver transplantation; indications for liver transplantation in alcoholic liver disease; and Immunosuppressive therapy. The statements on each topic were approved by participants at the AISF Transplant Hepatologist Expert Meeting (organized by the Permanent Committee on Liver Transplantation in Mondello on 4-5 October 2015), and are graded according to the Oxford classification of levels of evidence.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Italy.
| | | | | | - Riccardo Volpes
- Hepatology and Gastroenterology Unit, ISMETT-IRCCS, Palermo, Italy
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Caccamo L. Long-term nucleos(t)ide analog(s) monoprophylaxis in Delta coinfected liver transplant recipients. Transpl Infect Dis 2017; 19. [DOI: 10.1111/tid.12641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 09/21/2016] [Accepted: 11/06/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Lucio Caccamo
- HBP Surgery and Liver Transplant Center; Fondazione IRCCS Ospedale Maggiore Policlinico; Milano Italy
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Wang ML, Zhou QL, Chen EQ, Du LY, Yan LB, Bai L, He M, Tang H. Low Ratio of Treg to Th17 Cells After 36 Weeks of Telbivudine Therapy Predict HBeAg Seroconversion. Viral Immunol 2016; 29:332-342. [PMID: 27104358 DOI: 10.1089/vim.2016.0007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Changes of Treg/Th17 cells ratio and their associated cytokines have some correlations with an immune modulatory effect of Telbivudine treatment. The aim of our study was to investigate the role of the dynamic ratio of Treg/Th17 cells in the mechanism of LdT therapy and their relationships with the clinical responses. We detected the frequency and cytokines production of Treg and Th17 cells in 28 hepatitis B envelope antigen (HBeAg)-positive CHB patients at 0, 12, 24, 36, 48, and 96 weeks after initial LdT therapy. LdT could upregulate the frequency of Th17 cells and Th17 cells associated cytokines, downregulated the frequency of Treg cells and level of TGF-β, which leads to the decrease of Treg/Th17 ratio in HBeAg-positive CHB patients. Treg/Th17 ratio at treatment week 36 could independently predict HBeAg seroconversion in the first 2 years of Telbivudine treatment. Telbivudine therapy can decrease Treg/Th17 ratio, which may predict HBeAg seroconversion during treatment.
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Affiliation(s)
- Meng-Lan Wang
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Qiao-Ling Zhou
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - En-Qiang Chen
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Ling-Yao Du
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Li-Bo Yan
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Lang Bai
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Min He
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Hong Tang
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
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Rational Basis for Optimizing Short and Long-term Hepatitis B Virus Prophylaxis Post Liver Transplantation: Role of Hepatitis B Immune Globulin. Transplantation 2016; 99:1321-34. [PMID: 26038873 PMCID: PMC4539198 DOI: 10.1097/tp.0000000000000777] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates, such as entecavir or tenofovir, suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, and delay or obviate the need for liver transplantation in some patients. After liver transplantation, the combination of long-term antiviral and low-dose hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in greater than 90% of transplant recipients. Some forms of HBV prophylaxis need to be continued indefinitely after transplantation but, in patients with a low-risk of HBV recurrence (i.e., HBV DNA levels undetectable before transplantation), it is possible to discontinue HBIG and maintain only long-term nucleos(t)ide analogue(s) therapy. A more cautious approach is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e., HIV or hepatitis D virus coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those at risk of noncompliance with antiviral therapy. In this group, HBIG-free prophylaxis cannot be recommended. The combination of long-term antiviral and low-dose Hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in > 90% of liver transplant recipients. In patients with low HBV DNA levels, nucleos(t)ide analogue(s) treatment without HBIG is possible.
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Scherer ML, Sammons C, Nelson B, Hammer SM, Verna E. Anti-Hepatitis Virus Agents. CLINICAL VIROLOGY 2016:239-270. [DOI: 10.1128/9781555819439.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Xi ZF, Xia Q. Recent advances in prevention of hepatitis B recurrence after liver transplantation. World J Gastroenterol 2015; 21:829-835. [PMID: 25624716 PMCID: PMC4299335 DOI: 10.3748/wjg.v21.i3.829] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 08/31/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is the only effective treatment for hepatitis B virus (HBV)-related end-stage liver disease. However, without antiviral prophylaxis, the recurrence rate of hepatitis B is as high as 80%-100%, which leads to a 50% mortality rate in the first 2 years after liver transplantation. Combination therapy of hepatitis B immunoglobulin (HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%. The strategy of HBIG combined with lamivudine has been the standard treatment in many centers. However, the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the long-term efficacy of this strategy for the prevention of HBV reinfection. Recently, new nucleos(t)ide analogues, such as entecavir and tenofovir, have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection. These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation. Various therapies that are composed of entecavir, tenofovir, and lamivudine plus adefovir, with or without HBIG have been adopted in several liver transplant centers. This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.
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Varghese J, Sachan D, Reddy MS, Cherian T, Jothimani D, Venugopal K, Arikichenin O, Perumalla R, Narasimhan G, Shanmugam V, Vijaya S, Venkataraman J, Rela M. Hepatitis B immunoglobulin prophylaxis after liver transplantation: experience in a tertiary transplant centre. J Clin Exp Hepatol 2014; 4:209-13. [PMID: 25755562 PMCID: PMC4284215 DOI: 10.1016/j.jceh.2014.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 07/17/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Prophylaxis with hepatitis B immunoglobulin (HBIG) and nucleoside analogs can prevent hepatitis B virus (HBV) recurrence after liver transplant (LT). AIM To determine the efficacy and cost of maintaining immunoprophylaxis with HBIG and hyperimmune plasma (HIP) for 6 months after LT. MATERIAL & METHODS The study included 22 HBV related LT recipients who were on entecavir and either HBIG or HIP for 6 months. Post transplant HBIG or HIP dose and cost incurred towards prophylaxis were noted. The cost of 200 IU of HBIG at the time of study was Rs 8250/- (US Dollars 135) and that of 2000 IU of HIP was Rs 8000/- (USD 130.7). The loading and maintenance costs at end of 6 months were compared between the two groups. Response to HBIG and HIP was assessed by checking for HBsAg reactivity, anti HBs titer response and HBV DNA viral load. STATISTICAL ANALYSIS Median and range, Kruskal Wallis (KW) sign rank Sum Test and Correlation Coefficient (r2) was used for analysis. RESULTS Thirteen recipients received HBIG and 9 recipients HIP. The anti HBs response to HIP was significantly high compared to HBIG (KW Sign rank Sum test P < 0.05); titers remained high until the study period. Between 8 and 30 days, the titer achieved by both HBIG and HIP was similar (KW Sign rank Sum test not significant). Despite low anti HBs titer of <100 IU/L, none of the recipients on HBIG had HBsAg reactivity while 3 on HIP had transient HBsAg positivity. The total cost with HBIG was 13.9 times the cost of HIP. CONCLUSION HIP immunoprophylaxis in combination with entecavir achieves a high anti HBs titer at a significant low cost during anhepatic and loading phase. HBV reactivation rates with HBIG and HIP is low despite low anti HBs titer.
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Key Words
- ESLD, end-stage liver disease
- HBIG, hepatitis B immunoglobulin
- HBV recurrence
- HBV, hepatitis B virus
- HBsAg, hepatitis B surface antigen
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HIP, hyper-immune plasma
- HIV, human immunodeficiency virus
- Hepatitis B virus
- KW, Kruskal Wallis
- LT, liver transplantation
- NA, nucleos(t)ide analogs
- USD, US Dollars
- anti HBs Ab, anti hepatitis B virus antibody
- hepatitis B immunoglobulin
- hyper-immune plasma
- liver transplantation
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Affiliation(s)
- Joy Varghese
- Department of Hepatology & Liver Transplantation, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Deepti Sachan
- Department of Transfusion Medicine, Global Hospitals & Health City, Chennai, India
| | - Mettu S. Reddy
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Tom Cherian
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Dinesh Jothimani
- Department of Hepatology & Liver Transplantation, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Kota Venugopal
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Olithselvan Arikichenin
- Department of Hepatology & Liver Transplantation, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Rajasekar Perumalla
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Gomathy Narasimhan
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Vivekananthan Shanmugam
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Srinivasan Vijaya
- Department of Hepatology & Liver Transplantation, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
| | - Jayanthi Venkataraman
- Department of Hepatology & Liver Transplantation, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
- Address for correspondence: Dr. Jayanthi Venkataraman, Department of Gastroenterology and Hepatology, Global Hospitals & Health City, Chennai 600 100, India. Tel.: +91 44 2277700; fax: +91 44 22777100.
| | - Mohamed Rela
- Department of Liver Transplant & Hepato Biliary Surgery, Institute of Liver Diseases & Transplantation, Global Hospitals & Health City, Chennai, India
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Cholongitas E, Goulis I, Antoniadis N, Fouzas I, Imvrios G, Papanikolaou V, Akriviadis E. New nucleos(t)ide analogue monoprophylaxis after cessation of hepatitis B immunoglobulin is effective against hepatitis B recurrence. Transpl Int 2014; 27:1022-8. [PMID: 24909714 DOI: 10.1111/tri.12370] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 04/21/2014] [Accepted: 06/02/2014] [Indexed: 02/06/2023]
Abstract
New nucleos(t)ide agents (NAs) [entecavir (ETV) and tenofovir (TDF)] have made hepatitis B immunoglobulin (HBIG)-sparing protocols an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). Twenty-eight patients transplanted for HBV cirrhosis in our centre were prospectively evaluated. After LT, each patient received HBIG (1000 IU IM/day for 7 days and then monthly for 6 months) plus ETV or TDF and then continued with ETV or TDF monoprophylaxis. All patients had undetectable HBV DNA at the time of LT, and they were followed up with laboratory tests including glomerular filtration rate (GFR) after LT. All patients (11 under ETV and 17 under TDF) remained HBsAg/HBV DNA negative during the follow-up period [median: 21 (range 9-43) months]. GFR was not different between TDF and ETV groups of patients at 6 and 12 months and last follow-up (P value >0.05 for all comparisons). The two groups of patients were similar regarding their ratio of maximum rate of tubular phosphate reabsorption to the GFR (TmP/GFR). In conclusion, in this prospective study, we showed for the first time that maintenance therapy with ETV or TDF monoprophylaxis after 6 months of low-dose HBIG plus ETV or TDF after LT is highly effective and safe.
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Affiliation(s)
- Evangelos Cholongitas
- 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
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15
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Kasraianfard A, Watt KD, Lindberg L, Alexopoulos S, Rezaei N. HBIG Remains Significant in the Era of New Potent Nucleoside Analogues for Prophylaxis Against Hepatitis B Recurrence After Liver Transplantation. Int Rev Immunol 2014; 35:312-324. [PMID: 24911598 DOI: 10.3109/08830185.2014.921160] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Zhang Y, Kang S, Fang W, Wu X, Liang W. Network meta-analysis on prophylactic regimens against recurrent hepatitis B virus infection after liver transplantation. Hepatobiliary Surg Nutr 2014; 2:297-303. [PMID: 24570966 DOI: 10.3978/j.issn.2304-3881.2013.11.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 11/01/2013] [Indexed: 01/27/2023]
Abstract
BACKGROUND Previous meta-analyses of non-randomized studies suggested that the hepatitis B immunoglobulin (HBIG) and lamivudine (LAM) combination therapy was significantly better than HBIG or LAM alone in preventing hepatitis B virus (HBV) recurrence after transplantation. However, substantial evidences supporting the superiority of combination therapy are still insufficient. Therefore, we sought to conduct a multiple-treatment comparison to integrate current data which was based on randomized controlled trials (RCTs). METHODS We searched electronic databases of PubMed, Embase and the Cochrane Library for eligible literatures. Pair-wise meta-analyses were to synthesize studies comparing the same pair of treatments. Appropriate networks for overall and 1-year recurrence rates were established. Bayesian algorithm was used in multiple-treatment comparisons to compare relative effects of all included regimens. RESULTS Four RCTs on prophylaxis against HBV recurrence after liver transplantation, involving 162 participants, were included. HBIG mono-therapy, LAM mono-therapy and HBIG plus LAM showed no statistically difference in risk ratios (RRs) in terms of overall HBV recurrence rate in network meta-analysis. Nevertheless, HBIG mono-therapy had potential advantage compared with combination of HBIG and LAM in 1-year HBV recurrence rate [RR 0.00, 95% confidence interval (CI): 0.00 to 0.91] while the rest comparisons revealed no significance. The cumulative probabilities of treatments associated with the highest recurrence were (overall HBV recurrence rate, 1-year HBV recurrence rate): HBIG (18%, 1%), LAM (32%, 42%) and HBIG plus LAM (50%, 57%). CONCLUSIONS This network meta-analysis based on data from RCTs showed no significant differences among HBIG mono-therapy, LAM mono-therapy, combination of HBIG and LAM in overall HBV recurrence rate after liver transplantation. Further well designed and large-scale RCTs are warranted to clarify these issues.
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Affiliation(s)
- Yaxiong Zhang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Shiyang Kang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; ; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xuan Wu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; ; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenhua Liang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; ; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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Cholongitas E, Papatheodoridis GV. Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation. World J Gastroenterol 2013; 19:9189-9197. [PMID: 24409047 PMCID: PMC3882393 DOI: 10.3748/wjg.v19.i48.9189] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 10/29/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
The progress in treatment against hepatitis B virus (HBV) with the development of effective and well tolerated nucleotide analogues (NAs) has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence. This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation (LT). A literature search using the PubMed/Medline databases and consensus documents was performed. Pre-transplant therapy has been initially based on lamivudine, but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis. After LT, the combination of HBV immunoglobulin (HBIG) and NA is considered as the standard of care for prophylaxis against HBV recurrence. The combination of HBIG and lamivudine is related to higher rates of HBV recurrence, compared to the HBIG and entecavir or tenofovir combination. In HBIG-free prophylactic regimens, entecavir and tenofovir should be the first-line options. The choice of treatment for HBV recurrence depends on prior prophylactic therapy, but entecavir and tenofovir seem to be the most attractive options. Finally, liver grafts from hepatitis B core antibody (anti-HBc) positive donors can be safely used in hepatitis B surface antigen negative, preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.
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18
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Lindenger C, Castedal M, Cahlin C, Friman S. Excellent liver transplantation survival and prevention of hepatitis B recurrence using hepatitis B immunoglobulin and nucleoside or nucleotide analogue along with treating physician adherence to treatment protocol. Transplant Proc 2013; 45:1188-92. [PMID: 23622656 DOI: 10.1016/j.transproceed.2012.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
INTRODUCTION The introduction of hepatitis B immunoglobulin (HBIG) in the early 1990s dramatically reduced recurrence of hepatitis B after orthotopic liver transplantation (OLT) and thus improved survival. Today a combination of HBIG and a nucleoside or nucleotide analogue (NUC) is recommended as prophylaxis. The optimal protocol is yet to be commonly agreed upon. The aim of this study was to review our results over 25 years. PATIENTS AND METHODS All 56 patients (45 males and 11 females) who underwent OLT due to hepatitis B infection between 1985-2009 were included in the review. Median age at transplantation was 51 years (range, 18-66). Seventeen patients (30%) had hepatocellular carcinoma (HCC) at transplantation. RESULTS The 1- and 5-year overall survival rates were 89% and 77%, respectively. The 23 patients who underwent transplantation before 2000 showed 1- and 5-year survival rates of 82% and 61%, respectively; the 33 who underwent transplantation between 2000 and 2009, the rates were 94% and 90%, respectively (P < .01). There was no difference in the 5-year survival rate between patients who had or did not have been HCC (75% vs 78%, respectively). Recurrence of hepatitis B, defined as seroconversion to HBsAg positivity, was observed in 9 patients. Three transplantation cases before 1992 consequently did not receive HBIG. The remaining 6, who all underwent OLT between 1993 and 2001, were administered HBIG. In all 6 cases periods of low anti-HBs titers were registered prior to recurrence; treating physician noncompliance with the protocol may have contributed to the low anti-HBs titers. No recurrence was registered after 2001. CONCLUSION With a combination of HBIG and NUC, excellent OLT results can be achieved for hepatitis B. It is, however, still important to maintain sufficient anti-HBs titers to prevent recurrence.
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Affiliation(s)
- C Lindenger
- Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.
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19
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Roche B, Samuel D. Treatment of patients with HBV-related decompensated cirrhosis and liver transplanted patients. Clin Liver Dis 2013; 17:451-73. [PMID: 23905816 DOI: 10.1016/j.cld.2013.05.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antiviral therapy using newer nucleos(t)ide analogs with lower resistance rates could suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, delay or obviate liver transplantation in some patients, and reduce the risk of HBV recurrence. Some form of HBV prophylaxis needs to be continued indefinitely posttransplant. However, in patients with a low-risk of HBV recurrence it is possible to discontinue hepatitis B immunoglobulins and maintain long-term nucleos(t)ide analog therapy. Currently, treatment of posttransplantation hepatitis B is a less important clinical problem than it was historically because effective antiviral therapies exist to rescue patients who failed initial prophylaxis.
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Affiliation(s)
- Bruno Roche
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif F-94800, France
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20
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Tanaka T, Benmousa A, Marquez M, Therapondos G, Renner EL, Lilly LB. The long-term efficacy of nucleos(t)ide analog plus a year of low-dose HBIG to prevent HBV recurrence post-liver transplantation. Clin Transplant 2013; 26:E561-9. [PMID: 23061767 DOI: 10.1111/ctr.12022] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis B immunoglobulin (HBIG), given in combination with nucleos(t)ide therapy, has reduced the rate of recurrent hepatitis B virus (HBV) following liver transplantation (LT), although the most effective protocol is unknown. We have retrospectively evaluated the use of long-term nucleos(t)ide analog in combination with one yr of low-dose HBIG. One hundred and fifty-two adults with HBV-related liver disease underwent LT in our center from January 1999 to August 2009; of these, 132 patients who received one yr of HBIG combined with long-term nucleos(t)ide analogs (largely on lamivudine [LAM] alone, n = 97) afterward were included for the purposes of this study. Median follow-up post-transplantation was 1752 d. Patient survival was 93.9%, 86.9% and 84.1% at 1, 5, and 10 yr, respectively; none of the 17 deceased patients had recurrent HBV. HBV recurrence was observed in nine patients (all received LAM+HBIG), yielding recurrence rates of 2.3%, 5.1%, and 8.6% at 1, 3, and 5/10 yr, respectively. All recurrences were successfully managed, usually with additional antiviral treatment. In conclusion, this study, with its long-term follow-up, demonstrates that short course of low-dose HBIG (without anti-HBs monitoring) combined with the use of long-term nucleos(t)ide analog is effective and less cumbersome than many protocols in current use.
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Affiliation(s)
- Tomohiro Tanaka
- Liver Transplant Unit, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
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21
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Levitsky J, Doucette K. Viral hepatitis in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:147-68. [PMID: 23465008 DOI: 10.1111/ajt.12108] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J Levitsky
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Beckebaum S, Kabar I, Cicinnati VR. Hepatitis B and C in liver transplantation: new strategies to combat the enemies. Rev Med Virol 2012; 23:172-93. [PMID: 23239274 DOI: 10.1002/rmv.1734] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 10/29/2012] [Accepted: 11/01/2012] [Indexed: 12/16/2022]
Abstract
Hepatitis B immune globulin-free therapeutic regimens with a nucleos(t)ide analogue (NUC) or NUC combinations after liver transplantation (LT) are currently being investigated for their efficacy and safety as HBV re-infection prophylaxis in clinical studies. Recurrence rates differ among these studies as most of them are limited by a non-randomised study design, small sample size, lack of long-term data and varying time intervals for the switch from combined to purely virostatic prophylaxis. Post-transplant pre-emptive antiviral therapy with pegylated IFN and ribavirin is associated with low sustained virological response rates and was found to have no advantage over treatment of manifest HCV re-infection. Safety and efficacy of triple antiviral therapy including boceprevir or telaprevir in patients with manifest HCV re-infection are currently under investigation in clinical trials. Relevant drug interactions have been shown to occur during calcineurin inhibitor (CNI) and concomitant triple antiviral therapy, which vary with type of CNI and choice of HCV protease inhibitor. Newer direct-acting antivirals with lower or minimal toxicity, when used in combination with immunosuppressives, are worthy of further study in LT patients. This review focuses on hot topics in the management of hepatitis B and C patients before and after LT and offers a critical summarised selection of the corresponding relevant studies published in the current literature or presented at recent liver congresses.
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Affiliation(s)
- Susanne Beckebaum
- Department of Transplant Medicine, University Hospital Münster, Münster, Germany.
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Buti M, García-Samaniego J, Prieto M, Rodríguez M, Sánchez-Tapias JM, Suárez E, Esteban R. Documento de consenso de la AEEH sobre el tratamiento de la infección por el virus de la hepatitis B (2012). GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:512-28. [PMID: 22749508 DOI: 10.1016/j.gastrohep.2012.04.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Accepted: 04/23/2012] [Indexed: 12/13/2022]
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Abstract
Acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) is most commonly caused by acute severe exacerbation of CHB. The pathophysiology of ACLF in CHB is still poorly understood. Despite the identification of important predisposing factors and prognostic markers, ACLF in CHB remains a disease associated with high mortality. The majority of studies using nucleoside analog therapy did not show any significant improvement in survival, although larger prospective studies are needed. Liver transplantation is the definitive treatment for ACLF in CHB. The challenge ahead would be prognosticating cases with favorable or unfavorable outcomes in order to streamline patients for early transplantation or for medical therapy.
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Affiliation(s)
- Wai-Kay Seto
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
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25
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Li H, Xie HY, Zhou L, Wang WL, Liang TB, Zhang M, Zheng SS. Polymorphisms of CCL3L1/CCR5 genes and recurrence of hepatitis B in liver transplant recipients. Hepatobiliary Pancreat Dis Int 2011; 10:593-8. [PMID: 22146622 DOI: 10.1016/s1499-3872(11)60101-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The genetic diversity of chemokines and chemokine receptors has been associated with the outcome of hepatitis B virus infection. The aim of this study was to evaluate whether the copy number variation in the CCL3L1 gene and the polymorphisms of CCR5Δ32 and CCR5-2459A→G (rs1799987) are associated with recurrent hepatitis B in liver transplantation for hepatitis B virus infection-related end-stage liver disease. METHODS A total of 185 transplant recipients were enrolled in this study. The genomic DNA was extracted from whole blood, the copy number of the CCL3L1 gene was determined by a quantitative real-time PCR based assay, CCR5Δ32 was detected by a sizing PCR method, and a single-nucleotide polymorphism in CCR5-2459 was detected by restriction fragment length polymorphism PCR. RESULTS No CCR5Δ32 mutation was detected in any of the individuals from China. Neither copy number variation nor polymorphism in CCR5-2459 was associated with post-transplant re-infection with hepatitis B virus. However, patients with fewer copies (<4) of the CCL3L1 gene compared with the population median in combination with the CCR5G allele had a significantly higher risk for recurrent hepatitis B (odds ratio=1.93, 95% CI: 1.00-3.69; P=0.047). CONCLUSION Patients possessing the compound decreased functional genotype of both CCL3L1 and CCR5 genes might be more likely to have recurrence of hepatitis B after transplantation.
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Affiliation(s)
- Hong Li
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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Abstract
The management of hepatitis B in liver transplantation has evolved significantly over the past 2 decades. Introduction of hepatitis B immune globulin and subsequently nucleos(t)ide analogues has revolutionized transplantation for hepatitis B virus (HBV), increasing survival for patients transplanted for this indication. With the availability of new and potent antivirals for HBV, the need for liver transplant should continue to decrease in the coming years. Moreover, the newer antivirals with high resistance barriers will allow effective long-term viral prophylaxis and therefore, prevention of recurrence.
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Affiliation(s)
- Corinne Buchanan
- Center for Liver Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Abstract
Chronic hepatitis B continues to be a major global health burden. It accounts for a substantial impact on health care resources and finances in many parts of the world including Europe. Natural history and disease spectrum are varied, depending on when and how the infection is acquired. The chronic infective state increases patients' risk of progression to liver cirrhosis or hepatocellular carcinoma. Several treatment options are currently available, but their use depends on the stage of the patient's infection, which is influenced by both host and viral factors. The ultimate goals in hepatitis B treatment are to prevent disease progression, hepatic decompensation, hepatocellular carcinoma, and death. Patients with decompensated liver cirrhosis should be referred to specialized transplant centers in a timely manner.
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Karlas T, Hartmann J, Weimann A, Maier M, Bartels M, Jonas S, Mössner J, Berg T, Tillmann HL, Wiegand J. Prevention of lamivudine-resistant hepatitis B recurrence after liver transplantation with entecavir plus tenofovir combination therapy and perioperative hepatitis B immunoglobulin only. Transpl Infect Dis 2010; 13:299-302. [PMID: 21159112 DOI: 10.1111/j.1399-3062.2010.00591.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Combination therapy with antivirals plus hepatitis B immunoglobulin (HBIg) has become the standard treatment for prevention of post-liver transplant hepatitis B virus (HBV) recurrence. However, HBIg therapy is inconvenient and expensive. Alternative therapeutic approaches with modern nucleos(t)ide analogues are limited so far. The present case report describes prevention of HBV recurrence with entecavir and tenofovir. A 48-year-old male patient with hepatitis B-induced decompensated liver cirrhosis initially improved on lamivudine (LAM) until LAM resistance (rtL180M and rtM204V) emerged followed by renewed decompensation. Therefore, tenofovir was added to LAM leading to undetectable HBV DNA (<200 copies/mL). Six months later, low-level viremia (479 copies/mL) was detected. Treatment was escalated to tenofovir plus entecavir. HBV DNA became negative again, and the patient underwent orthotopic liver transplantation. HBIg was administered during transplantation (10,000 IU) and on the second and third postoperative days (total dose 26,000 IU). Subsequently, the anti-hepatitis B surface (HBs) titer rose to 1477 IU/L at day 4 post transplantation. Although HBIg should have been continued, the patient remained on combination therapy with tenofovir plus entecavir only. The anti-HBs titer decreased and became negative 4 months later. However, under continued combination therapy with oral antivirals, HBV DNA and hepatitis B surface antigen remained negative during the entire follow-up of 21 months after liver transplantation. Combination therapy with entecavir plus tenofovir may prevent post-liver transplant hepatitis B recurrence even without HBIg maintenance therapy. This case illustrates that combination oral antiviral therapy might substitute for HBIg as indefinite prophylactic regimen due to profound antiviral efficacy and low risk of viral resistance. Efficacy and safety must be further investigated in randomized controlled trials.
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Affiliation(s)
- T Karlas
- Department of Medicine, Dermatology and Neurology, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany
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Cholongitas E, Papatheodoridis GV. Management of HBV Infection and Liver Transplantation. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 2010:748-761. [DOI: 10.1002/9781444314403.ch45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Neumann AU, Phillips S, Levine I, Ijaz S, Dahari H, Eren R, Dagan S, Naoumov NV. Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells. Hepatology 2010; 52:875-85. [PMID: 20593455 PMCID: PMC3086357 DOI: 10.1002/hep.23778] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Antibodies are thought to exert antiviral activities by blocking viral entry into cells and/or accelerating viral clearance from circulation. In particular, antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) confer protection, by binding circulating virus. Here, we used mathematical modeling to gain information about viral dynamics during and after single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B) antibodies in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, whereas antibody HBV-19 recognizes a linear epitope on the HBsAg. The kinetic profiles of the decline of serum HBV DNA and HBsAg revealed partial blocking of virion release from infected cells as a new antiviral mechanism, in addition to acceleration of HBV clearance from the circulation. We then replicated this approach in vitro, using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics. In vitro, HepeX-B treatment of HBsAg-producing cells showed cellular uptake of antibodies, resulting in intracellular accumulation of viral particles. Blocking of HBsAg secretion also continued after HepeX-B was removed from the cell culture supernatants. CONCLUSION These results identify a novel antiviral mechanism of antibodies to HBsAg (anti-HBs) involving prolonged blocking of the HBV and HBsAg subviral particles release from infected cells. This may have implications in designing new therapies for patients with chronic HBV infection and may also be relevant in other viral infections.
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Affiliation(s)
- Avidan U. Neumann
- Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - Sandra Phillips
- Institute of Hepatology, University College London, United Kingdom
| | - Idit Levine
- Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - Samreen Ijaz
- Hepatitis Laboratory, Health Protection Agency, Colindale, United Kingdom
| | - Harel Dahari
- Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
- Department of Medicine, Section of Hepatology, University of Illinois at Chicago, Chicago, IL USA
| | - Rachel Eren
- XTL Biopharmaceuticals Ltd., Kiryat Weizmann Science Park, Rehovot, Israel
| | - Shlomo Dagan
- XTL Biopharmaceuticals Ltd., Kiryat Weizmann Science Park, Rehovot, Israel
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Degertekin B, Han SHB, Keeffe EB, Schiff ER, Luketic VA, Brown RS, Emre S, Soldevila-Pico C, Reddy KR, Ishitani MB, Tran TT, Pruett TL, Lok ASF, the NIH HBV-OLT Study Group. Impact of virologic breakthrough and HBIG regimen on hepatitis B recurrence after liver transplantation. Am J Transplant 2010; 10:1823-33. [PMID: 20346062 PMCID: PMC2910807 DOI: 10.1111/j.1600-6143.2010.03046.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre-OLT and HBIG regimens post-OLT. Data from the NIH HBV-OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1-81) post-OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log(10) copies/mL, 74% were receiving antiviral therapy. Twenty-five patients experienced virologic breakthrough before OLT. Post-OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high-dose, IV low-dose, intramuscular low-dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre-OLT as long as rescue therapy is administered pre- and post-OLT.
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Affiliation(s)
- Bulent Degertekin
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA
| | | | - Emmet B. Keeffe
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA
| | | | | | | | | | | | | | | | - Tram T. Tran
- Cedars Sinai Medical Center, Los Angeles, CA, USA
| | | | - Anna S. F. Lok
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI
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Collaborators
Natalie Bzowej, Robert Gish, Jamie Zagorsk, Tram Tran, Amy Crumley, Paul Gaglio, Maria Martin, Raymond T Chung, Diana Tsui, Marian Bihrle, Michael Ishitani, Heidi Togerson, Sukru Emre, Mark Sturdevant, Javaluyas Aniceto, Robert Perrillo, Cheryl Denham, Emmet Keeffe, Lucinda Porter, Steve Han, Pearl Kim-Hong, Val Peacock, Consuelo Soldevila-Pico, Joy Peter, Eugene Schiff, Maria Torres, Rajender Reddy, Timothy Siropaides, Timothy Pruett, Velimir A C Luketic, Stacy McLeod, Anna Lok, Bulent Degertekin, Terese Howell, Donna Harsh, Munira Hussain, Jim Imus, Morton Brown,
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Katz LH, Tur-Kaspa R, Guy DG, Paul M. Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation. Cochrane Database Syst Rev 2010:CD006005. [PMID: 20614442 DOI: 10.1002/14651858.cd006005.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Recurrence of hepatitis B virus (HBV) infection in the liver graft is a grave complication following liver transplantation for HBV cirrhosis. Hepatitis B immunoglobulin (HBIg) seems effective in increasing survival after liver transplantation. HBIg and anti-viral drugs are given alone or in combination for its prevention. OBJECTIVES To assess the benefits and harms of different regimens for preventing HBV reactivation following liver transplantation. SEARCH STRATEGY We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2010. We attempted to identify further trials by reviewing the reference lists and contacting the principal authors of identified trials. SELECTION CRITERIA Randomised clinical trials addressing benefits and harms of lamivudine or adefovir dipivoxil alone or in combination with hepatitis B immunoglobulins (HBIg) for preventing recurrent HBV infection in patients who are liver transplanted due to HBV infection with or without hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS Two authors independently assessed the trials for risk of bias and extracted data. We contacted study authors whenever information was lacking. We collected information on adverse events. The primary outcomes were all-cause mortality and reappearance of hepatitis B surface antigen in serum after liver transplantation. Relative risks were calculated from individual trials. MAIN RESULTS Four trials, recruiting 136 participants, were included. Two trials compared lamivudine alone versus HBIg alone. Randomisation was performed one week after transplantation in one of the trials and after six months after transplantation in another; from transplantation until randomisation, HBIg alone was given to all patients in the two trials. A third trial compared combination treatment with lamivudine and HBIg versus lamivudine alone after one month of combination treatment, and a fourth trial compared the combination of lamivudine and HBIg versus a combination of lamivudine and adefovir dipivoxil after at least 12-month of lamivudine and HBIg combination treatment. Statistically significant differences were not detected in any of the comparisons and outcomes. All trials were open-labelled, and none of the trials were adequately powered to show a difference in HBV recurrence. No meta-analyses were performed since the identified trials assessed different comparisons. AUTHORS' CONCLUSIONS This review could not derive clear evidence from randomised clinical trials for the treatment of patients with chronic HBV following liver transplantation for preventing recurrence of HBV infection. Large randomised clinical trials comparing long-term combination treatment to each of the monotherapy alone, including the newer antiviral drugs, are needed.
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Affiliation(s)
- Lior H Katz
- Gastroenterology Department, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel, 52621
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Bihl F, Russmann S, Gurtner V, Di Giammarino L, Pizzi-Bosman L, Michel M, Cerny A, Hadengue A, Majno P, Giostra E, Castelli D, Mentha G. Hyperimmune anti-HBs plasma as alternative to commercial immunoglobulins for prevention of HBV recurrence after liver transplantation. BMC Gastroenterol 2010; 10:71. [PMID: 20598161 PMCID: PMC2912239 DOI: 10.1186/1471-230x-10-71] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Accepted: 07/04/2010] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis B immune globulins (HBIG) in combination with nucleos(t)ide analogues (NA) are effectively used for the prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, associated treatment costs for HBIG are exceedingly high. METHODS Fresh frozen plasma obtained from blood donors with high anti-HBs levels (hyperimmune plasma, HIP) containing at least 4,500 IU anti-HBs was used as alternative treatment for HBV recurrence prophylaxis post-LT. RESULTS Twenty-one HBV-related LT recipients received HIP starting at transplantation, followed by long-term combination treatment with NA. Mean follow-up time was 4.5 years (range 0.5-12.6) and each patient received on average 8.2 HIP per year (range 5.8-11.4). Anti-HBs terminal elimination kinetic after HIP administration was 20.6 days (range 13.8-30.9), which is comparable to values reported for commercial HBIG products. All 21 patients remained free of HBV recurrence during follow-up and no transfusion-transmitted infection or other serious complication was observed. Seven patients developed reversible mild transfusion reactions. The cost for one HIP unit was US$140; average yearly HBIG treatment cost was US$1,148 per patient, as compared to US$25,000-100,000 for treatment with commercial HBIG. CONCLUSION The results of this study suggest that the use of HIP may be a useful and economical approach for the prevention of HBV recurrence post-LT if used in combination with NA. Additional prospective controlled studies in larger populations are needed to confirm these results.
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Affiliation(s)
- Florian Bihl
- Department of Gastroenterology and Hepatology, University Hospital of Geneva, Switzerland.
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Yuefeng M, Weili F, Wenxiang T, Ligang X, Guiling L, Hongwei G, Wencai L, Xiaoguang W, Wei M, Zhongyi F. Long-term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation. Clin Transplant 2010; 25:517-22. [PMID: 20560989 DOI: 10.1111/j.1399-0012.2010.01290.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The aim of this study is to examine the efficacy of long-term prophylaxis with lamivudine (LAM) after a course of post-operative hepatitis B immunoglobulin (HBIG) in patients who underwent liver transplantation (LT) for hepatitis B virus (HBV)-related disease. RESULT The medical records of HBV-infected patients who underwent a LT in our institution between July 2001 and May 2005 were reviewed. There were 15 liver transplant recipients who were administered HBIG for <18 months and used LAM as a maintenance prophylaxis regime enrolled in this study. At enrollment, all patients were hepatitis B surface antigen (HBsAg) positive and three patients were HBeAg positive. There were 13 patients who were HBV DNA positive with a mean viral load of 5.4 log copies/mL, and among them, 12 recipients were on antiviral therapy with LAM (100 mg/d orally) for 12-168 d, resulting in HBV DNA negative levels in nine patients prior to their transplant. HBV recurrence post-LT was noted in two patients who had very high-HBV DNA levels pre-LT. Both of these patients showed LAM-resistant mutation at the time of recurrence. The 11 patients who were HBV DNA negative before LT (low-risk patients) had no HBV recurrence during a follow-up at a median of 58 months post-LT. This included five patients who had intermittent low-level HBV DNA post-LT (HBsAg negative), of whom two had YMDD mutation and these two were given adefovir in addition to LAM. CONCLUSION Our retrospective study demonstrated excellent long-term outcomes in the low-risk patients treated with LAM after a short course of HBIG.
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Affiliation(s)
- M Yuefeng
- Department of Hepatobiliary Surgery, Dalian Institute of Hepatobiliary Surgery, Dalian Friendship Hospital, Dalian, China
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Weber NK, Forman LM, Trotter JF. HBIg discontinuation with maintenance oral anti-viral therapy and HBV vaccination in liver transplant recipients. Dig Dis Sci 2010; 55:505-9. [PMID: 19802696 DOI: 10.1007/s10620-009-0999-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2009] [Accepted: 09/17/2009] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatitis B (HBV) is an uncommon indication for liver transplantation in the US accounting for approximately 5% of cases. Recurrence prophylaxis is typically long-term hepatitis B immune-globulin (HBIg) and an oral anti-HBV agent. Because of high HBIg costs and improving efficacy of new oral agents, there is increasing interest in HBIg discontinuation. AIM To describe results of a protocol at our center including HBV vaccination and HBIg discontinuation. METHODS All patients received HBIg therapy and an oral anti-viral agent from the time of transplant. Patients transplanted for HBV with a stable post-operative clinical course underwent HBV vaccination and HBIg discontinuation. After HBIg discontinuation, patients were monitored for HBV recurrence for at least one year. Recurrence was defined as either viral (HBV-DNA 10(4) copies/ml on two consecutive occasions) or hepatitis (viral recurrence with elevated liver transaminases). RESULTS Of 1182 recipients, 36 (3%) had HBV. Twenty-four were excluded from the protocol, and the remaining 12 patients underwent HBIg withdrawal. Median age at HBIg discontinuation was 56 (range, 36-70) years, median time from transplant to HBIg discontinuation was 62.8 (range, 27.5-128) months, and median time of follow-up after discontinuation was 27.4 (range, 13-69) months. Of the 12 patients vaccinated, no patients maintained HBSAb >or= 10 IU/l at last follow-up. There was no viral or hepatitis recurrence and no deaths or graft loss. CONCLUSIONS HBIg discontinuation with maintenance oral anti-viral monotherapy is safe and effective for HBV liver transplant recipients. Vaccination is not effective in this population.
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Affiliation(s)
- Nicholas K Weber
- Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, 1635 N Ursula, Aurora, CO 80045, USA.
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Affiliation(s)
- J Levitsky
- Division of Hepatology and Organ Transplantation, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Katz LH, Paul M, Guy DG, Tur-Kaspa R. Prevention of recurrent hepatitis B virus infection after liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? Systematic review and meta-analysis. Transpl Infect Dis 2009; 12:292-308. [PMID: 20002355 DOI: 10.1111/j.1399-3062.2009.00470.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To evaluate antiviral prophylaxis against hepatitis B virus (HBV) following liver transplantation. METHODS Systematic review and meta-analysis. Clinical trials and comparative cohort studies comparing the use of hepatitis B immunoglobulin (HBIg), antivirals, or both following liver transplantation for HBV infection were included. The primary outcome was reappearance of hepatitis B surface antigen (HBsAg). Other outcomes included all-cause and HBV-related mortality, HB-related active liver disease, and reappearance of HBV DNA after transplantation. Relative risks (RR) with 95% confidence intervals (CIs) are reported. RESULTS Twenty studies (22 comparisons) were included. Ten studies compared HBIg to combination treatment, 9 compared antivirals to combination treatment, and 3 compared lamivudine (LAM) to HBIg. Combination treatment reduced HBsAg reappearance (RR 0.28; 95% CI 0.12-0.66), and was superior to HBIg alone in all other outcome measures. Combination treatment was significantly better than antivirals in preventing reappearance of HBsAg (RR 0.31; 95% CI 0.22-0.44), even when low-dose HBIg was given. No significant difference was found between HBIg and LAM monotherapy for all measured outcomes. Major limitations with regard to comparability of the study groups in non-randomized trials were revealed. CONCLUSIONS Combination treatment with HBIg and LAM reduced HBV recurrence following liver transplantation, compared with HBIg or LAM alone, and reduced mortality compared with HBIg alone.
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Affiliation(s)
- L H Katz
- Liver Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
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Papatheodoridis GV, Cholongitas E, Archimandritis AJ, Burroughs AK. Current management of hepatitis B virus infection before and after liver transplantation. Liver Int 2009; 29:1294-305. [PMID: 19619264 DOI: 10.1111/j.1478-3231.2009.02085.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
The progress in treatment against hepatitis B virus (HBV) has substantially improved the outcome of all HBV-infected patients. We systematically reviewed the existing data in the management of HBV transplant patients in order to assess the optimal regimen in the pretransplant setting, for post-transplant prophylaxis and for therapy of HBV recurrent infection. All data suggest that an effective pretransplant anti-HBV therapy prevents post-transplant HBV recurrence. Pretransplant therapy has been based on lamivudine with addition of adefovir upon lamivudine resistance, but the use of newer, potent high-genetic barrier agents is expected to improve long-term efficacy. Moreover, it may lead to improvement of liver function, which sometimes removes the need for transplantation, although more objective criteria for removal from waiting lists are required. After liver transplantation, the combination of HBV immunoglobulin and one nucleos(t)ide analogue, mostly lamivudine, is currently the best approach, almost eliminating the probability of HBV recurrence. Treatment of post-transplant HBV recurrence has been mainly studied with lamivudine, but it will be most effective with entecavir and tenofovir, which have a low risk of resistance. In conclusion, the newer anti-HBV agents improve the treatment of HBV both pretransplant and post-transplant. HBV immunoglobulin is still used in combination with an anti-HBV agent for post-transplant prophylaxis. Monoprophylaxis with one of the new anti-HBV agents might be possible, particularly in patients preselected as having a low risk of HBV recurrence, but further data are needed and strategies to ensure compliance must be used.
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Affiliation(s)
- George V Papatheodoridis
- 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, 114 Vas. Sophias avenue, Athens, Greece.
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Almeida AM, Silva DID, Guerra Jr AA, Silva GD, Acurcio FDA. Revisão sistemática da eficácia do interferon alfa (convencional, peguilado) e lamivudina para o tratamento da hepatite crônica B. CAD SAUDE PUBLICA 2009; 25:1667-77. [PMID: 19649408 DOI: 10.1590/s0102-311x2009000800003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A hepatite crônica B constitui um grave problema de saúde pública e vem demonstrando crescentes gastos com financiamento de medicamentos de dispensação em caráter excepcional e de alto custo no Sistema Único de Saúde (SUS). O objetivo do estudo foi comparar a eficácia do interferon (convencional; peguilado - PEG2a) e lamivudina (LAM) para o tratamento da hepatite crônica B, pelo método de revisão sistemática selecionando ensaios clínicos randomizados e controlados identificados nas bases PubMed e LILACS. As medidas de resultado consideradas foram resposta virológica, soroconversão, resposta bioquímica, resposta histológica e efeitos adversos. Foram selecionados 35 artigos. A presença ou ausência do HBeAg e os níveis de alanina amino transferase (ALT) no pré-tratamento demonstraram papel fundamental na indicação terapêutica inicial. O tratamento com interferons convencionais permite a inativação da doença por longos períodos de tempo, podendo resultar em soroconversão HBsAg. O PEG 2a demonstrou eficácia superior ao interferon e LAM e efeitos colaterais semelhantes ao interferon. A LAM apresenta vantagem de ser sensível para os pacientes HBeAg negativo e apresenta como maior desvantagem o desenvolvimento de resistência.
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Post-liver transplant hepatitis B prophylaxis: the role of oral nucleos(t)ide analogues. Curr Opin Organ Transplant 2009; 14:225-30. [PMID: 19373086 DOI: 10.1097/mot.0b013e32832b1f32] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW The established gold standard for prophylaxis against hepatitis B virus (HBV) recurrence post-liver transplant is combination hepatitis B immune globulin (HBIG) and lamivudine. This therapy reduces the risk of recurrence to less than 5% at 5 years; however, the cost of HBIG has led to the investigation of alternatives. This paper reviews the HBIG-sparing alternatives achieved with lamivudine and the prospects for the newer anti-HBV agents in post-liver transplant prophylaxis. RECENT FINDINGS When used with lamivudine as part of combination prophylaxis, low-dose intramuscular HBIG is equivalent to high-dose intravenous HBIG. There is recent evidence that in patients receiving HBIG/lamivudine, HBIG can be replaced with adefovir dipivoxil at 6-12 months post-liver transplant without precipitating recurrence. Furthermore, a recent study showed that primary prophylaxis with combination adefovir/lamivudine therapy without the use of long-term HBIG was effective and well tolerated as primary prophylaxis. SUMMARY Although there are few studies of potent newer anti-HBV agents such as entecavir or tenofovir being used as HBV prophylaxis, the properties of these drugs suggest that they should replace lamivudine within HBV prophylaxis regimes.
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Jiang L, Jiang LS, Cheng NS, Yan LN. Current prophylactic strategies against hepatitis B virus recurrence after liver transplantation. World J Gastroenterol 2009; 15:2489-99. [PMID: 19468999 PMCID: PMC2686907 DOI: 10.3748/wjg.15.2489] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Prophylactic strategies against hepatitis B virus (HBV) recurrence after liver transplantation (LT) are essential for patients with HBV-related disease. Before LT, lamivudine (LAM) was proposed to be down-graded from first- to second-line therapy. In contrast, adefovir dipivoxil (ADV) has been approved not only as first-line therapy but also as rescue therapy for patients with LAM resistance. Furthermore, combination of ADV and LAM may result in lower risk of ADV resistance than ADV monotherapy. Other new drugs such as entecavir, telbivudine and tenofovir, are probably candidates for the treatment of hepatitis-B-surface-antigen-positive patients awaiting LT. After LT, low-dose intramuscular hepatitis B immunoglobulin (HBIG), in combination with LAM, has been regarded as the most cost-effective regimen for the prevention of post-transplant HBV recurrence in recipients without pretransplant LAM resistance and rapidly accepted in many transplant centers. With the introduction of new antiviral drugs, new hepatitis B vaccine and its new adjuvants, post-transplant HBIG-free therapeutic regimens with new oral antiviral drug combinations or active HBV vaccination combined with adjuvants will be promising, particularly in those patients with low risk of HBV recurrence.
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Abstract
Combination therapy with hepatitis B immunoglobulin (HBIG) plus nucleos(t)ide analogue have reduced the rate of hepatitis B virus (HBV) recurrence post-transplantation to less than 10% at long-term. HBV recurrence diagnosed after 3 years post-transplantation is extremely rare. Considering the cost and the constraints of HBV prophylaxis it was suggested to decrease the amount of HBIG given and possibly to discontinue HBIG administration. The additional debate was on the need to maintain or not any HBV prophylaxis at long-term or to maintain monoprophylaxis with one or two nucleos(t)ide analogues or to administer HBV vaccine: The supporters of this strategy argued that HBV recurrence can be easily controlled by administration of nucleos(t)ide analogues. However, it was shown that 50-80% of patients maintain HBV DNA in the liver, serum or peripheral mononuclear blood cells long-term after transplantation. In patients receiving monoprophylaxis with nucleos(t)ide analogues the risk of HBV reinfection increases with time due to HBV mutant strains. Vaccine protocols used to replace HBIG prophylaxis gave disappointing results. Combination protocols using low-doses of intramuscular HBIG plus nucleos(t)ide analogues have been associated with a low rate of HBV reinfection. In conclusion, long-term prophylaxis should be maintained in most patients except those with anti-HBs seroconversion.
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Affiliation(s)
- D Samuel
- Inserm, Unité 785, Villejuif, F-94804, France.
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Luo Y, Lo CM, Cheung CK, Lau GK, Wong J. Hepatitis B virus-specific CD4 T cell immunity after liver transplantation for chronic hepatitis B. Liver Transpl 2009; 15:292-9. [PMID: 19243002 DOI: 10.1002/lt.21674] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cellular immunity plays an important role in the long-term control of hepatitis B virus (HBV) infection. We studied the changes in HBV-specific CD4 T cell immunity after orthotopic liver transplantation (OLT) for chronic hepatitis B under antiviral prophylaxis. T cell proliferation and interferon-gamma production in response to in vitro challenge with HBV-encoded antigens were tested in 40 OLT recipients without HBV recurrence and in 12 OLT recipients with HBV recurrence more than 1 year after transplantation, and they were compared to 40 subjects with chronic HBV infection and to 23 subjects with self-limited HBV infection. The frequency and magnitude of the HBV-specific CD4 T cell response were significantly lower in 40 OLT recipients with HBV clearance, but the T cell reactivity to mitogen (phytohemagglutinin) and recall antigen (tetanus toxoid) was maintained. In the 12 OLT recipients with HBV recurrence, however, the HBV-specific T cell immunity was enhanced to a level comparable to that of patients with chronic hepatitis B, and the level was dependent on the serum viral load. In conclusion, HBV-specific CD4 T cell immunity is antigen-driven and evanesces with viral clearance, hence providing a favorable milieu for reactivation once prophylaxis is withdrawn. The cellular immunity in recipients with recurrence is not significantly different from that of individuals with chronic hepatitis B.
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Affiliation(s)
- Ying Luo
- Department of Hepatobiliary Surgery, General Hospital of PLA, Beijing, China
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Yin MT, Brust JCM, Tieu HV, Hammer SM. Antiherpesvirus, Anti?Hepatitis Virus, and Anti?Respiratory Virus Agents. CLINICAL VIROLOGY 2009:217-264. [DOI: 10.1128/9781555815981.ch12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Beckebaum S, Sotiropoulos GC, Gerken G, Cicinnati VR. Hepatitis B and liver transplantation: 2008 update. Rev Med Virol 2009; 19:7-29. [DOI: 10.1002/rmv.595] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Roche B, Samuel D. Liver transplantation in viral hepatitis: prevention of recurrence. Best Pract Res Clin Gastroenterol 2008; 22:1153-69. [PMID: 19187873 DOI: 10.1016/j.bpg.2008.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
End-stage liver disease caused by the hepatitis B and C viruses (HBV and HCV) are major indications for liver transplantation. Outcome depends largely on the prevention of allograft reinfection. The advent of long-term hepatitis B immune globulin administration and the introduction of new antiviral agents were a major breakthrough in the management of these patients. Today, survival after orthotopic liver transplantation (OLT) is similar to that of patients transplanted for HBsAg-negative liver disease, and the risk of recurrence is below 10%. In contrast, HCV reinfection is almost constant and significantly impairs patient and graft survival. Factors that may influence disease severity and consequently progression of HCV graft injury remain unclear. Pre-transplantation and prophylactic post-transplantation antiviral treatments are limited by low applicability and poor tolerance. Treatment of established graft lesions with combination therapy gave promising results, with sustained virological response in 25-45% of patients, but indications, modality and duration of treatment should be assessed.
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Affiliation(s)
- Bruno Roche
- Assistance Publique-Hopitaux de Paris, Hopital Paul Brousse, Centre Hepato-Biliaire, Villejuif, France
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Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology 2008; 48:1460-6. [PMID: 18925641 DOI: 10.1002/hep.22524] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
UNLABELLED Prior to effective prophylaxis, liver transplantation for hepatitis B virus (HBV)-related disease was frequently complicated by recurrence, which could be severe and rapidly progressive. Combination hepatitis B immunoglobulin (HBIG) and lamivudine prophylaxis reduces this rate of recurrence to <5% at 5 years; however, HBIG administration is costly and inconvenient. We conducted a multicenter randomized study of adefovir dipivoxil substitution for low-dose intramuscular (IM) HBIG in patients without HBV recurrence at least 12 months posttransplantation for HBV-related disease. Thirty-four patients were randomized, 16 to adefovir (1 patient withdrew consent at 3 months and is not considered in the results) and 18 to continue HBIG. All continued lamivudine. Groups were well matched by age, sex, and time since transplantation (median, 4.5 years), and background virological risk for HBV recurrence (30% of patients in the adefovir group, 24% in the HBIG group having detectable HBV DNA at transplantation). All patients were alive at study completion without recurrence. One patient in the adefovir group became hepatitis B surface antigen-positive at 5 months but was persistently HBV DNA undetectable via polymerase chain reaction (sensitivity 14 IU/mL) over the following 20 months. Median creatinine was not significantly changed over the course of the study in either group. One patient in the adefovir group with a background of diabetic and hypertensive nephropathy (baseline creatinine 150 micromol/L) developed increased creatinine leading to dose reduction and ultimately cessation of adefovir at 15 months. Yearly cost of combination adefovir/lamivudine prophylaxis was $8,290 versus $13,718 IM HBIG/lamivudine. CONCLUSION Compared with combination HBIG plus lamivudine prophylaxis, combination adefovir plus lamivudine provides equivalent protection against recurrent HBV infection but with better tolerability and less cost.
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Affiliation(s)
- Peter W Angus
- Victorian Liver Transplant Unit, Austin Health, Victoria, Australia.
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Akay S, Karasu Z. Hepatitis B immune globulin and HBV-related liver transplantation. Expert Opin Biol Ther 2008; 8:1815-22. [DOI: 10.1517/14712598.8.11.1815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Abstract
Liver transplantation for hepatitis B represents 5-10 % of all liver transplantations performed in Europe. The prognosis after liver transplantation is related to the efficacy of prophylaxis of HBV graft reinfection. The risk of HBV reinfection is directly related to the HBV viral load at transplantation. HBV prophylaxis after transplantation with long-term administration of anti-HBS immune globulins (HBIG) or with monoprophylaxis with lamivudine can reduce significantly the risk of HBV recurrence mainly in patients without active HBV replication. Antivirals such as lamivudine, adefovir, entecavir or tenofovir can control HBV replication in patients with decompensated HBV cirrhosis waiting for transplantation. However, there is a risk of HBV viral breakthrough during nucleo (t) side antiviral treatment. The use of an antiviral alone or in combination should take into account the antiviral efficacy and the risk of viral resistance. The post-transplant combination of antiviral therapy and HBIG prophylaxis is very effective in reducing the rate of HBV reinfection to less than 10 % even in patients with HBV replication at transplantation. In the absence of active viral replication at transplantation, the possibilty to discontinue HBIG prophylaxis at long-term after transplantation with maintenance of antiviral treatment or HBV vaccination is in evaluation. The use of new antiviral therapies (nucleos(t)ide analogues) has dramatically improved the prognosis of patients with HBV reinfection of the graft. The current 5-year survival after liver transplantation for HBV related liver disease is 85 %. In conclusion, the prophylaxis of HBV reinfection combining antiviral therapy prior to transplantation, and combination of HBIG and antiviral therapy post-transplantation is effective in reducing the rate of HBV reinfection to less than 10 %.
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Liver Transplantation for Hepatitis B Virus Patients: Long-Term Results of Three Therapeutic Approaches. Transplant Proc 2008; 40:1961-4. [DOI: 10.1016/j.transproceed.2008.05.071] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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