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1
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Perrillo R, Garrido LF, Ma TW, Rahimi R, Lilly B. Vaccination with HepB-CpG vaccine in individuals undergoing immune suppressive drug therapy. Vaccine 2023:S0264-410X(23)00716-8. [PMID: 37353450 DOI: 10.1016/j.vaccine.2023.06.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/06/2023] [Accepted: 06/11/2023] [Indexed: 06/25/2023]
Abstract
BACKGROUND Immunosuppressed patients are a targeted group for HBV vaccination but suboptimal antibody responses occur when traditional recombinant vaccines are used. METHODS We tested an FDA approved immune adjuvanted HBV vaccine (HEPLISAV--B® or HepB-CpG) in medically immune suppressed individuals. HepB-CpG was given to 10 patients taking biologic agents or anti-rejection therapy. Each received vaccine at time 0 and week 4 with a third dose at week 12 if anti-HBs remained less than 10 mIU/mL. RESULTS Seroprotective anti-HBs developed in 70 % of participants by week 24. Those taking biologic agents responded more rapidly and a third dose was generally needed in those transplanted. By week 24, most taking biologics but only 2 of 6 on anti-rejection treatment had antibody levels exceeding 100 mIU/mL. CONCLUSIONS Seroprotective anti-HBs developed in 70 % with HepB-CpG. Antibody responses were more rapid in those taking biologic agents but a third dose improved antibody responses in transplanted participants.
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Affiliation(s)
- Robert Perrillo
- Hepatology Division, Baylor Scott and White Medical Center, Dallas, TX, United States.
| | - Luis Felipe Garrido
- Hepatology Division, Baylor Scott and White Medical Center, Dallas, TX, United States
| | - Tsung-Wei Ma
- Baylor Scott and White Research Institute, United States
| | - Robert Rahimi
- Hepatology Division, Baylor Scott and White Medical Center, Dallas, TX, United States
| | - Barbara Lilly
- Baylor Scott and White Research Institute, United States
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2
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Battistella S, Zanetto A, Gambato M, Germani G, Senzolo M, Burra P, Russo FP. The Role of Antiviral Prophylaxis in Preventing HBV and HDV Recurrence in the Setting of Liver Transplantation. Viruses 2023; 15:1037. [PMID: 37243124 PMCID: PMC10224456 DOI: 10.3390/v15051037] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/15/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Hepatitis B virus (HBV) is a prevalent underlying disease, leading to liver transplantation (LT) for both decompensated cirrhosis and hepatocellular carcinoma (HCC). The hepatitis delta virus (HDV) affects approximately 5-10% of HBsAg carriers, accelerating the progression of liver injury and HCC. The initial introduction of HBV immunoglobulins (HBIG), and then of nucleos(t)ide analogues (NUCs), considerably improved the survival of HBV/HDV patients post-transplantation, as they helped prevent re-infection of the graft and recurrence of liver disease. Combination therapy with HBIG and NUCs is the primary post-transplant prophylaxis strategy in patients transplanted for HBV- and HDV-related liver disease. However, monotherapy with high-barrier NUCs, such as entecavir and tenofovir, is safe and also effective in some individuals who are at low risk of HBV reactivation. To address the problems of organ shortage, last-generation NUCs have facilitated the use of anti-HBc and HBsAg-positive grafts to meet the ever-increasing demand for grafts.
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Affiliation(s)
- Sara Battistella
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 35128 Padova, Italy
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 35128 Padova, Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
| | - Giacomo Germani
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (S.B.); (A.Z.); (M.G.); (M.S.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 35128 Padova, Italy
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Jacobson IM, Brown RS, McMahon BJ, Perrillo RP, Gish R. An Evidence-based Practical Guide to Vaccination for Hepatitis B Virus. J Clin Gastroenterol 2022; 56:478-492. [PMID: 35389923 DOI: 10.1097/mcg.0000000000001695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
The hepatitis B virus (HBV) is highly infectious, with over 292 million chronically infected people worldwide and up to 2.4 million in the United States. Following infection, clinically silent liver damage can ensue, but symptoms or signs of advanced disease, including cirrhosis and hepatocellular carcinoma, can take decades to emerge. HBV has the heaviest public health burden of all hepatitis viruses and has now surpassed other major communicable diseases (eg, HIV, diarrheal disease, malaria, tuberculosis) as a leading cause of death globally. Preventing transmission is essential, and efforts are in place to reinforce screening, vaccination, and routine follow-up. Three safe and effective vaccines are available in the United States and other countries for HBV prevention, and the benefits of vaccination in preventing infection and its sequelae have been substantiated. For the first time in over 25 years, a new Food and Drug Administration-approved vaccine is available that offers a high degree of immunogenicity after 2, rather than 3, injections. Persistent challenges include the underutilization of vaccination, choice of vaccine, incomplete vaccinations, varying needs in different populations, management of nonresponders or those with undocumented or incompletely documented vaccination courses, and questions about whether and when booster injections may be needed. A panel of US academic hepatologists with expertise and experience in preventing and managing HBV infection have collaborated to write this practical clinical paper intended to guide clinicians in vaccinating for HBV and address questions that regularly arise in the clinic.
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Affiliation(s)
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY
| | - Brian J McMahon
- University of Washington, Seattle, WA
- University of Alaska
- Alaska Native Tribal Health Consortium, Anchorage, AK
| | - Robert P Perrillo
- Hepatology Division, Baylor Scott and White Medical Center, University of Texas Southwestern, Dallas, TX
| | - Robert Gish
- Loma Linda University, Loma Linda
- UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA
- University of Nevada Las Vegas and Reno Schools of Medicine, Las Vegas, NV
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4
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Jo HS, Khan JF, Han JH, Yu YD, Kim DS. Efficacy and Safety of Hepatitis B Virus Vaccination Following Hepatitis B Immunoglobulin Withdrawal After Liver Transplantation. Transplant Proc 2021; 53:3016-3021. [PMID: 34740450 DOI: 10.1016/j.transproceed.2021.09.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/24/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND Hepatitis B immunoglobulin (HBIG) and oral nucleoside/nucleotide analogs have been the mainstay of hepatitis B virus (HBV) prophylaxis after liver transplantation. However, long-term HBIG administration could have disadvantages, such as an increase in medical costs and the development of mutant HBV strains. This study aimed to investigate the safety and efficacy of HBV vaccination after the withdrawal of HBIG after liver transplantation. METHODS This prospective open-label single-arm observational clinical trial enrolled 41 patients who underwent liver transplantation between 2010 and 2016 because of a condition related to chronic HBV infection. At the time of enrollment, all patients had taken entecavir and discontinued HBIG administration. When hepatitis B surface antibody titer was undetectable after the withdrawal of HBIG, a recombinant HBV vaccine was injected intramuscularly at month 0, 1, and 6. RESULTS After excluding 5 patients who dropped out and 2 patients who had a persistent hepatitis B surface antibody titer, 9 (26.5%) of 34 patients had a positive vaccination response. The median hepatitis B surface antibody titer at seroconversion was 86 (12-1000) IU/L, and those at the end of follow-up were 216 (30-1000) IU/L. No patients experienced HBV recurrence during the study period. Sex (female, odds ratio 32.91 [1.83-592.54], P = .018) and the dosing interval of HBIG before withdrawal (≥90 days, 16.21 [1.21-217.31], P = .035) were independent contributing factors for positive response to the vaccination. CONCLUSION HBV vaccination still deserves consideration as active immunoprophylaxis after liver transplantation because it could provide added immunity to nucleoside/nucleotide analogs monotherapy with excellent cost-effectiveness.
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Affiliation(s)
- Hye-Sung Jo
- Division of Hepatobiliarypancreas (HBP) Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Johann Faizal Khan
- Division of Hepatobiliarypancreas (HBP) Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea; Department of Hepatobiliary Surgery and Liver Transplantation, Hospital Selayang, Selangor, Malaysia
| | - Jae Hyun Han
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young-Dong Yu
- Division of Hepatobiliarypancreas (HBP) Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Dong-Sik Kim
- Division of Hepatobiliarypancreas (HBP) Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea.
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Duvoux C, Belli LS, Fung J, Angelico M, Buti M, Coilly A, Cortesi P, Durand F, Féray C, Fondevila C, Lebray P, Martini S, Nevens F, Polak WG, Rizzetto M, Volpes R, Zoulim F, Samuel D, Berenguer M. 2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation. Aliment Pharmacol Ther 2021; 54:583-605. [PMID: 34287994 DOI: 10.1111/apt.16374] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/25/2020] [Accepted: 04/01/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Prophylaxis of HBV recurrence is critical after liver transplantation in HBV patients. Despite new prophylactic schemes, most European LT centres persist on a conservative approach combining hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogues (NA). AIM This setting prompted the European Liver Intestine Transplantation Association (ELITA) to look for a consensus on the prevention of HBV recurrence. METHODS Based on a 4-round Delphi process, ELITA investigated 16 research questions and established 50 recommendations. RESULTS Prophylaxis should be driven according to 3 simplified risk groups: Low and high virological risk patients, with undetectable and detectable HBV DNA pre-LT, respectively, and special populations (HDV, HCC, poorly adherent patients). In low-risk patients, short-term (4 weeks) combination of third-generation NA+ HBIG, or third generation NA monotherapy can be considered as prophylactic options. In high-risk patients, HBIG can be discontinued once HBV DNA undetectable. Combined therapy for 1 year is advised. HBV-HCC patients should be treated according to their virological risk. In HDV/HBV patients, indefinite dual prophylaxis remains the gold standard. Full withdrawal of HBV prophylaxis following or not HBV vaccination should only be attempted in the setting of clinical trials. Organs from HBsAg+ve donors may be considered after assessment of risks, benefits, and patient consent. They should not be used if HDV is present. In poorly adherent patients, dual long-term prophylaxis is recommended. Budget impact analysis should be taken into account to drive prophylactic regimen. CONCLUSIONS These ELITA recommendations should stimulate a more rational and homogeneous approach to HBV prophylaxis across LT programs.
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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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7
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Lenci I, Milana M, Grassi G, Manzia TM, Gazia C, Tisone G, Angelico R, Baiocchi L. Hepatitis B virus recurrence after liver transplantation: An old tale or a clear and present danger? World J Gastroenterol 2020; 26:2166-2176. [PMID: 32476783 PMCID: PMC7235198 DOI: 10.3748/wjg.v26.i18.2166] [Citation(s) in RCA: 9] [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: 02/11/2020] [Revised: 03/12/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) recurrence after liver transplantation (LT) has been described more than 50 years ago. Similarly, to other clinical conditions, in which impairment of host immune defense favors viral replication, early reports described in details recurrence and reactivation of HBV in liver transplant recipients. The evidence of a possible, severe, clinical evolution of HBV reappearance in a significant percentage of these patients, allowed to consider, for some years, HBV positivity a contraindication for LT. Moving from the old to the new millennium this picture has changed dramatically. Several studies contributed to establish efficient prophylactic protocols for HBV recurrence and with the advent of more potent anti-viral drugs an increased control of infection was achieved in transplanted patients as well as in the general immune-competent HBV population. Success obtained in the last decade led some authors to the conclusion that HBV is now to consider just as a "mere nuisance". However, with regard to HBV and LT, outstanding issues are still on the table: (1) A standard HBV prophylaxis protocol after transplant has not yet been clearly defined; (2) The evidence of HBV resistant strains to the most potent antiviral agents is claiming for a new generation of drugs; and (3) The possibility of prophylaxis withdrawal in some patients has been demonstrated, but reliable methods for their selection are still lacking. The evolution of LT for HBV is examined in detail in this review together with the description of the strategies adopted to prevent HBV recurrence and their pros and cons.
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Affiliation(s)
- Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Giuseppe Grassi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Tommaso M Manzia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Carlo Gazia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Giuseppe Tisone
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Roberta Angelico
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
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Rodrigues IC, Ferreira da Silva R, de Cássia Martins Alves da Silva R, Camarero de Felício HC. Effectiveness Analysis of the Immunization Against Hepatitis B in Liver Transplantation Patients. Transplant Proc 2020; 52:1365-1369. [PMID: 32199649 DOI: 10.1016/j.transproceed.2019.12.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 12/06/2019] [Indexed: 12/01/2022]
Abstract
OBJECTIVE This article analyzes the effectiveness of a super-accelerated immunization schedule against hepatitis B in patients who have received a liver transplantation. METHODS This is a quantitative and retrospective study based on secondary data of medical records from 177 patients who have received a liver transplantation at the Hospital de Base in São José do Rio Preto, São Paulo State, Brazil, between 1998 and 2016. RESULTS From the total number of participants, 72.89% were male, 39.55% had a cirrhosis diagnosis with associated causes, 23.16% had hepatocellular carcinoma, 53.11% were classified according to Child-Turcotte-Pugh C score, 58.76% had the hepatitis C virus, 97.18% had received an unconventional immunization schedule, and seroconversion was 36.63% among those with an unconventional schedule. The fact that the patient had the hepatitis C virus was statistically significant considering the lack of protection of the vaccine against the hepatitis B virus; their chances were 5 times higher of not seroconverting at the end of the immunization schedule. CONCLUSION The need for high immediate protection in a short term may justify using unconventional immunization schedules in patients who make it to the transplantation waiting list without any previous immunization.
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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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Vatansever S, Farajov R, Yılmaz HC, Zeytunlu M, Kılıç M. The efficiency of low-dose hepatitis B immunoglobulin plus nucleos(t)ide analogs in preventing posttransplant hepatitis B virus recurrence. Turk J Med Sci 2019; 49:1019-1024. [PMID: 31385669 PMCID: PMC7018359 DOI: 10.3906/sag-1808-86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Background/aim In this study, the efficiency of using low-dose hepatitis B immunoglobulin (HBIG) plus antiviral treatment according to individual needs has been evaluated in posttransplant hepatitis B virus (HBV) patients. Materials and methods We retrospectively evaluated 179 patients who were admitted between 2009 and 2014. Five thousand IU intravenous HBIG was given in the anhepatic phase, and 400 IU/day intramuscular (IM) HBIG was given in the posttransplant period. After HBsAg seroconversion, 400 IU IM HBIG was continued as prophylaxis every two weeks. Results The average follow-up period was 26 (2–65) months. Seventy patients had hepatocellular carcinoma (HCC). The HBV recurrence was 4.5% in the first year, and 5.8% in the third year. The HBsAg became negative in 11 (2–63) days, and anti-HBs became positive in 9 (1–31) days. HBsAg positivity occurred in 6 patients during the follow-up period. Five of these patients were those who underwent transplantation due to HCC. In 5 of the HCC patients, in whom HBsAg became positive, tumor recurrence was observed after 0.3–9.9 months. HBsAg positivity was more frequently detected in patients with HCC (P = 0.009). Conclusion The HBV recurrence should be evaluated as a predictor of the HCC recurrence in patients who were transplanted due to HCC.
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Affiliation(s)
- Sezgin Vatansever
- Department of Gastroenterology, Atatürk Training and Research Hospital, İzmir Katip Çelebi University, İzmir, Turkey
| | - Rasim Farajov
- Department of Liver Transplantation, Kent Hospital, İzmir, Turkey
| | | | - Murat Zeytunlu
- Department of Liver Transplantation, Kent Hospital, İzmir, Turkey
| | - Murat Kılıç
- Department of Liver Transplantation, Kent Hospital, İzmir, Turkey
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Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498919 DOI: 10.1007/978-94-024-1603-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the principles of antiviral therapy, treatment strategies, medications and recommendations for AECHB, HBV-ACLF, HBV-related liver cirrhosis, HBV-related HCC, and liver transplantation.
Severe exacerbation of chronic hepatitis B is closely related to continuous HBV replication. Therefore, inhibiting HBV replication to reduce viral load may block disease progression and improve the quality of life of these patients. ETV or TDF has been recommend first-line drug for the treatment of AECHB. A hyperactive immune response due to continuous HBV replication is the main mechanism for development of severe hepatitis B. In addition to comprehensive treatment, early administration of potent nucleoside analogs can rapidly reduce HBV DNA concentration, relieve immune injury induced by HBV, and reduce liver inflammation and patient mortality. Antiviral agents have become important in the treatment of severe exacerbation of chronic hepatitis B. Long-term antiviral treatment with nucleoside analogs can delay or reverse the progress of liver cirrhosis. Virologic response, viral resistance and adverse drug reactions should be closely monitored during treatment. The treatment should be optimized for maximum effect based on each patient’s responses. Effective antiviral therapy can suppress HBV replication and reduce the incidence of HBV-related HCC. Patients with HBV-related HCC should receive individualized and optimal multidisciplinary comprehensive treatment. Anti-viral drugs with high efficacy, low resistance and low adverse drug reactions should be selected to improve the patient’s quality of life and prolong survival time. Methods to prevent HBV reinfection after liver transplantation include passive immunization (HBIG), antiviral treatment (nucleoside analogs) and active immunization (hepatitis B vaccine). Clinical trials involving sequential combination therapy with NUC and Peg-IFN have shown statistically significant decline in HBsAg levels on treatment and high rates of sustained post-treatment serologic response. Combination therapy with novel DAA and immunotherapeutic approach may hold promise to overcome both cccDNA persistence and immune escape, representing a critical step towards HBV cure.
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12
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Wong TCL, Fung JYY, Chok KSH, Cheung TT, Chan ACY, Dai WC, Ng KKC, Chan SC, Lo CM. Hepatitis B Vaccination in Patients Receiving Oral Antiviral Therapy Without Hepatitis B Immunoglobulin After Liver Transplant. Transplant Proc 2018; 50:3681-3688. [PMID: 30577255 DOI: 10.1016/j.transproceed.2018.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 06/22/2018] [Accepted: 07/04/2018] [Indexed: 02/08/2023]
Abstract
UNLABELLED Our study aimed to determine if a double-dose pre-S containing hepatitis B virus (HBV) vaccination (Sci-B-Vac) could elicit an adequate and sustainable immune response in HBV patients who developed spontaneous hepatitis B surface antibody (anti-HBs) response after liver transplant. PATIENTS AND METHODS All patients who received transplants for HBV-related disease for >1 year with normal graft function and hepatitis B surface antigen seronegativity were evaluated. They received a 40-μg HBV vaccine if they were responders in our previous vaccine trial, if anti-HBs was positive for >1 year after liver transplant (LT), or if a peak anti-HBs at any time point after LT was >100 mIU/mL. Primary endpoint was the development of anti-HBs ≥ 10 mIU/mL from previous negative value or a 1-log increase from baseline. RESULTS A total of 86 patients were recruited; 5 were responders from a previous trial; 45 patients had detectable anti-HBs >1 year after LT, and 36 patients had an anti-HBs >100 mIU/mL. All (5/5, 100%) previous responders responded to booster vaccination. For the remaining 81 patients, 10 of 81 (12.3%) responded. CONCLUSION All previous responders responded to booster vaccination, implying durability and memory of HBV immune response, which is an important prerequisite for definitive host immunity for HBV. In patients who had spontaneous anti-HBs production after LT, a single vaccination can induce response in 12.3% of patients.
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Affiliation(s)
- T C L Wong
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - J Y Y Fung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - K S H Chok
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - T T Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - A C Y Chan
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - W C Dai
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - K K C Ng
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - S C Chan
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - C M Lo
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
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13
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Lens S, García-Eliz M, Fernández I, Castells L, Bonacci M, Mas A, Crespo G, Buti M, Prieto M, Forns X. Shorter hepatitis B immunoglobulin administration is not associated to hepatitis B virus recurrence when receiving combined prophylaxis after liver transplantation. Liver Int 2018; 38:1940-1950. [PMID: 29660249 DOI: 10.1111/liv.13858] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 03/29/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The combination of hepatitis B immunoglobulin and a nucleos(t)ide analogues has markedly reduced the rate of hepatitis B virus recurrence after liver transplantation; however, the optimal duration of hepatitis B immunoglobulin has not been clarified. This lack of consensus perpetuates the use of different strategies. The aim of this study was to evaluate the risk factors associated to hepatitis B virus recurrence after liver transplantation in a large cohort of patients under different hepatitis B immunoglobulin regimens. METHODS Retrospective multicentre analysis of hepatitis B virus-related liver transplantation recipients receiving combined prophylaxis (hepatitis B immunoglobulin + nucleos(t)ide analogues). The strategy of short-term hepatitis B immunoglobulin was compared to lifelong administration. Hepatitis B virus recurrence was defined as positive HBsAg after liver transplantation. RESULTS Three hundred and thirty-eight patients were analysed. After a median follow-up period of 72 months, 37 patients (11%) developed hepatitis B virus recurrence. Hepatocellular carcinoma recurrence and lamivudine resistance after liver transplantation were the only factors independently associated to hepatitis B virus recurrence (HR 5.4 [2.3-12] and 9.3 [4.2-20] respectively P < .001). HBsAg reappearance after hepatitis B virus recurrence was transient (16 patients), persistent (15) or alternant (6). The hepatitis B immunoglobulin regimen did not have an impact on the rate or evolution of hepatitis B virus recurrence. Overall, patient survival was good and not influenced by hepatitis B virus recurrence (82% at 5 years). Fulminant liver failure, hepatitis C coinfection or hepatocellular carcinoma at liver transplantation were independent risk factors for lower survival. CONCLUSIONS Liver transplantation is an effective treatment for hepatitis B virus-related liver disease. Since the introduction of combined prophylaxis the rate of hepatitis B virus recurrence is very low. However, lifelong hepatitis B immunoglobulin administration does not seem necessary to reduce hepatitis B virus recurrence.
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Affiliation(s)
- Sabela Lens
- Liver Unit, Hospital Clínic, IDIBAPS and CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | | | | | - Lluis Castells
- Internal Medicine, Hepatology Section, Hospital Vall Hebron, CIBERehd, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Martin Bonacci
- Liver Unit, Hospital Clínic, IDIBAPS and CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Antoni Mas
- Liver Unit, Hospital Clínic, IDIBAPS and CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Gonzalo Crespo
- Liver Unit, Hospital Clínic, IDIBAPS and CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - María Buti
- Internal Medicine, Hepatology Section, Hospital Vall Hebron, CIBERehd, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Martín Prieto
- Liver Unit, CIBERehd, Hospital La Fe, Valencia, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, IDIBAPS and CIBERehd, Universitat de Barcelona, Barcelona, Spain
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14
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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15
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Active immunization in patients transplanted for hepatitis B virus related liver diseases: A prospective study. PLoS One 2017; 12:e0188190. [PMID: 29145470 PMCID: PMC5690662 DOI: 10.1371/journal.pone.0188190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 10/29/2017] [Indexed: 02/07/2023] Open
Abstract
Introduction Prophylactic administration of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs) is the standard treatment for controlling hepatitis B virus (HBV) recurrence after liver transplantation (LT). Since lifelong use of HBIG is expensive and inconvenient and the antibodies level in anti-hepatitis B surface (HBs) is not sustainable and stable, an alternative strategy is to produce anti-HBs antibodies by active immunization. Our present study aimed to prospectively investigate the efficacy and safety of procedural HBV vaccination in transplanted patients. Methods Recipients who had undergone LT for hepatitis B related liver diseases more than one year before, with no evidence of HBV recurrence or rejection and normal liver function were enrolled. All subjects received the hepatitis B vaccine (40 μg) by intramuscular injection at months 0, 1, 2, 6 and 12 after enrollment with continuous administration of NAs. The liver function and anti-HBs titers were measured before each vaccination and HBIG (400U) was administrated intramuscularly when anti-HBs titer was lower than 30 IU/L during the course. The results of routine blood tests, liver function, concentration of immunosuppressant, and HBV-DNA copies were monitored during the research. After completion of the vaccination procedure, recipients were regarded as responders if their anti-HBs greater than 30 IU/L were maintained for up to six months without using HBIG and vaccine. Results Twenty-seven patients were enrolled in this study and the average anti-HBs titer before vaccination was 19.86±14.80 IU/L. The average anti-HBs titer of the nine responders at the end of the follow-up was 57.14±22.75 IU/L, giving an overall response rate of 33.3% (9/27). There were no reports of reactivation of HBV, rejection, severe anaphylaxis or other adverse events. Responders and non-responders showed their significant difference in anti-HBs titers after the fourth vaccination (P<0.01). Moreover, the majority of non-responders (11/18, 63.64%) had high LY/EO rates (lymphocyte number/eosinophil number>15) while most responders (8/9, 88.89%) had low LY/EO rates at the beginning of vaccination (P = 0.019). Conclusions Active immunization is an effective, cost-saving, and safe method for the prevention of HBV reactivation in patients transplanted for hepatitis B virus related liver diseases. The LY/EO rate may be a valuable indicator in selecting potential recipients for vaccination.
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Aggeletopoulou I, Davoulou P, Konstantakis C, Thomopoulos K, Triantos C. Response to hepatitis B vaccination in patients with liver cirrhosis. Rev Med Virol 2017; 27. [PMID: 28905444 DOI: 10.1002/rmv.1942] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 08/11/2017] [Accepted: 08/14/2017] [Indexed: 12/16/2022]
Abstract
Hepatitis B vaccination is strongly recommended for all infants and children but also for adults who are at risk of HBV infection. Attempts to immunize patients with liver cirrhosis have been proven relatively ineffective, and several strategies have already been used to improve the immune response in this group. The primary aim of this review is to examine, discuss, and summarize the immunogenicity of hepatitis B vaccination in patients with liver cirrhosis. MEDLINE search identified 11 studies (n = 961). The dose of the vaccine and the schedule of the vaccination varied. The response rates to the HBV vaccination ranged from 16% to 87% among patients with cirrhosis regardless of the number and vaccine dose. In particular, patients who received the standard dose of vaccination achieved seroprotection rates ranged from 16% to 79% (mean response rate 38%) and those who received a double dose achieved relatively better seroprotection rates (range: 26%-87%; mean response rate 53%). The overall mean response rate to the HBV vaccination was 47%. In conclusion, cirrhotic patients achieve lower seroprotection rates after the completion of HBV vaccination series. Several strategies have tried to improve the immunogenicity; however, there is a great need for additional studies to further explore (1) the immune response in relation to poor vaccination responsiveness confounding factors, (2) novel strategies to improve immunogenicity, and (3) the immune mechanism underlying the differences in response rates to HBV vaccination.
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Affiliation(s)
| | - Panagiota Davoulou
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
| | | | | | - Christos Triantos
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece
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17
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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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Fung J. HBV therapeutic vaccines and cccDNA inhibitors - emergence of a cure. Liver Transpl 2016; 22:52-56. [PMID: 27576205 DOI: 10.1002/lt.24617] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/16/2016] [Accepted: 08/25/2016] [Indexed: 01/13/2023]
Affiliation(s)
- James Fung
- The Liver Transplant Centre, Queen Mary Hospital, Hong Kong.
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19
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Liver transplantation and hepatitis B virus infection: towards an immunoglobulin-free antiviral treatment after transplantation. Curr Opin Organ Transplant 2016; 21:219-23. [PMID: 26859222 DOI: 10.1097/mot.0000000000000293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This article provides an update on the latest development on deploying oral nucleosides in an immunoglobulin-free regime against hepatitis B virus (HBV) recurrence after liver transplantation. RECENT FINDINGS Entecavir and tenofovir are the two newer oral nucleosides that are associated with a low virological rebound rate at less than 2% at 5 years. As a result, they have been applied as standalone treatment against HBV recurrence after liver transplantation without immunoglobulin. Recent evidence has shown that a hepatitis B surface antigen seroclearance rate of 86% and 91% after 1 and 2 years was achievable with entecavir monotherapy. Moreover, none of the patients had histological graft damage because of HBV recurrence and an overall survival over 80% at 7 years has been reported. SUMMARY With newer and more potent oral nucleos(t)ide (NA) available, a hepatitis B immune globulin-free regimen after liver transplantation has become safe and feasible for suppression of HBV recurrence after liver transplantation, and for avoidance of HBV-related graft complications.
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20
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Duan BW, Lu SC, Lai W, Liu XE, Liu Y. The detection of (total and ccc) HBV DNA in liver transplant recipients with hepatitis B vaccine against HBV reinfection. Hum Vaccin Immunother 2016; 11:2490-4. [PMID: 26177383 DOI: 10.1080/21645515.2015.1063755] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
To investigate the levels of hepatitis B virus total DNA (HBV DNA) and covalently closed circular (ccc) DNA in liver transplant recipients who received hepatitis B vaccination, including responders and non-responders, following liver transplantation due to hepatitis B-related diseases and to investigate the efficacy of hepatitis B immune reconstitution against HBV reinfection. Twenty responders and 34 non-responders were enrolled in the present study. The levels of HBV total DNA and ccc DNA in peripheral blood mononuclear cells (PBMCs) and the liver and plasma were detected by real-time polymerase chain reaction (PCR). Fifty-three blood samples and 38 liver allograft tissues were acquired. For the responders, the mean serum titer for anti-HBs (antibodies against hepatitis B surface antigen) was 289 (46.64-1000) IU/ml. Also for the responders, HBV total DNA was detected in PBMCs for one recipient and in the liver for another recipient, but ccc DNA was not detected in either of those 2 recipients. For the non-responders, HBV total DNA was detected in PBMCS for 2 recipients, neither of whom had ccc DNA. Also for the non-responders, HBV total DNA was detected in the livers of 3 recipients, 2 of whom also had ccc DNA. All responders had discontinued hepatitis B immunoglobulin (HBIG), and 13 responders had discontinued antiviral agents. One responder experienced HBV recurrence during the follow-up period. For the majority of liver transplant recipients, no HBV total DNA or ccc DNA was detected in the blood or liver. The lack of HBV total DNA and ccc DNA both in PBMCs and the liver in liver transplant recipients who received hepatitis B vaccination to prevent HBV reinfection should be a prerequisite for the withdrawal of HBIG and/or antiviral agents.
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Affiliation(s)
- Bin-Wei Duan
- a Department of Hepatobiliary Surgery and Liver Transplantation Program ; Beijing You-An Hospital; Capital Medical University ; Beijing , China
| | - Shi-Chun Lu
- b Institute & Hospital of Hepatobiliary Surgery; Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA; Chinese PLA Medical School; Chinese PLA General Hospital ; Beijing , China
| | - Wei Lai
- c Department of General Surgery ; Chengdu First People's Hospital ; Sichuan , China
| | - Xue-En Liu
- d Department of Microbiology and Infectious Disease Center ; School of Basic Medical Sciences; Peking University Health Science Center ; Beijing , China
| | - Yuan Liu
- a Department of Hepatobiliary Surgery and Liver Transplantation Program ; Beijing You-An Hospital; Capital Medical University ; Beijing , China
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21
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Yoshizawa A, Yamashiki N, Ueda Y, Kaido T, Okajima H, Marusawa H, Chiba T, Uemoto S. Long-term efficacy of hepatitis B vaccination as post-transplant prophylaxis in hepatitis B surface antigen (HBsAg) positive recipients and HBsAg negative recipients of anti-hepatitis B core positive grafts. Hepatol Res 2016; 46:541-51. [PMID: 26348993 DOI: 10.1111/hepr.12586] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 08/23/2015] [Accepted: 08/30/2015] [Indexed: 02/08/2023]
Abstract
AIM Hepatitis B virus (HBV) reactivation after liver transplantation in HBV patients, or in HBV negative recipients of anti-hepatitis B core (HBc) positive grafts, has been prevented by prophylactic use of hepatitis B immunoglobulin (HBIG) and/or nucleoside/nucleotide analogs (NA). Vaccination against HBV is an alternative that may provide a chance to discontinue prophylaxis by producing anti-hepatitis B surface (HBs) antibodies. METHODS We retrospectively reviewed 40 HBV positive recipients (HBV+ group) and 27 HBV negative recipients of anti-HBc positive grafts (HBV-/anti-HBc+ graft group), who were administrated double-dose hepatitis B vaccination. Recipients were regarded as responders when anti-HBs greater than 100 IU/L was maintained for 6 months or more without HBIG. Response rates of vaccine and long-term outcomes were analyzed. RESULTS Eighteen of the 40 patients in the HBV+ group (45%) and 18 of the 27 patients in the HBV-/anti-HBc+ graft group (67%) responded to vaccination after a median of four and three times, respectively. Younger age was the only independent factor associated with vaccine response in the HBV-/anti-HBc+ graft group (P = 0.03), whereas no factor was found to be an independent predictor for vaccine response in the HBV+ group. Among the 18 responders in the HBV+ group, 17 remained without NA or HBIG 8.2 years after the start of vaccination. Ten of those required periodic booster vaccination. All 18 responders in the HBV-/anti-HBc+ graft group remained free from HBV prophylaxis 6.2 years after the start of vaccination. CONCLUSION Younger recipients have a greater chance to develop sufficient anti-HBs after double-dose HBV vaccination, leading to discontinue HBV prophylaxis.
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Affiliation(s)
- Atsushi Yoshizawa
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Yoshihide Ueda
- Organ Transplantation Unit, Kyoto University, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Organ Transplantation Unit, Kyoto University, Kyoto, Japan
| | - Hideaki Okajima
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Organ Transplantation Unit, Kyoto University, Kyoto, Japan
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22
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Usui M, Sugimoto K, Kato H, Murata Y, Tanemura A, Kuriyama N, Azumi Y, Kishiwada M, Mizuno S, Sakurai H, Takei Y, Isaji S. Discontinuation of Hepatitis B Immunoglobulin by Long-term Hepatitis B Vaccine Inoculation in Preventing Hepatitis B Recurrence After Liver Transplantation. Transplant Proc 2016; 48:1179-1183. [PMID: 27320582 DOI: 10.1016/j.transproceed.2015.12.110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/30/2015] [Indexed: 12/13/2022]
Abstract
INTRODUCTION For the patients undergoing liver transplantation for hepatitis B virus (HBV)-related diseases, hepatitis B immunoglobulin (HBIG) should be administered to prevent reinfection. Because HBIG is highly expensive and a blood product, an alternative strategy using HBV vaccination has been made in an attempt to discontinue use of HBIG. The aim of this study was to evaluate the impact of long-term HBV vaccination for discontinuation of HBIG, paying attention to the status of active immunization using T-cell proliferation assay. PATIENTS AND METHODS Among the 144 recipients who underwent liver transplantation in our hospital, 16 had HBV-related liver diseases; the 14 patients who had received vaccination were subjects in our study. To evaluate the status of active immunization, T-cell proliferation was examined by counting the number of T cells after adding HBV vaccine to the culture supernatant of T cells, and tumor necrosis factor α and interferon γ were measured in the culture supernatant. RESULTS The ratio of male/female was 13/1 (median age: 55 years; range: 37 years to 67 years). The median follow-up time was 102 months (range: approximately 14 months to 148 months). All 14 patients were free of HBV recurrence. HBIG-free status could be achieved in 9 patients (64.3%) during the treatment period for more than 50 months after beginning of HBV vaccination, of whom 5 (35.7%) became HBV vaccine-free. T-cell proliferation was confirmed by fact that the stimulation index ranged from 2.34 to 5.2 in the patients who were HBIG-free. CONCLUSION Long-term HBV vaccination after LT is a useful and effective treatment in preventing HBV recurrence, allowing the discontinuation of HBIG treatment.
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Affiliation(s)
- M Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan.
| | - K Sugimoto
- Hepatogastroenterology, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - H Kato
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - Y Murata
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - A Tanemura
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - N Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - Y Azumi
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - M Kishiwada
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - S Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - H Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - Y Takei
- Hepatogastroenterology, Mie Graduate School of Medicine, Tsu, Mie, Japan
| | - S Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie Graduate School of Medicine, Tsu, Mie, Japan
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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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Maiwall R, Kumar M. Prevention and Treatment of Recurrent Hepatitis B after Liver Transplantation. J Clin Transl Hepatol 2016; 4:54-65. [PMID: 27047773 PMCID: PMC4807144 DOI: 10.14218/jcth.2015.00041] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 02/01/2016] [Accepted: 02/01/2016] [Indexed: 12/13/2022] Open
Abstract
Chronic hepatitis B is a global health problem that leads to development of various complications, such as cirrhosis, liver cancer, and liver failure requiring liver transplantation. The recurrence of hepatitis B virus (HBV) post-liver transplantation is a major cause of allograft dysfunction, cirrhosis of the allograft, and graft failure. Patients with high viral load at the time of transplantation, hepatitis B e antigen (HBeAg) positivity, or those with a history of anti-viral drug resistance are considered as high-risk for recurrent HBV post-liver transplantation, while patients with low viral load, including HBeAg negative status, acute liver failure, and hepatitis D virus (HDV) co-infection are considered to be at low-risk for recurrent HBV post-liver transplantation. Antivirals for patients awaiting liver transplantation(LT) cause suppression of HBV replication and reduce the risk of recurrent HBV infection of the allograft and, therefore, all HBV patients with decompensated cirrhosis should be treated with potent antivirals with high genetic barrier to resistance (entecavir or tenofovir) prior to liver transplantation. Prevention of post-liver transplantation recurrence should be done using a combination of hepatitis B immunoglobulin (HBIG) and antivirals in patients at high risk of recurrence. Low dose HBIG, HBIG-free protocols, and monoprophylaxis with high potency antivirals can still be considered in patients at low risk of recurrence. Even, marginal grafts from anti-HBc positive donors can be safely used in hepatitis B surface antigen (HBsAg) negative, preferably in anti-hepatitis B core (HBc)/anti-hepatitis B surface (HBs) positive recipients. In this article, we aim to review the mechanisms and risk factors of HBV recurrence post-LT in addition to the various treatment strategies proposed for the prevention of recurrent HBV infection.
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Affiliation(s)
- Rakhi Maiwall
- Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar
- Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
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Togashi J, Akamatsu N, Sugawara Y, Kaneko J, Tamura S, Tanaka T, Arita J, Sakamoto Y, Hasegawa K, Kokudo N. One-year extended, monthly vaccination prophylaxis combined with hepatitis B immune globulin for hepatitis B after liver transplantation. Hepatol Res 2016; 46:E51-E59. [PMID: 25899139 DOI: 10.1111/hepr.12526] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Revised: 04/03/2015] [Accepted: 04/13/2015] [Indexed: 12/29/2022]
Abstract
AIM The feasibility of vaccination in liver transplant recipients is highly controversial, and the present study aimed to investigate the efficacy of a 1-year extended, monthly vaccine prophylaxis protocol of a second-generation recombinant vaccine for transplant recipients. METHODS The recombinant hepatitis B vaccine (10 µg) was administrated s.c. every month for 12 months as the vaccination protocol to 39 liver transplant recipients in stable condition, including those with hepatitis B-related chronic liver disease (n = 30), those with acute hepatitis B liver failure (hepatitis B surface antibody [HBsAb], n = 4), and those with hepatitis B core antibody positive grafts (n = 5). A fixed dose of hepatitis B immune globulin (HBIG) was administrated during the study based on the monoprophylaxis approach, and the increase in the hepatitis B surface antibody titer was measured to evaluate the efficacy of the vaccination. RESULTS The vaccination protocol was initiated a mean of 54 months (range, 13-124) after liver transplantation, and all patients tolerated the vaccination well without adverse effects. The overall hepatitis B virus (HBV) recurrence rate was 5% (2/39) based on hepatitis B surface antigen positivity, and 2% (1/39) based on HBV DNA detectability. Six (15%) patients showed a good response to vaccination with an increase in the HBsAb titer greater than 100 IU/L at the end of vaccination, but only three (8%) maintained an adequate HBsAb level to spare HBIG during the 2-year observation period. CONCLUSION While a few patients demonstrated an adequate response to vaccination, the clinical indication for the HBV vaccination for liver transplant recipients is currently minimal.
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Affiliation(s)
- Junichi Togashi
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
- Department of Surgery, Tokyo Rosai Hospital, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Junichi Kaneko
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Sumihito Tamura
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Tomohiro Tanaka
- Department of Organ Transplant Service, University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, University of Tokyo, Tokyo, Japan
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Onoe T, Tahara H, Tanaka Y, Ohdan H. Prophylactic managements of hepatitis B viral infection in liver transplantation. World J Gastroenterol 2016; 22:165-175. [PMID: 26755868 PMCID: PMC4698483 DOI: 10.3748/wjg.v22.i1.165] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 11/11/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is a considerably effective treatment for patients with end-stage hepatitis B virus (HBV)-related liver disease. However, HBV infection often recurs after LT without prophylaxis. Since the 1990s, the treatment for preventing HBV reinfection after LT has greatly progressed with the introduction of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs), resulting in improved patient survival. The combination therapy consisting of high-dose HBIG and lamivudine is highly efficacious for preventing the recurrence of HBV infection after LT and became the standard prophylaxis for HBV recurrence. However, mainly due to the high cost of HBIG treatment, an alternative protocol for reducing the dose and duration of HBIG has been evaluated. Currently, combination therapy using low-dose HBIG and NAs is considered as the most efficacious and cost-effective prophylaxis for post-LT HBV reinfection. Recently, NA monotherapy and withdrawal of HBIG from combination therapy, along with the development of new, potent high genetic barrier NAs, have provided promising efficacy, especially for low-risk recipients. This review summarizes the prophylactic protocol and their efficacy including prophylaxis of de novo HBV infection from anti-HBc antibody-positive donors. In addition, challenging approaches such as discontinuation of all prophylaxis and active immunity through hepatitis B vaccination are discussed.
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Fung J. Management of chronic hepatitis B before and after liver transplantation. World J Hepatol 2015; 7:1421-1426. [PMID: 26052387 PMCID: PMC4450205 DOI: 10.4254/wjh.v7.i10.1421] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Revised: 01/29/2015] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation remains the only curative option for eligible patients with complications of chronic hepatitis B (CHB) infection, including severe acute hepatitis flares, decompensated cirrhosis, and hepatocellular carcinoma. In general, all patients with CHB awaiting liver transplantation should be treated with oral nucleos(t)ide analogs (NAs) with high barriers to resistance to prevent potential flares of hepatitis and reduce disease progression. After liver transplantation, lifelong antiviral therapy is also required to prevent graft hepatitis, which may lead to subsequent graft loss. Although combination therapy using NA and hepatitis B immune globulin (HBIG) has been the regimen most widely adopted for over a decade, recent studies have demonstrated that newer NAs with low rates of resistance are effective in preventing graft hepatitis even without the use of HBIG, achieving excellent long term outcome. For patients without pre-existing resistant mutations, monotherapy with a single NA has been shown to be effective. For those with resistant strains, a combination of nucleoside analog and nucleotide analog should be used. To date, clinical trials using therapeutic vaccination have shown suboptimal response, as CHB patients likely have an immune deficit against HBV epitopes. Future strategies include targeting different sites of the hepatitis B replication cycle and restoring the host immunity response to facilitate complete viral eradication.
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Ohno Y, Mita A, Ikegami T, Masuda Y, Urata K, Nakazawa Y, Kobayashi A, Miyagawa S. Successful active immunization using a hepatitis B virus vaccination protocol for a recipient with hepatitis B core antibody-positive liver graft. Transplant Proc 2015; 46:721-5. [PMID: 24767333 DOI: 10.1016/j.transproceed.2013.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 11/26/2013] [Accepted: 12/10/2013] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Donor shortages occasionally necessitate the use of hepatic allografts from hepatitis B core antibody-positive (HBcAb+) donors, with an attendant risk of post-transplantation hepatitis B virus (HBV) infection. The aim of the present study was to develop and evaluate a protocol of active immunization for prevention of post-transplantation de novo HBV infection in patients receiving liver grafts from HBcAb+ donors. PATIENTS AND METHODS Ten patients who had received HBcAb+ liver grafts at Shinshu University Hospital between October 1996 and December 2012 were enrolled. All the recipients were negative for HBV serological tests, and HBV-DNA. Hepatitis B immunoglobulin (HBIG) was given routinely in the peritransplantation and post-transplantation periods, without antiviral drugs. Subcutaneous vaccination with recombinant HBV was given at a dosage of 20 μg in adults and 5 μg in children concomitant with HBIG until acquisition of active immunization. The timing to start HBV vaccination was dependent on the condition of the patient. RESULTS The median follow-up period after liver transplantation was 140 months, and the median period after transplantation until the start of vaccination was 7.0 months. Nine patients (90%) acquired active immunity after a median number of 4 (range, 2-13) vaccinations (hepatitis B surface antibody >300 mIU/mL for 1 year, or >100 mIU/mL thereafter), and did not require HBIG administration thereafter. None had any side effects of HBV vaccination or developed hepatitis B infection during the study period. Four fast responders who achieved antibody high titers by active immunization within 9 months received pretransplantation vaccinations, whereas 5 slow responders did not. CONCLUSIONS Our vaccination protocol provides a new effective strategy for prevention of de novo hepatitis B infection after liver transplantation in recipients with HBcAb+ liver grafts. Pretransplantation HBV vaccination was helpful for the post-transplantation vaccine response.
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Affiliation(s)
- Y Ohno
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - A Mita
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
| | - T Ikegami
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Y Masuda
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - K Urata
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Y Nakazawa
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - A Kobayashi
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - S Miyagawa
- Division of Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan
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Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Reestablishment of active immunity against HBV graft reinfection after liver transplantation for HBV-related end stage liver disease. J Immunol Res 2014; 2014:764234. [PMID: 25759834 PMCID: PMC4352506 DOI: 10.1155/2014/764234] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 11/18/2014] [Indexed: 02/05/2023] Open
Abstract
Background. The aim of this study was to establish a hepatitis B virus (HBV) vaccination protocol among orthotopic liver transplantation (OLT) recipients under the coverage of a low-dose hepatitis B immunoglobulin (HBIG) combined with an antiviral agent prophylaxis protocol. Method. Two hundred OLT recipients were included in this study. The vaccine was injected at months 0, 1, 2, and 6. Low-dose HBIG combined with antiviral agent prophylaxis protocol was continued before reestablishment of active immunity against HBV in order to maintain a steady anti-HBs titer. Results. Active immunity against HBV was reestablished in 50 patients, for an overall response rate of 25%. Of the 50 patients, 24 discontinued HBIG without any HBV graft reinfection during a follow-up period of 26.13 ± 7.05 months. 21 patients discontinued both HBIG and antiviral agents during a follow-up period of 39.86 ± 15.47 months, and 4 patients among them appeared to be HBsAg positive. There was no recipient death or graft loss because of HBV reinfection. Conclusions. Vaccination preventing HBV reinfection for OLT recipients is feasible. The strategy withdrawal of HBIG with induction of active immunity against hepatitis B is reasonable for long-term survivors of OLT; however, discontinuation nucleoside analogues should be cautious.
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Harmancı Ö, Selçuk H, Haberal M. Prophylaxis against Recurrence in Liver Transplantation Patients with Hepatitis B Virus: What is New? J Clin Transl Hepatol 2014; 2:259-65. [PMID: 26356785 PMCID: PMC4521236 DOI: 10.14218/jcth.2014.00023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/17/2014] [Accepted: 09/18/2014] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) causes an endemic infection that affects nearly 2 billion patients worldwide. It is one of the leading causes of liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation (LT). Recurrence of HBV infection after LT is due to specific HBV-host genome interactions. Although hepatitis B immunoglobulin treatment constituted the backbone of HBV recurrence, use of the nucleoside and nucleotide analogs (especially the ones with a higher genetic barrier to resistance), either alone or in combination, offer us new and powerful options in overcoming this serious issue.
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Affiliation(s)
- Özgür Harmancı
- Department of Gastroenterology, Başkent University Medical School, Ankara, Turkey
- Correspondence to: Özgür Harmancı, Department of Gastroenterology, Başkent University Medical School, Mareşal Fevzi çakmak Cad. No:45 Bahçelievler, 06490, Ankara, Turkey. Tel: +90-312-212-6868, Fax: +90-312-215-0835. E-mail:
| | - Haldun Selçuk
- Department of Gastroenterology, Başkent University Medical School, Ankara, Turkey
| | - Mehmet Haberal
- Department of General Surgery, Başkent University Medical School, Ankara, Turkey
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Ishigami M, Honda T, Ishizu Y, Onishi Y, Kamei H, Hayashi K, Ogura Y, Hirooka Y, Goto H. Frequent incidence of escape mutants after successful hepatitis B vaccine response and stopping of nucleos(t)ide analogues in liver transplant recipients. Liver Transpl 2014; 20:1211-20. [PMID: 24961506 DOI: 10.1002/lt.23935] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 06/05/2014] [Indexed: 12/21/2022]
Abstract
The combination of nucleos(t)ide analogues (NAs) and hepatitis B immune globulin has been established as safe and effective prophylaxis against hepatitis B virus (HBV) reactivation after liver transplantation (LT). However, the essential weak point of this regimen is its high cost. The hepatitis B (HB) vaccine is an attractive alternative that costs less, and it enables some patients to have sufficiently high hepatitis B surface antibody (HBsAb) titers. Almost no data exist on whether NAs can be stopped safely in such successfully vaccinated patients. We investigated the incidence of HB vaccine escape mutants in liver recipients who had sufficient HBsAb titers after LT and stopped NAs. Among 18 HBV carriers and 7 non-HBV patients who received grafts from hepatitis B core antibody-positive donors, 2 HBV carriers and 6 non-HBV patients who achieved HBsAb titers >100 IU/L for >3 months after posttransplant vaccination were weaned from NAs. For the patients who showed viremia, we analyzed amino acid sequences of the HB envelope protein, and we performed a statistical analysis for the factors associated with viremia. In 4 of the 8 patients who achieved sufficient HBsAb levels after vaccination and stopped NAs, HBV DNA appeared after a median of 12 months. A sequence analysis showed various amino acid mutations, including the a-determinant, in the HB envelope region. Frequent vaccination was shown to be a statistically significant risk factor for inducing viremia. In conclusion, although the HB vaccine is an effective substitute for prophylaxis against HBV reactivation in some patients after LT, frequent vaccination could be a risk factor for producing escape mutants. Our data demonstrate not only that caution must be exercised in stopping NAs in effectively vaccinated patients (especially in patients vaccinated frequently) but also that it is important to set stopping rules for vaccination in transplant patients.
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Affiliation(s)
- Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University School of Medicine, Nagoya, Japan
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Verna EC. Hepatitis viruses and liver transplantation: evolving trends in antiviral management. Clin Liver Dis 2014; 18:575-601. [PMID: 25017077 DOI: 10.1016/j.cld.2014.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Viral hepatitis is both a leading indication for liver transplant (LT) and an important cause of posttransplant graft loss and mortality. Treatment and prevention of hepatitis B virus in LT recipients, with the observed corresponding improvement in post-LT outcomes, is among the great success stories in transplantation. By comparison, treatment of hepatitis C virus with safe and effective regimens is only just becoming a reality. Chronic hepatitis E virus infection in LT recipients represents a newly described phenomenon that can also lead to graft loss; early diagnosis and treatment may be key in the management of these patients.
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Affiliation(s)
- Elizabeth C Verna
- Division of Digestive and Liver Diseases, Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032, USA.
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Roche B, Samuel D. Prevention of hepatitis B virus reinfection in liver transplant recipients. Intervirology 2014; 57:196-201. [PMID: 25034488 DOI: 10.1159/000360944] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates such as entecavir or tenofovir could suppress hepatitis B virus (HBV) replication, improve liver function, delay or obviate the need for liver transplantation in some patients, and reduce the risk of HBV recurrence. The combination of long-term antiviral and low-dose hepatitis B immune globulin (HBIG) can effectively prevent HBV recurrence in more than 90% of transplant recipients. Some form of HBV prophylaxis needs be continued indefinitely after transplantation. However, 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 long-term antiviral therapy. A more cautious approach to prophylaxis regimen is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e. HIV or HDV coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those with a risk of noncompliance to antiviral therapy.
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Affiliation(s)
- Bruno Roche
- Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France
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35
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Krawczyk A, Ludwig C, Jochum C, Fiedler M, Heinemann FM, Shouval D, Roggendorf M, Roggendorf H, Lindemann M. Induction of a robust T- and B-cell immune response in non- and low-responders to conventional vaccination against hepatitis B by using a third generation PreS/S vaccine. Vaccine 2014; 32:5077-82. [PMID: 24975813 DOI: 10.1016/j.vaccine.2014.06.076] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 05/03/2014] [Accepted: 06/13/2014] [Indexed: 12/22/2022]
Abstract
Non-responsiveness to conventional hepatitis B vaccines in individuals at high risk of exposure to hepatitis B virus (HBV) is an important public health problem and of particular relevance in health care providers. Yeast-derived conventional HBsAg vaccines fail to induce protective antibody titers in up to 10% of immune competent vaccinees. Therefore, a third generation HBV vaccine, Sci-B-Vac™, was developed which contains in addition to the small S antigen the PreS1 and PreS2 antigens. This vaccine proved to induce a highly potent cellular and humoral immune response in healthy individuals as well as protective antibody levels in non- and low-responders to conventional HBV vaccines. The aim of the study was to examine whether Sci-B-Vac™ triggers cellular and humoral immunity in individuals who failed immunization with conventional vaccines. We immunized 21 volunteers (15 non- and 6 low-responders) according to the standard vaccination schedule (0, 4 and 24 weeks), determined the cellular immunity by proliferation assay and interferon (IFN)-γ ELISpot and measured the anti-HBs antibody titers prior to each vaccination and four weeks after the third vaccine dose. Following three vaccinations, PreS/S-specific T-cell proliferation was detected in 8 out of 15 non-responders and 5 out of 6 low-responders. Specific IFN-γ responses were measured in 2 out of 15 non-responders and 4 out of 6 low-responders. All but one (20/21) study participants developed anti-HBs titers ≥10IU/l after three vaccinations. Anti-HBs ≥100IU/L were detected in 12 out of 15 non-responders and in 6 out of 6 low-responders. Anti-HBs ≥10IU/l and <100IU/l were found in 2 non-responders. These results indicate that Sci-B-Vac™ induces cellular immunity as well as protective anti-HBs antibody titers in non- and low-responders. In conclusion, these results confirm that Sci-B-Vac™ should be administered to non-responders to conventional HBV vaccines and patients with impaired immune function.
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Affiliation(s)
- Adalbert Krawczyk
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
| | - Charlotte Ludwig
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
| | - Christoph Jochum
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
| | - Melanie Fiedler
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
| | - Falko M Heinemann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
| | - Daniel Shouval
- Hadassah Medical Center, Liver Unit, POB 12000, Jerusalem 91120, Israel.
| | - Michael Roggendorf
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
| | - Hedwig Roggendorf
- Institute of Molecular Immunology, University Hospital TUM, Schneckenburgerstr. 8, 81675 München, Germany.
| | - Monika Lindemann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany.
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Wong TCL, Fung JYY, Lo CM. Prevention of recurrent hepatitis B infection after liver transplantation. Hepatobiliary Pancreat Dis Int 2013; 12:465-72. [PMID: 24103275 DOI: 10.1016/s1499-3872(13)60074-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recurrence of hepatitis B virus (HBV) infection after liver transplantation can lead to graft loss and a reduction in long-term survival. The purpose of this review is to summarize the current therapeutic options for preventing HBV recurrence in liver transplant recipients. DATA SOURCES Up to January 2013, studies that were published in MEDLINE and EMBASE on prevention of HBV recurrence after liver transplantation were reviewed. RESULTS There have been remarkable advancements in the past two decades on the prevention of HBV recurrence after liver transplantation, from the discovery of hepatitis B immune globulin (HBIG) and lamivudine monotherapy to the combination therapy using HBIG and lamivudine. With the development of newer and stronger antiviral agents, the need for life-long HBIG is doubtful. With their low resistance profile, oral antiviral prophylaxis using these new agents alone is sufficient and is associated with excellent outcome. CONCLUSIONS Restoration of host HBV immunity with adoptive immunity transfer and vaccination may represent the ultimate strategy to withdraw prophylactic treatment and to achieve a drug free regimen against HBV recurrence after liver transplantation.
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Affiliation(s)
- Tiffany C L Wong
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
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Villamil FG, Cairo FM. Hepatitis B virus: Prevention of recurrent infection. Clin Liver Dis (Hoboken) 2013; 2:169-172. [PMID: 30992855 PMCID: PMC6448646 DOI: 10.1002/cld.224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 04/04/2013] [Accepted: 05/27/2013] [Indexed: 02/04/2023] Open
Affiliation(s)
| | - Fernando M. Cairo
- Liver Transplantation Unit, British Hospital, Buenos Aires, Argentina
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38
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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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Matsuzaki T, Tatsuki I, Otani M, Akiyama M, Ozawa E, Miuma S, Miyaaki H, Taura N, Hayashi T, Okudaira S, Takatsuki M, Isomoto H, Takeshima F, Eguchi S, Nakao K. Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation. J Gastroenterol Hepatol 2013; 28:1217-22. [PMID: 23432697 DOI: 10.1111/jgh.12182] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/01/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Currently, hepatitis B virus (HBV) re-infection after liver transplantation (LT) can be almost completely suppressed by the administration of HBV reverse transcriptase inhibitors and hepatitis B immunoglobulins. However, after transplantation, there is no indicator of HBV replication because tests for the serum hepatitis B surface antigen and HBV-DNA are both negative. Therefore, the criteria for reducing and discontinuing these precautions are unclear. In this study, we examined the serum HBV core-related antigen (HBcrAg) and intrahepatic covalently closed circular DNA (cccDNA) in order to determine if these could be useful markers for HBV re-infection. METHODS Thirty-one patients underwent LT for HBV-related liver disease at Nagasaki University Hospital from 2001 to 2010. Of these, 20 cases were followed up for more than 1 year (median follow-up period, 903 days). We measured serum HBcrAg and intrahepatic cccDNA levels in liver tissue. In addition, in nine cases, we assessed the serial changes of HBcrAg and intrahepatic cccDNA levels from preoperative periods to stable periods. RESULTS We examined serum HBcrAg and intrahepatic cccDNA levels in 20 patients (35 samples). HBcrAg and cccDNA levels were significantly correlated with each other (r = 0.616, P < 0.001). From a clinical aspect, the fibrosis stage was significantly lower in both HBcrAg- and cccDNA-negative patients than in HBcrAg- or cccDNA-positive patients. CONCLUSIONS HBcrAg and cccDNA were useful as HBV re-infection markers after LT. Keeping patients' HBcrAg and cccDNA negative after LT might contribute to long-term graft survival.
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Affiliation(s)
- Toshihisa Matsuzaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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John S, Andersson KL, Kotton CN, Hertl M, Markmann JF, Cosimi AB, Chung RT. Prophylaxis of hepatitis B infection in solid organ transplant recipients. Therap Adv Gastroenterol 2013; 6:309-319. [PMID: 23814610 PMCID: PMC3667476 DOI: 10.1177/1756283x13487942] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Rates of transmission of hepatitis B virus (HBV) infection from organ donors with HBV markers to recipients along with reactivation of HBV during immunosuppression following transplantation have fallen significantly with the advent of hepatitis B immune globulin (HBIg) and effective antiviral therapy. Although the availability of potent antiviral agents and HBIg has highly impacted the survival rate of HBV-infected patients after transplantation, the high cost associated with this practice represents a major financial burden. The availability of potent antivirals with high genetic barrier to resistance and minimal side effects have made it possible to recommend an HBIg-free prophylactic regimen in selected patients with low viral burden prior to transplant. Significant developments over the last two decades in the understanding and treatment of HBV infection necessitate a re-appraisal of the guidelines for prophylaxis of HBV infection in solid organ transplant recipients.
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Affiliation(s)
- Savio John
- Division of Gastroenterology and Hepatology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY 13210, USA and SUNY Upstate Medical University, Syracuse, NY, USA (formerly Hepatology Division, Massachusetts General Hospital, Boston, MA, USA)
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41
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Feng L, Niu Y, Chen H, You H, Zang Y, Li L, Shan S, Tan Y, Jia J, Shen Z. Immunogenicity of different hepatitis B virus vaccination schedules in liver transplant recipients. Hepatol Res 2013; 43:495-501. [PMID: 23157373 DOI: 10.1111/j.1872-034x.2012.01102.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Revised: 08/28/2012] [Accepted: 08/31/2012] [Indexed: 02/08/2023]
Abstract
AIM To compare the immunogenicity of two modified hepatitis B virus (HBV) vaccination schedules in liver transplant recipients. Hepatitis B immunoglobulin (HBIG) in combination with nucleoside/nucleotide analogs (NUCs) is the recommended prophylaxis for preventing HBV recurrence following liver transplantation (LT). However, HBIG treatment is expensive. Active immunization with hepatitis B vaccine would be a preferable alternative prophylaxis to replace HBIG treatment. However, the overall response rate to standard vaccination (given at months 0, 1 and 6) is relatively low in immune-compromised patients. METHODS Two cohorts of 114 subjects were immunized with recombinant HBV vaccine containing S-antigen. The patients in the rapid schedule group were immunized with 40 μg HBV vaccine at months 0, 1, 2 and 3, and with 20 μg at months 4, 5 and 6. The patients in the accelerated schedule group were immunized with 40 μg of HBV vaccine at days 0, 7, 14 and 28, and 20 μg at months 2, 3 and 4. RESULTS The overall response rate was 16.7% (19/114) and all responders discontinued HBIG injection and only one patient developed HBV recurrence. The response rate was 24.6% (14/57) and 8.8% (5/57) in the rapid vaccination and the accelerated vaccination schedules, respectively (P = 0.024). CONCLUSION HBV vaccination may induce endogenous anti-HBs to replace HBIG in selected patients. Vaccination schedules may influence vaccine response, and individual optimization may improve response rate to HBV vaccination.
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Affiliation(s)
- Lijuan Feng
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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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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Abstract
Vaccination of immunocompromised patients is challenging both regarding efficacy and safety. True efficacy data are lacking so existing recommendations are based on immune responses and safety data. Inactivated vaccines can generally be used without risk but the patients who are most at risk for infectious morbidity and mortality as a result of their severely immunosuppressed state are also those least likely to respond to vaccination. However, vaccination against pneumococci, Haemophilus influenzae and influenza are generally recommended. Live vaccines must be used with care because the risk for vaccine-associated disease exists.
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Affiliation(s)
- Per Ljungman
- Department of Haematology, Karolinska University Hospital, Division of Haematology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
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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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Crespo G, Mariño Z, Navasa M, Forns X. Viral hepatitis in liver transplantation. Gastroenterology 2012; 142:1373-1383.e1. [PMID: 22537446 DOI: 10.1053/j.gastro.2012.02.011] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 01/30/2012] [Accepted: 02/08/2012] [Indexed: 12/11/2022]
Abstract
Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus.
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Affiliation(s)
- Gonzalo Crespo
- Liver Unit, Hospital Clinic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
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46
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Fox AN, Terrault NA. The option of HBIG-free prophylaxis against recurrent HBV. J Hepatol 2012; 56:1189-1197. [PMID: 22274310 DOI: 10.1016/j.jhep.2011.08.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 08/01/2011] [Accepted: 08/10/2011] [Indexed: 12/17/2022]
Abstract
Since the early 1990's, hepatitis B immune globulin (HBIG) has been central to the prevention of hepatitis B virus (HBV) recurrence after liver transplantation. When used in combination with oral nucleos(t)ide analogues, HBIG prevents reinfection with HBV in ⩾90% of transplant recipients. While HBIG is highly efficacious, its use is undermined by its high cost. Because of this limitation, there have been many studies of alternative regimens seeking to minimize the dose or duration of HBIG without sacrificing low HBV recurrence rates. Toward that goal, lower dose intramuscular HBIG in combination with oral nucleos(t)ide analogues has been shown to be highly efficacious in preventing disease recurrence and represents a significant cost savings when compared with high dose intravenous administration. The withdrawal of HBIG after a defined course of combination HBIG and oral antivirals has also been shown to be effective, particularly if combination antiviral therapy is used. The ability to achieve undetectable HBV DNA levels pre-transplantation in the majority of patients may contribute to the high efficacy of these HBIG "light" regimens. Additionally, the success of antiviral rescue therapy for those patients who fail prophylaxis and develop recurrent HBV infection post-transplant has provided the impetus to move increasingly towards HBIG-free approaches. New techniques to detect occult HBV in hepatic and extrahepatic sites may allow clinicians to define a subgroup of patients in whom withdrawal of HBIG or all prophylaxis may be applicable.
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Affiliation(s)
- Alyson N Fox
- Medicine and Transplant Surgery, University of California San Francisco, San Francisco, United States
| | - Norah A Terrault
- Medicine and Transplant Surgery, University of California San Francisco, San Francisco, United States.
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Ishigami M, Onishi Y, Ito T, Katano Y, Ito A, Hirooka Y, Kiuchi T, Goto H. Anti-hepatitis B surface immunoglobulin reduction in early postoperative period after liver transplantation in hepatitis B virus-positive patients. Hepatol Res 2011; 41:1189-98. [PMID: 21955512 DOI: 10.1111/j.1872-034x.2011.00884.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM We investigated a protocol that lowered the necessary dose of anti-hepatitis B surface immunoglobulin (HBIg) with frequent monitoring of hepatitis B surface antigen (HBsAg) and antibody (HBsAb) levels in the early post-transplant period. METHODS Fifteen hepatitis B virus (HBV)-positive patients were studied. We administered a nucleoside analog from the preoperative period, high dose HBIg was used intraoperatively (200 IU/kg in the patients who weighed less than 50 kg, and 10 000 IU in those who weighed more than or equal to 50 kg) and was continued every day (5000-10 000 IU/day). Thereafter, HBIg was administered to keep the target trough titers. We evaluated the effectiveness and safety of this protocol for preventing HBV reactivation. RESULTS The average use of HBIg during the first three postoperative months (POM) was 27.9 ± 9.6 Kilo International Units. The average cost was $US11 800 in the first three postoperative months, compared with other previously reported protocols (about $20 000-40 000). HBV reactivation was detected in only one patient (6.7%) during the median follow up of 64 months (range: 12-86 months). CONCLUSIONS The present protocol for HBIg administration, which used frequent monitoring of HBsAg and HBsAb levels to determine the minimum required dose, was both safe and effective, and contributed to overall cost saving after liver transplantation.
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Affiliation(s)
- Masatoshi Ishigami
- Departments of Gastroenterology Transplant Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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48
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Fox AN, Terrault NA. Individualizing hepatitis B infection prophylaxis in liver transplant recipients. J Hepatol 2011; 55:507-509. [PMID: 21601598 DOI: 10.1016/j.jhep.2011.04.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 04/01/2011] [Accepted: 04/03/2011] [Indexed: 01/11/2023]
Affiliation(s)
- Alyson N Fox
- Division of Gastroenterology, University of California, San Francisco, San Francisco, CA 94143-0538, USA
| | - Norah A Terrault
- Division of Gastroenterology, University of California, San Francisco, San Francisco, CA 94143-0538, USA.
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Lenci I, Tisone G, Di Paolo D, Marcuccilli F, Tariciotti L, Ciotti M, Svicher V, Perno CF, Angelico M. Safety of complete and sustained prophylaxis withdrawal in patients liver-transplanted for HBV-related cirrhosis at low risk of HBV recurrence. J Hepatol 2011; 55:587-593. [PMID: 21251938 DOI: 10.1016/j.jhep.2010.12.036] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2010] [Revised: 12/13/2010] [Accepted: 12/14/2010] [Indexed: 02/09/2023]
Abstract
BACKGROUND & AIMS HBV reactivation after liver transplantation may be related to persistence of covalently closed circular (ccc) DNA. We investigated the safety of HBV prophylaxis withdrawal in selected HBV transplanted patients. METHODS Thirty patients transplanted 64-195months earlier (23 males, median age 56yrs), HBsAg-positive, HBeAg, and HBV-DNA negative at transplant (43% HCV/HDV co-infected), with undetectable intrahepatic total and ccc-DNA were enrolled. All patients underwent HBIg withdrawal and continued lamivudine with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Those with confirmed intrahepatic total and ccc-DNA undetectability 24weeks after stopping HBIg, also underwent lamivudine withdrawal and were followed-up without prophylaxis. RESULTS Twenty-five patients did not exhibit signs of HBV recurrence after prophylaxis withdrawal (median follow-up 28.7months, range 22-42). Five patients became HBsAg-positive: one early after HBIg withdrawal, the other four after HBIG and lamivudine withdrawal. None of these patients experienced clinically relevant events. In the first patient, HBIg were reinstituted with prompt HBsAg negativization. Of the other four, one remained HBsAg-positive with detectable HBV-DNA and mild ALT elevation and was successfully treated with tenofovir. In the remaining three, HBsAg positivity was transient and followed by anti-HBs seroconversion, thus no antiviral treatment was needed. CONCLUSIONS Patients with undetectable HBV viremia at transplant and no evidence of intrahepatic total and cccDNA may safely undergo cautious weaning of prophylaxis, showing low rate of HBV recurrence after a 2 year follow-up. Undetectability of intrahepatic ccc-DNA may help to identify patients at low-risk of recurrence, yet studies with longer follow-up are needed.
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Affiliation(s)
- Ilaria Lenci
- Hepatology, Tor Vergata University, Rome, Italy.
| | | | | | - Fabio Marcuccilli
- Laboratory of Molecular Virology, Tor Vergata University, Rome, Italy
| | | | - Marco Ciotti
- Laboratory of Molecular Virology, Tor Vergata University, Rome, Italy
| | - Valentina Svicher
- Laboratory of Molecular Virology, Tor Vergata University, Rome, Italy
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McCaughan GW. Prevention of post liver transplant HBV recurrence. Hepatol Int 2011; 5:876-81. [PMID: 22020819 DOI: 10.1007/s12072-011-9293-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Accepted: 06/18/2011] [Indexed: 12/18/2022]
Abstract
BACKGROUND Twenty years ago, liver transplantation for hepatitis B had been a relative contraindication to universal HBV recurrence and poor outcomes. Over the ensuing two decades, there has been refinement of prevention strategies in order to minimize HBV recurrence in the allograft. RESULTS Currently, the most efficacious and cost-effective strategies include newer oral antiviral drugs in combination with low doses of hepatitis B immunoglobulin (HBIG). More recently, strategies have been successful in withdrawing HBIG and newer approaches of HBIG avoidance are currently under development. CONCLUSION Thus, 20 years afterward, HBV recurrence is <5% and outcomes following liver transplantation are excellent.
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Affiliation(s)
- Geoffrey W McCaughan
- The AW Morrow Gastroenterology and Liver Centre, The Centenary Research Institute, Royal Prince Alfred Hospital and The University of Sydney, Missenden Road, Camperdown, NSW, 2050, Australia.
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