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Yu T, Zhang M, Zhang H, Zheng J, Shen C, Jiang N, Zou L, Wang J, Yu Y, Zhang Q, Yu S, Huang Y, Huang Y, Zhang J, Qiu C, Zhang W, Meng Z. Evidence of Residual Ongoing Viral Replication in Chronic Hepatitis B Patients Successfully Treated With Nucleos(t)ide Analogues. J Infect Dis 2023; 227:675-685. [PMID: 36546708 DOI: 10.1093/infdis/jiac493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Chronic hepatitis B is usually treated with nucleos(t)ide analogues (NAs). However, a cure is rarely achieved, even with years of treatment. Here, we investigated whether viral replication is completely halted and how long covalently closed circular DNA (cccDNA) persists in patients successfully treated with NAs. METHODS A series of longitudinal serum samples and a collection of cross-sectional liver biopsies were obtained from patients successfully treated with NAs. Viral variants in serum HBV RNA were enumerated by deep sequencing. Viral replication intermediates in hepatocytes were directly visualized by in situ hybridization. The apparent half-life of each cccDNA was estimated. RESULTS Three of 6 successfully treated patients demonstrated clear evidence of a small proportion of virus evolution, although the overwhelming proportion of variants were identical or possessed a similar degree of divergence through time. The apparent half-life of variants was estimated to be from approximately 7.42 weeks to infinite. Hepatocytes remained positive for cytoplasmic nucleocapsids-associated relaxed circular DNA in 4 of 7 liver needle biopsies. CONCLUSIONS We conclude that even after prolonged treatment, a small proportion of the cccDNA reservoir is constantly replenished by continued low-level HBV replication, whereas a large proportion of the cccDNA reservoir persists over time.
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Affiliation(s)
- Tong Yu
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Miaoqu Zhang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Hanyue Zhang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Jianming Zheng
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Chuan Shen
- Department of Infectious Disease, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
- Clinical Research Center for Infectious Disease of Hebei Province, Shijiazhuang, China
| | - Ning Jiang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Lei Zou
- Department of Infectious Disease, Yancheng Second People's Hospital, Yancheng, China
| | - Jing Wang
- Department of Infectious Disease, Jingan District Central Hospital of Shanghai, Shanghai, China
| | - Yiqi Yu
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Qiran Zhang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Shuili Yu
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Yanfang Huang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxian Huang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Chao Qiu
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Wenhong Zhang
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
| | - Zhefeng Meng
- Minhang Hospital and Institutes of Biomedical Sciences and Huashan Hospital, Fudan University, Shanghai, China
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2
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Lou B, Ma G, Lv F, Yuan Q, Xu F, Dong Y, Lin S, Tan Y, Zhang J, Chen Y. Baseline Quantitative Hepatitis B Core Antibody Titer Is a Predictor for Hepatitis B Virus Infection Recurrence After Orthotopic Liver Transplantation. Front Immunol 2021; 12:710528. [PMID: 34777339 PMCID: PMC8579009 DOI: 10.3389/fimmu.2021.710528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 10/08/2021] [Indexed: 11/13/2022] Open
Abstract
Objective Hepatitis B virus (HBV) reinfection is a serious complication that arise in patients who undergo hepatitis B virus related liver transplantation. We aimed to use biomarkers to evaluate the HBV reinfection in patients after orthotopic liver transplantation. Methods Seventy-nine patients who underwent liver transplantation between 2009 and 2015 were enrolled, and levels of biomarkers were analyzed at different time points. Cox regression and receiver operating characteristic (ROC) curves of different markers at baseline were used to analyze sustained hepatitis B surface antigen (HBsAg) loss. The Kaplan-Meier method was used to compare the levels of the biomarkers. Results Among the 79 patients, 42 sustained HBsAg loss with a median time of 65.2 months (12.0-114.5, IQR 19.5) after liver transplantation and 37 patients exhibited HBsAg recurrence with a median time of 8.8 (0.47-59.53, IQR 19.47) months. In the ROC curve analysis, at baseline, 4.25 log10 IU/mL qHBcAb and 2.82 log10 IU/mL qHBsAg showed the maximum Youden’s index values with area under the curves (AUCs) of 0.685and 0.651, respectively. The Kaplan-Meier method indicated that qHBsAg and quantitative antibody against hepatitis B core antigen (qHBcAb) levels in the two groups were significantly different (p = 0.031 and 0.006, respectively). Furthermore, the Cox regression model confirmed the predictive ability of qHBcAb at baseline (AUC = 0.685). Conclusion Lower pretransplantation qHBcAb is associated with HBV infection. The baseline concentration of qHBcAb is a promising predictor for the recurrence of HBV in patients undergoing liver transplantation and can be used to guide antiviral treatment for HBV infection.
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Affiliation(s)
- Bin Lou
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province , Hangzhou, China.,Institute of Laboratory Medicine, Zhejiang University, Hangzhou, China
| | - Guanghua Ma
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Feifei Lv
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Quan Yuan
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Science, Xiamen University, Xiamen, China
| | - Fanjie Xu
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yuejiao Dong
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Sha Lin
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yajun Tan
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jie Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yu Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province , Hangzhou, China.,Institute of Laboratory Medicine, Zhejiang University, Hangzhou, China
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3
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Higuera-de-la-Tijera F, Castro-Narro GE, Velarde-Ruiz Velasco JA, Cerda-Reyes E, Moreno-Alcántar R, Aiza-Haddad I, Castillo-Barradas M, Cisneros-Garza LE, Dehesa-Violante M, Flores-Calderón J, González-Huezo MS, Márquez-Guillén E, Muñóz-Espinosa LE, Pérez-Hernández JL, Ramos-Gómez MV, Sierra-Madero J, Sánchez-Ávila JF, Torre-Delgadillo A, Torres R, Marín-López ER, Kershenobich D, Wolpert-Barraza E. Asociación Mexicana de Hepatología A.C. Clinical guideline on hepatitis B. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:403-432. [PMID: 34483073 DOI: 10.1016/j.rgmxen.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.
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Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Mexico City, Mexico
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Mexico City, Mexico
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | - L E Cisneros-Garza
- Centro de Enfermedades Hepáticas, Hospital San José, Nuevo León, Monterrey, Mexico
| | - M Dehesa-Violante
- Fundación Mexicana para la Salud Hepática A.C. (FUNDHEPA), Mexico City, Mexico
| | - J Flores-Calderón
- Departamento de Gastroenterología, Hospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia Gastrointestinal, ISSSEMYM, Metepec, Estado de México, Mexico
| | - E Márquez-Guillén
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - L E Muñóz-Espinosa
- Clínica de Hígado, Departamento de Medicina Interna, Hospital Universitario "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - M V Ramos-Gómez
- Departamento de Gastroenterología, Centro Médico Nacional "20 de Noviembre", ISSSTE, Mexico City, Mexico
| | - J Sierra-Madero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - J F Sánchez-Ávila
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - R Torres
- Hospital de Infectología del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | | | - D Kershenobich
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
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4
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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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5
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Higuera-de-la-Tijera F, Castro-Narro GE, Velarde-Ruiz Velasco JA, Cerda-Reyes E, Moreno-Alcántar R, Aiza-Haddad I, Castillo-Barradas M, Cisneros-Garza LE, Dehesa-Violante M, Flores-Calderón J, González-Huezo MS, Márquez-Guillén E, Muñóz-Espinosa LE, Pérez-Hernández JL, Ramos-Gómez MV, Sierra-Madero J, Sánchez-Ávila JF, Torre-Delgadillo A, Torres R, Marín-López ER, Kershenobich D, Wolpert-Barraza E. Asociación Mexicana de Hepatología A.C. Clinical guideline on hepatitis B. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:S0375-0906(21)00061-6. [PMID: 34384668 DOI: 10.1016/j.rgmx.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.
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Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología, Hospital General de México «Dr. Eduardo Liceaga», Ciudad de México, México
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara «Fray Antonio Alcalde», Guadalajara, Jalisco, México
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Ciudad de México, México
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Ciudad de México, México
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional «La Raza», IMSS, Ciudad de México, México
| | - L E Cisneros-Garza
- Centro de Enfermedades Hepáticas, Hospital San José, Nuevo León, Monterrey, México
| | - M Dehesa-Violante
- Fundación Mexicana para la Salud Hepática A.C. (FUNDHEPA), Ciudad de México, México
| | - J Flores-Calderón
- Departamento de Gastroenterología, Hospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia Gastrointestinal, ISSSEMYM, Metepec, Estado de México, México
| | - E Márquez-Guillén
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - L E Muñóz-Espinosa
- Clínica de Hígado, Departamento de Medicina Interna, Hospital Universitario «Dr. José E. González», Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México «Dr. Eduardo Liceaga», Ciudad de México, México
| | - M V Ramos-Gómez
- Departamento de Gastroenterología, Centro Médico Nacional «20 de Noviembre», ISSSTE, Ciudad de México, México
| | - J Sierra-Madero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - J F Sánchez-Ávila
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ciudad de México, México
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - R Torres
- Hospital de Infectología del Centro Médico Nacional «La Raza», IMSS, Ciudad de México, México
| | | | - D Kershenobich
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
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6
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Lai Q, Mennini G, Giovanardi F, Rossi M, Giannini EG. Immunoglobulin, nucleos(t)ide analogues and hepatitis B virus recurrence after liver transplant: A meta-analysis. Eur J Clin Invest 2021; 51:e13575. [PMID: 33866547 PMCID: PMC8365701 DOI: 10.1111/eci.13575] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/04/2021] [Accepted: 04/13/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Prophylaxis with hepatitis B immunoglobulin (HBIG) represents an efficient strategy for reducing the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). Unfortunately, the long-term use of HBIG presents high costs. Therefore, the use of prophylaxis based only on nucleos(t)ide analogues (NUC) has been recently postulated. The present meta-analysis aimed to evaluate the impact of HBIG ± NUC vs HBIG alone or NUC alone in post-LT HBV recurrence prophylaxis. MATERIALS AND METHODS A systematic literature search was performed using PubMed and Cochrane databases. The primary outcome investigated was the HBV recurrence after LT. Three analyses were done comparing the effect of (a) HBIG + NUC vs HBIG alone; (b) HBIG+NUC vs NUC alone; and (c) HBIG alone vs NUC alone. Sub-analyses were also performed investigating the effect of low and high genetic barrierto-recurrence NUC. RESULTS Fifty-one studies were included. The summary OR (95%CI) showed a decreased risk with the combination of HBIG + NUC vs HBIG alone for HBV recurrence, being 0.36 (95% CI = 0.22-0.61; P < .001). HBIG + NUC combined treatment reduced HBV reappearance respect to NUC alone (OR = 0.22; 95% CI = 0.16-0.30; P < .0001). Similarly, HBIG alone was significantly better than NUC alone in preventing HBV recurrence (OR = 0.20; 95% CI = 0.09-0.44; P < .0001). CONCLUSIONS Prophylaxis with HBIG is relevant in preventing post-LT HBV recurrence. Its combination with NUC gives the best results in terms of protection. The present results should be considered in light of the fact that also old studies based on lamivudine use were included. Studies exploring in detail high genetic barrier-to-recurrence NUC and protocols with definite use of HBIG are needed.
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Affiliation(s)
- Quirino Lai
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Gianluca Mennini
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Francesco Giovanardi
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Massimo Rossi
- General Surgery and Organ Transplantation UnitDepartment of General and Specialistic SurgeryUmberto I Polyclinic of RomeSapienza University of RomeRomeItaly
| | - Edoardo G. Giannini
- Gastroenterology UnitDepartment of Internal MedicineUniversity of GenoaIRCCS Ospedale Policlinico San MartinoGenoaItaly
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7
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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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8
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Rodríguez M, Buti M, Esteban R, Lens S, Prieto M, Suárez E, García-Samaniego J. Consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B virus infection (2020). GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:559-587. [PMID: 32778356 DOI: 10.1016/j.gastrohep.2020.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.
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Affiliation(s)
- Manuel Rodríguez
- Sección de Hepatología, Servicio de Digestivo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España.
| | - María Buti
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Rafael Esteban
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Sabela Lens
- Servicio de Hepatología, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Universidad de Barcelona, Barcelona, España
| | - Martín Prieto
- Sección de Hepatología, Servicio de Medicina Digestiva, Hospital Universitari ì Politècnic La Fe, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Valencia, España
| | - Emilio Suárez
- Unidad de Enfermedades Digestivas, Hospital Universitario Virgen de Valme, Sevilla, España
| | - Javier García-Samaniego
- Unidad de Hepatología, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, España.
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9
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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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10
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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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Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, Hu TH, Yang HI, Lu SN, Ni YH, Chuang WL, Lee CM, Wu JC, Chen PJ, Liaw YF. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc 2019; 118:7-38. [PMID: 30527436 DOI: 10.1016/j.jfma.2018.11.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 01/10/2023] Open
Abstract
The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Affiliation(s)
- Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan.
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hwa-I Yang
- Department of Genomic Research Center, Sinica Academia, Taipei, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Won-Long Chuang
- Division of Hepatobiliary and Pancreas, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jaw-Chin Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan
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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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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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14
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Gane EJ. Is hepatitis B immune globulin still needed after liver transplantation for chronic hepatitis B? Hepatology 2017; 66:1023-1025. [PMID: 28555932 DOI: 10.1002/hep.29292] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 05/24/2017] [Indexed: 01/01/2023]
Affiliation(s)
- Edward J Gane
- New Zealand Liver Transplant Unit Auckland City Hospital, Auckland, New Zealand
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15
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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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16
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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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17
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18-75. [PMID: 27044762 PMCID: PMC4825166 DOI: 10.3350/cmh.2016.22.1.18] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 01/10/2023] Open
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18
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Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10:1-98. [PMID: 26563120 PMCID: PMC4722087 DOI: 10.1007/s12072-015-9675-4] [Citation(s) in RCA: 1930] [Impact Index Per Article: 214.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023]
Abstract
Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
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Affiliation(s)
- S K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - M Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - G K Lau
- Division of Gastroenterology and Hepatology, Humanity and Health Medical Centre, Hong Kong SAR, China
- The Institute of Translational Hepatology, Beijing, China
| | - Z Abbas
- Department of Hepatogastroenterlogy, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - H L Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - C J Chen
- Genomics Research Center, Academia Sinica, National Taiwan University, Taipei, Taiwan
| | - D S Chen
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - H L Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - P J Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - R N Chien
- Liver Research Unit, Chang Gung Memorial Hospital and University, Chilung, Taiwan
| | - A K Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - J L Hou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Guangzhou, China
| | - W Jafri
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - J Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - C L Lai
- Department of Medicine, University of Hong Kong, Hong Kong, China
| | - H C Lee
- Internal Medicine Asan Medical Center, Seoul, Korea
| | - S G Lim
- Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
| | - C J Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - S Locarnini
- Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia
| | - M Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - R Mohamed
- Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - M Omata
- Yamanashi Hospitals (Central and Kita) Organization, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan
| | - J Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - T Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songkhla, Thailand
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | - J Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - F S Wang
- Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China
| | - L Wei
- Peking University Hepatology Institute, Beijing, China
| | - M F Yuen
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Hong Kong, Pofulam, Hong Kong
| | - S S Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China
| | - J H Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Ku W, Wang U, Nguyen MH. Efficacy and effectiveness of anti-HBV therapy with early withdrawal of HBIG prophylaxis to prevent HBV recurrence following liver transplantation. Expert Opin Biol Ther 2015; 15:665-77. [PMID: 25865452 DOI: 10.1517/14712598.2015.1025045] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION The traditional regimen for prophylaxis of hepatitis B recurrence post-liver transplantation is to use hepatitis B immune globulin (HBIG) along with oral antiviral therapy; however, it is unclear when it is safe to discontinue HBIG after certain time point and to maintain patients with only oral antiviral therapy. Several studies have suggested that maintenance with oral anti-hepatitis B virus (HBV) therapy following short-term or no HBIG following the immediate post-transplantation period may also be safe and effective in prevention of HBV recurrence. AREAS COVERED We reviewed relevant literature to determine the effectiveness of early withdrawal of HBIG after liver transplantation and its effect on prevention of HBV recurrence. We used PubMed to search for any studies that used HBIG-free or short-term HBIG protocols with continued anti-HBV therapy. Short-term is defined as 12 months or less, and it is an evolving concept as new data on shorter and shorter duration becomes available. Additionally, a mini-quantitative analysis of the studies was performed using studies that involved the use of entecavir and tenofovir as anti-HBV therapy with or without HBIG. EXPERT OPINION Patients who are considered low risk for HBV recurrence at the time of liver transplant may safely be able to utilize a short-term duration of HBIG with indefinite antiviral maintenance therapy afterwards, whereas high-risk patients will likely need long-term HBIG in combination with antiviral therapy.
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Affiliation(s)
- Winston Ku
- Stanford University Medical Center, Division of Gastroenterology and Hepatology , 750 Welch Rd, Suite #210, Palo Alto, CA 94304 , USA
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Jiménez-Pérez M, González-Grande R, Mostazo Torres J, González Arjona C, Rando-Muñoz FJ. Management of hepatitis B virus infection after liver transplantation. World J Gastroenterol 2015; 21:12083-12090. [PMID: 26576093 PMCID: PMC4641126 DOI: 10.3748/wjg.v21.i42.12083] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Revised: 07/04/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation (LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B (CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins (HBIG) during the 1990s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance (e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors (with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.
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21
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Song ZL, Cui YJ, Zheng WP, Teng DH, Zheng H. Application of nucleoside analogues to liver transplant recipients with hepatitis B. World J Gastroenterol 2015; 21:12091-12100. [PMID: 26576094 PMCID: PMC4641127 DOI: 10.3748/wjg.v21.i42.12091] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 08/22/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is a common yet serious infectious disease of the liver, affecting millions of people worldwide. Liver transplantation is the only possible treatment for those who advance to end-stage liver disease. Donors positive for hepatitis B virus (HBV) core antibody (HBcAb) have previously been considered unsuitable for transplants. However, those who test negative for the more serious hepatitis B surface antigen can now be used as liver donors, thereby reducing organ shortages. Remarkable improvements have been made in the treatment against HBV, most notably with the development of nucleoside analogues (NAs), which markedly lessen cirrhosis and reduce post-transplantation HBV recurrence. However, HBV recurrence still occurs in many patients following liver transplantation due to the development of drug resistance and poor compliance with therapy. Optimized prophylactic treatment with appropriate NA usage is crucial prior to liver transplantation, and undetectable HBV DNA at the time of transplantation should be achieved. NA-based and hepatitis B immune globulin-based treatment regimens can differ between patients depending on the patients' condition, virus status, and presence of drug resistance. This review focuses on the current progress in applying NAs during the perioperative period of liver transplantation and the prophylactic strategies using NAs to prevent de novo HBV infection in recipients of HBcAb-positive liver grafts.
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Buti M, Tabernero D, Mas A, Homs M, Prieto M, Rodríguez-Frías F, Casafont F, Casillas R, González A, Miras M, Herrero JI, Castells L, Esteban R. Hepatitis B virus quasispecies evolution after liver transplantation in patients under long-term lamivudine prophylaxis with or without hepatitis B immune globulin. Transpl Infect Dis 2015; 17:208-220. [PMID: 25641570 DOI: 10.1111/tid.12360] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 12/23/2014] [Accepted: 01/18/2015] [Indexed: 12/22/2022]
Abstract
AIMS To investigate an optimal long-term prophylactic strategy for prevention of hepatitis B virus (HBV) recurrence after liver transplantation, we conducted a randomized study of 29 transplant recipients receiving a short course of hepatitis B immune globulin (HBIg) + lamivudine (LAM), followed by randomization to long-term prophylaxis with LAM with or without HBIg. METHODS The efficacy and safety, and impact on survival and HBV recurrence of these 2 prophylactic regimens were compared over a mean period of 10 years. In patients with viral recurrence, the HBV quasispecies in the surface/polymerase region were studied by ultra-deep pyrosequencing (UDPS). RESULTS The 10-year survival rate was 76% and was not affected by the type of prophylaxis. Four patients had hepatitis B surface antigen (HBsAg) recurrence within the first 48 months after orthotopic liver transplantation (OLT). HBsAg-positive and -negative patients showed similar mean survival times, with no differences between the 2 regimens. Low HBV DNA levels were transiently detected in 32% of HBsAg-negative patients. UDPS showed major changes after OLT in the HBV quasispecies of patients with viral recurrence, which may be explained by a "bottleneck" effect of OLT together with prophylactic therapy. CONCLUSION Long-term survival after OLT in end-stage chronic hepatitis B patients was good with both prophylactic strategies. However, low, transient HBV DNA levels were detected even in the absence of HBsAg, showing the importance of continuing HBV prophylaxis.
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Affiliation(s)
- M Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.mesot2014.o78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Xi ZF, Xia Q. Recent advances in prevention of hepatitis B recurrence after liver transplantation. World J Gastroenterol 2015; 21:829-835. [PMID: 25624716 PMCID: PMC4299335 DOI: 10.3748/wjg.v21.i3.829] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 08/31/2014] [Accepted: 12/08/2014] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is the only effective treatment for hepatitis B virus (HBV)-related end-stage liver disease. However, without antiviral prophylaxis, the recurrence rate of hepatitis B is as high as 80%-100%, which leads to a 50% mortality rate in the first 2 years after liver transplantation. Combination therapy of hepatitis B immunoglobulin (HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%. The strategy of HBIG combined with lamivudine has been the standard treatment in many centers. However, the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the long-term efficacy of this strategy for the prevention of HBV reinfection. Recently, new nucleos(t)ide analogues, such as entecavir and tenofovir, have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection. These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation. Various therapies that are composed of entecavir, tenofovir, and lamivudine plus adefovir, with or without HBIG have been adopted in several liver transplant centers. This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.
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Wang P, Tam N, Wang H, Zheng H, Chen P, Wu L, He X. Is hepatitis B immunoglobulin necessary in prophylaxis of hepatitis B recurrence after liver transplantation? A meta-analysis. PLoS One 2014; 9:e104480. [PMID: 25102072 PMCID: PMC4125198 DOI: 10.1371/journal.pone.0104480] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 07/09/2014] [Indexed: 12/12/2022] Open
Abstract
Background & Aims Application of nucleoside analogues and hepatitis B immunoglobulin (HBIG) has reduced hepatitis B virus (HBV) recurrence rate after liver transplantation (LT) dramatically. Recent data suggests therapy without HBIG is also effective. We sought to evaluate the necessity of HBIG in prophylaxis of HBV recurrence after LT. Methods A meta-analysis was performed. PubMed/MEDLINE, Web of Knowledge and other databases were searched for eligible literatures. The major end points were recurrence rate, patient survival, and YMDD mutant. Risk difference (RD) or risk ratio (RR) was calculated to synthesize the results. Results Nineteen studies with a total of 1484 patients were included in this analysis. Application of HBIG was helpful to reduce HBV recurrence [P<0.001; RD = 0.16; 95% confidence interval (CI)(0.12, 0.20)] and virus mutants [P<0.001; RR = 3.13; 95%CI (1.86–5.26)], it also improved patients' 1-year [P = 0.03; RD = 0.08; 95%CI (0.01, 0.15)] and 3-year survival rates [P = 0.005; RD = 0.17; 95%CI(0.05, 0.28)]. No significant difference was found for patients' 5-year survival [P = 0.46; RD = −0.06; 95%CI (−0.21, 0.10)]. Sub-group analysis showed that in patients with positive pre-operative HBV DNA status, HBIG was necessary to reduce HBV recurrence rate (P<0.001; RD = 0.42; 95%CI (0.32, 0.52)). In patients with negative HBV DNA, combined therapy gained no significant advantages (P = 0.18; RD = 0.06; 95%CI (−0.03, 0.14)). Non-Lamivudine (non-LAM) antiviral drugs performed as well as combination therapy in prophylaxis of HBV recurrence after LT (P = 0.37; RD = 0.06; 95%CI (−0.02, 0.14)). Conclusions HBIG with nucleoside analogues is helpful to reduce HBV recurrence and virus mutants. The necessity of HBIG in prophylaxis of HBV recurrence after LT when using new potent nucleoside analogues, especially for patients with negative pre-transplant HBV DNA status remains to be evaluated.
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Affiliation(s)
- Peijie Wang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Ngalei Tam
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Hepatobiliary Surgery Department, the University of Hong Kong - Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Haochen Wang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huanwei Zheng
- Liver Disease Department, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China
- Clinical Center for Liver Disease, University of Texas, Southwestern Medical Center, Dallas, Texas, United States of America
| | - Philip Chen
- Nephrology Department, University of Texas, Southwestern Medical Center, Dallas, Texas, United States of America
| | - Linwei Wu
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail:
| | - Xiaoshun He
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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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: 19] [Impact Index Per Article: 1.7] [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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Kasraianfard A, Watt KD, Lindberg L, Alexopoulos S, Rezaei N. HBIG Remains Significant in the Era of New Potent Nucleoside Analogues for Prophylaxis Against Hepatitis B Recurrence After Liver Transplantation. Int Rev Immunol 2014; 35:312-324. [PMID: 24911598 DOI: 10.3109/08830185.2014.921160] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Zhang Y, Kang S, Fang W, Wu X, Liang W. Network meta-analysis on prophylactic regimens against recurrent hepatitis B virus infection after liver transplantation. Hepatobiliary Surg Nutr 2014; 2:297-303. [PMID: 24570966 DOI: 10.3978/j.issn.2304-3881.2013.11.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 11/01/2013] [Indexed: 01/27/2023]
Abstract
BACKGROUND Previous meta-analyses of non-randomized studies suggested that the hepatitis B immunoglobulin (HBIG) and lamivudine (LAM) combination therapy was significantly better than HBIG or LAM alone in preventing hepatitis B virus (HBV) recurrence after transplantation. However, substantial evidences supporting the superiority of combination therapy are still insufficient. Therefore, we sought to conduct a multiple-treatment comparison to integrate current data which was based on randomized controlled trials (RCTs). METHODS We searched electronic databases of PubMed, Embase and the Cochrane Library for eligible literatures. Pair-wise meta-analyses were to synthesize studies comparing the same pair of treatments. Appropriate networks for overall and 1-year recurrence rates were established. Bayesian algorithm was used in multiple-treatment comparisons to compare relative effects of all included regimens. RESULTS Four RCTs on prophylaxis against HBV recurrence after liver transplantation, involving 162 participants, were included. HBIG mono-therapy, LAM mono-therapy and HBIG plus LAM showed no statistically difference in risk ratios (RRs) in terms of overall HBV recurrence rate in network meta-analysis. Nevertheless, HBIG mono-therapy had potential advantage compared with combination of HBIG and LAM in 1-year HBV recurrence rate [RR 0.00, 95% confidence interval (CI): 0.00 to 0.91] while the rest comparisons revealed no significance. The cumulative probabilities of treatments associated with the highest recurrence were (overall HBV recurrence rate, 1-year HBV recurrence rate): HBIG (18%, 1%), LAM (32%, 42%) and HBIG plus LAM (50%, 57%). CONCLUSIONS This network meta-analysis based on data from RCTs showed no significant differences among HBIG mono-therapy, LAM mono-therapy, combination of HBIG and LAM in overall HBV recurrence rate after liver transplantation. Further well designed and large-scale RCTs are warranted to clarify these issues.
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Affiliation(s)
- Yaxiong Zhang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Shiyang Kang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; ; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xuan Wu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; ; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenhua Liang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; ; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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Cholongitas E, Papatheodoridis GV. Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation. World J Gastroenterol 2013; 19:9189-9197. [PMID: 24409047 PMCID: PMC3882393 DOI: 10.3748/wjg.v19.i48.9189] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 10/29/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
The progress in treatment against hepatitis B virus (HBV) with the development of effective and well tolerated nucleotide analogues (NAs) has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence. This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation (LT). A literature search using the PubMed/Medline databases and consensus documents was performed. Pre-transplant therapy has been initially based on lamivudine, but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis. After LT, the combination of HBV immunoglobulin (HBIG) and NA is considered as the standard of care for prophylaxis against HBV recurrence. The combination of HBIG and lamivudine is related to higher rates of HBV recurrence, compared to the HBIG and entecavir or tenofovir combination. In HBIG-free prophylactic regimens, entecavir and tenofovir should be the first-line options. The choice of treatment for HBV recurrence depends on prior prophylactic therapy, but entecavir and tenofovir seem to be the most attractive options. Finally, liver grafts from hepatitis B core antibody (anti-HBc) positive donors can be safely used in hepatitis B surface antigen negative, preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.
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Lindenger C, Castedal M, Cahlin C, Friman S. Excellent liver transplantation survival and prevention of hepatitis B recurrence using hepatitis B immunoglobulin and nucleoside or nucleotide analogue along with treating physician adherence to treatment protocol. Transplant Proc 2013; 45:1188-92. [PMID: 23622656 DOI: 10.1016/j.transproceed.2012.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
INTRODUCTION The introduction of hepatitis B immunoglobulin (HBIG) in the early 1990s dramatically reduced recurrence of hepatitis B after orthotopic liver transplantation (OLT) and thus improved survival. Today a combination of HBIG and a nucleoside or nucleotide analogue (NUC) is recommended as prophylaxis. The optimal protocol is yet to be commonly agreed upon. The aim of this study was to review our results over 25 years. PATIENTS AND METHODS All 56 patients (45 males and 11 females) who underwent OLT due to hepatitis B infection between 1985-2009 were included in the review. Median age at transplantation was 51 years (range, 18-66). Seventeen patients (30%) had hepatocellular carcinoma (HCC) at transplantation. RESULTS The 1- and 5-year overall survival rates were 89% and 77%, respectively. The 23 patients who underwent transplantation before 2000 showed 1- and 5-year survival rates of 82% and 61%, respectively; the 33 who underwent transplantation between 2000 and 2009, the rates were 94% and 90%, respectively (P < .01). There was no difference in the 5-year survival rate between patients who had or did not have been HCC (75% vs 78%, respectively). Recurrence of hepatitis B, defined as seroconversion to HBsAg positivity, was observed in 9 patients. Three transplantation cases before 1992 consequently did not receive HBIG. The remaining 6, who all underwent OLT between 1993 and 2001, were administered HBIG. In all 6 cases periods of low anti-HBs titers were registered prior to recurrence; treating physician noncompliance with the protocol may have contributed to the low anti-HBs titers. No recurrence was registered after 2001. CONCLUSION With a combination of HBIG and NUC, excellent OLT results can be achieved for hepatitis B. It is, however, still important to maintain sufficient anti-HBs titers to prevent recurrence.
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Affiliation(s)
- C Lindenger
- Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.
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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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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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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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Tanaka T, Benmousa A, Marquez M, Therapondos G, Renner EL, Lilly LB. The long-term efficacy of nucleos(t)ide analog plus a year of low-dose HBIG to prevent HBV recurrence post-liver transplantation. Clin Transplant 2013; 26:E561-9. [PMID: 23061767 DOI: 10.1111/ctr.12022] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis B immunoglobulin (HBIG), given in combination with nucleos(t)ide therapy, has reduced the rate of recurrent hepatitis B virus (HBV) following liver transplantation (LT), although the most effective protocol is unknown. We have retrospectively evaluated the use of long-term nucleos(t)ide analog in combination with one yr of low-dose HBIG. One hundred and fifty-two adults with HBV-related liver disease underwent LT in our center from January 1999 to August 2009; of these, 132 patients who received one yr of HBIG combined with long-term nucleos(t)ide analogs (largely on lamivudine [LAM] alone, n = 97) afterward were included for the purposes of this study. Median follow-up post-transplantation was 1752 d. Patient survival was 93.9%, 86.9% and 84.1% at 1, 5, and 10 yr, respectively; none of the 17 deceased patients had recurrent HBV. HBV recurrence was observed in nine patients (all received LAM+HBIG), yielding recurrence rates of 2.3%, 5.1%, and 8.6% at 1, 3, and 5/10 yr, respectively. All recurrences were successfully managed, usually with additional antiviral treatment. In conclusion, this study, with its long-term follow-up, demonstrates that short course of low-dose HBIG (without anti-HBs monitoring) combined with the use of long-term nucleos(t)ide analog is effective and less cumbersome than many protocols in current use.
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Affiliation(s)
- Tomohiro Tanaka
- Liver Transplant Unit, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada
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Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. Am J Transplant 2013; 13:353-62. [PMID: 23137006 DOI: 10.1111/j.1600-6143.2012.04315.x] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 09/03/2012] [Accepted: 09/18/2012] [Indexed: 01/25/2023]
Abstract
The combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues [NA(s)] is considered as the standard of care for prophylaxis against HBV recurrence after liver transplantation (LT), but the optimal protocol is controversial. We evaluated the efficacy of the newer NAs with high genetic barrier (hgbNA) [i.e. entecavir (ETV) or tenofovir (TDF)] with or without HBIG as prophylaxis against HBV recurrence after LT. In total, 519 HBV liver transplant recipients from 17 studies met the inclusion criteria and they were compared to those under lamivudine (LAM) and HBIG who had been selected in our previous review. Patients under HBIG and LAM developed HBV recurrence (115/1889 or 6.1%): (a) significantly more frequently compared to patients under HBIG and a hgbNA [1.0% (3/303), p < 0.001], and (b) numerically but not significantly more frequently compared to the patients who received a newer NA after discontinuation of HBIG [3.9% (4/102), p = 0.52]. The use of a hgbNA without any HBIG offered similar antiviral prophylaxis compared to HBIG and LAM combination, if the definition of HBV recurrence was based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11]. Our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence after LT.
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Affiliation(s)
- E Cholongitas
- 4th Department of Internal Medicine, Aristotle University Medical School, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.
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Beckebaum S, Kabar I, Cicinnati VR. Hepatitis B and C in liver transplantation: new strategies to combat the enemies. Rev Med Virol 2012; 23:172-93. [PMID: 23239274 DOI: 10.1002/rmv.1734] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 10/29/2012] [Accepted: 11/01/2012] [Indexed: 12/16/2022]
Abstract
Hepatitis B immune globulin-free therapeutic regimens with a nucleos(t)ide analogue (NUC) or NUC combinations after liver transplantation (LT) are currently being investigated for their efficacy and safety as HBV re-infection prophylaxis in clinical studies. Recurrence rates differ among these studies as most of them are limited by a non-randomised study design, small sample size, lack of long-term data and varying time intervals for the switch from combined to purely virostatic prophylaxis. Post-transplant pre-emptive antiviral therapy with pegylated IFN and ribavirin is associated with low sustained virological response rates and was found to have no advantage over treatment of manifest HCV re-infection. Safety and efficacy of triple antiviral therapy including boceprevir or telaprevir in patients with manifest HCV re-infection are currently under investigation in clinical trials. Relevant drug interactions have been shown to occur during calcineurin inhibitor (CNI) and concomitant triple antiviral therapy, which vary with type of CNI and choice of HCV protease inhibitor. Newer direct-acting antivirals with lower or minimal toxicity, when used in combination with immunosuppressives, are worthy of further study in LT patients. This review focuses on hot topics in the management of hepatitis B and C patients before and after LT and offers a critical summarised selection of the corresponding relevant studies published in the current literature or presented at recent liver congresses.
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Affiliation(s)
- Susanne Beckebaum
- Department of Transplant Medicine, University Hospital Münster, Münster, Germany.
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Buti M, García-Samaniego J, Prieto M, Rodríguez M, Sánchez-Tapias JM, Suárez E, Esteban R. Documento de consenso de la AEEH sobre el tratamiento de la infección por el virus de la hepatitis B (2012). GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:512-28. [PMID: 22749508 DOI: 10.1016/j.gastrohep.2012.04.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2012] [Accepted: 04/23/2012] [Indexed: 12/13/2022]
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Stravitz RT, Shiffman ML, Kimmel M, Puri P, Luketic VA, Sterling RK, Sanyal AJ, Cotterell AH, Posner MP, Fisher RA. Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation. Liver Int 2012; 32:1138-45. [PMID: 22348467 DOI: 10.1111/j.1478-3231.2012.02770.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 01/24/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND Hepatitis B immune globulin (HBIg) with or without nucleos(t)ide analogue (NA) inhibitors has been shown to prevent recurrence of hepatitis B virus (HBV) following orthotopic liver transplantation (OLT). However, the use of HBIg has many disadvantages. AIMS The present study was performed to determine if converting patients from HBIg ± NA to combination NA therapy could prevent recurrence of HBV. METHODS Twenty-one recipients without evidence of HBV recurrence on HBIg ± NA for ≥ 6 months were enrolled. Patients received their last injection of HBIg at the time they initiated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; Truvada(®) ) and were followed up for 31.1 ± 9.0 [range 15-47] months. RESULTS After 1 year, 3 patients (14%) had detectable HBsAg, one of whom was non-compliant. Two of 3 with recurrence cleared HBsAg by last follow-up on TDF/FTC; the non-compliant patient became HBV DNA-undetectable with re-institution of TDF/FTC. TDF/FTC saved $12,469/year over our standard-of-care, monthly intramuscular HBIg/lamivudine. There was no evidence of a general adverse effect of TDF/FTC on renal function. However, 3 patients developed reversible acute renal failure; on renal biopsy, 1 had possible TDF/FTC-induced acute tubular necrosis. CONCLUSIONS Substitution of TDF/FTC for HBIg prevented recurrence of HBV DNA in 100% (20/20) of patients who were compliant with the medication and led to substantial cost savings over HBIg-containing regimens.
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Affiliation(s)
- R Todd Stravitz
- Section of Hepatology, Division of Gastroenterology, Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
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40
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Abstract
UNLABELLED The guideline on the management of chronic hepatitis B (CHB) was first developed in 2004 and revised in 2007 by the Korean Association for the Study of the Liver (KASL). Since then there have been many developments, including the introduction of new antiviral agents and the publications of many novel research results from both Korea and other countries. In particular, a large amount of knowledge on antiviral resistance--which is a serious issue in Korea--has accumulated, which has led to new strategies being suggested. This prompted the new guideline discussed herein to be developed based on recent evidence and expert opinion. TARGET POPULATION The main targets of this guideline comprise patients who are newly diagnosed with CHB and those who are followed or treated for known CHB. This guideline is also intended to provide guidance for the management of patients under the following special circumstances: malignancy, transplantation, dialysis, coinfection with other viruses, pregnancy, and children.
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MESH Headings
- Acute Disease
- Adolescent
- Adult
- Aged
- Alanine Transaminase/blood
- Antiviral Agents/therapeutic use
- Asian People
- Aspartate Aminotransferases/blood
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/etiology
- Child
- Child, Preschool
- Coinfection/drug therapy
- DNA, Viral/blood
- Drug Resistance, Viral
- Drug Therapy, Combination
- Female
- Hepatitis B Surface Antigens/blood
- Hepatitis B e Antigens/blood
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Humans
- Immunosuppression Therapy
- Infectious Disease Transmission, Vertical/prevention & control
- Liver/pathology
- Liver/physiology
- Liver Cirrhosis/physiopathology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/etiology
- Liver Transplantation
- Male
- Middle Aged
- Pregnancy
- Renal Dialysis
- Republic of Korea
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Abstract
The management of chronic hepatitis B virus (HBV) infection requires understanding the natural history of the disease as well as the risks, benefits, and limitations of the therapeutic options. This article covers the principles governing when to start antiviral therapy, discusses recent advances using hepatitis B surface antigen quantification to better define various phases of infection, describes the use of HBV core, precore, and viral genotyping as well as host IL28B genotyping to predict response to interferon therapy, and reports on the management of HBV in 3 special populations (pregnancy, postliver transplantation, and in the setting of chemotherapy or immunosuppression).
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Affiliation(s)
- Alexander Kuo
- Division of Gastroenterology, University of California, San Diego, 92103, USA.
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42
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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: 62] [Impact Index Per Article: 4.8] [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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43
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Chang MS, Brown RS. Hepatitis B and Liver Transplantation: Update in Management before and after Transplantation. CURRENT HEPATITIS REPORTS 2011; 10:255-261. [DOI: 10.1007/s11901-011-0108-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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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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45
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Abstract
The management of hepatitis B in liver transplantation has evolved significantly over the past 2 decades. Introduction of hepatitis B immune globulin and subsequently nucleos(t)ide analogues has revolutionized transplantation for hepatitis B virus (HBV), increasing survival for patients transplanted for this indication. With the availability of new and potent antivirals for HBV, the need for liver transplant should continue to decrease in the coming years. Moreover, the newer antivirals with high resistance barriers will allow effective long-term viral prophylaxis and therefore, prevention of recurrence.
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Affiliation(s)
- Corinne Buchanan
- Center for Liver Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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46
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Abstract
Passive immunization employs preformed antibodies provided to an individual that can prevent or treat infectious diseases. There are several situations in which passive immunization can be used: for persons with congenital or acquired immunodeficiency, prophylactic administration when there is a likelihood of exposure to a particular infection, or treatment of a disease state already acquired by the individual. Passive immunization is limited by short duration (typically weeks to months), variable response, and adverse reactions. This article focuses on specific immunoglobulins for preventing or treating infectious diseases, as these are the most likely scenarios one might encounter in primary care practice.
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Affiliation(s)
- Christopher P Raab
- Thomas Jefferson University, 1020 Walnut Street, Philadelphia, PA 19107, USA.
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Cholongitas E, Goulis J, Akriviadis E, Papatheodoridis GV. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis b virus recurrence after liver transplantation: a systematic review. Liver Transpl 2011; 17:1176-90. [PMID: 21656655 DOI: 10.1002/lt.22354] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NUCs) is currently recommended as prophylaxis against the recurrence of hepatitis B virus (HBV) after liver transplantation (LT), but the optimal protocol is a matter of controversy. The aim of this study was the identification of factors associated with post-LT HBV recurrence in patients receiving HBIG and NUCs. We searched MEDLINE and PubMed for studies in English about the effectiveness of HBIG and NUCs [lamivudine (LAM) and/or adefovir dipivoxil (ADV)] against post-LT HBV recurrence (January 1998 to June 2010). Forty-six studies, which included 2162 HBV LT recipients, met the selection criteria. Patients receiving HBIG and LAM experienced HBV recurrence more frequently than patients receiving HBIG and ADV with or without LAM [6.1% (115/1889) versus 2.0% (3/152), P = 0.024], although they also were more frequently treated with indefinite HBIG prophylaxis (90% versus 57%, P < 0.001). For patients receiving HBIG and LAM, a lower frequency of HBV recurrence was associated with a high HBIG dosage (≥10,000 IU/day) versus a low HBIG dosage (<10,000 IU/day) during the first week after LT [3.2% (14/440) versus 6.5% (80/1233), P = 0.016], but the HBIG protocol had no impact on HBV recurrence in patients receiving HBIG and ADV. In conclusion, in comparison with the combination of HBIG and LAM, the combination of HBIG and ADV is associated with a lower rate of HBV recurrence after LT. Patients receiving HBIG and LAM should be given a high dosage of HBIG during the first week after LT, but a lower dosage can be used safely in patients receiving HBIG and ADV. Further studies with newer and more potent anti-HBV agents are definitely required.
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Affiliation(s)
- Evangelos Cholongitas
- Fourth Department of Internal Medicine, Aristotle University Medical School, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.
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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: 14] [Impact Index Per Article: 1.0] [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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49
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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: 60] [Impact Index Per Article: 4.3] [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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Abstract
Chronic hepatitis B continues to be a major global health burden. It accounts for a substantial impact on health care resources and finances in many parts of the world including Europe. Natural history and disease spectrum are varied, depending on when and how the infection is acquired. The chronic infective state increases patients' risk of progression to liver cirrhosis or hepatocellular carcinoma. Several treatment options are currently available, but their use depends on the stage of the patient's infection, which is influenced by both host and viral factors. The ultimate goals in hepatitis B treatment are to prevent disease progression, hepatic decompensation, hepatocellular carcinoma, and death. Patients with decompensated liver cirrhosis should be referred to specialized transplant centers in a timely manner.
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