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Svicher V, Salpini R, D’Anna S, Piermatteo L, Iannetta M, Malagnino V, Sarmati L. New insights into hepatitis B virus lymphotropism: Implications for HBV-related lymphomagenesis. Front Oncol 2023; 13:1143258. [PMID: 37007163 PMCID: PMC10050604 DOI: 10.3389/fonc.2023.1143258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
HBV is one of the most widespread hepatitis viruses worldwide, and a correlation between chronic infection and liver cancer has been clearly reported. The carcinogenic capacity of HBV has been reported for other solid tumors, but the largest number of studies focus on its possible lymphomagenic role. To update the correlation between HBV infection and the occurrence of lymphatic or hematologic malignancies, the most recent evidence from epidemiological and in vitro studies has been reported. In the context of hematological malignancies, the strongest epidemiological correlations are with the emergence of lymphomas, in particular non-Hodgkin's lymphoma (NHL) (HR 2.10 [95% CI 1.34-3.31], p=0.001) and, more specifically, all NHL B subtypes (HR 2.14 [95% CI 1.61-2.07], p<0.001). Questionable and unconfirmed associations are reported between HBV and NHL T subtypes (HR 1.11 [95% CI 0.88-1.40], p=0.40) and leukemia. The presence of HBV DNA in peripheral blood mononuclear cells has been reported by numerous studies, and its integration in the exonic regions of some genes is considered a possible source of carcinogenesis. Some in vitro studies have shown the ability of HBV to infect, albeit not productively, both lymphomonocytes and bone marrow stem cells, whose differentiation is halted by the virus. As demonstrated in animal models, HBV infection of blood cells and the persistence of HBV DNA in peripheral lymphomonocytes and bone marrow stem cells suggests that these cellular compartments may act as HBV reservoirs, allowing replication to resume later in the immunocompromised patients (such as liver transplant recipients) or in subjects discontinuing effective antiviral therapy. The pathogenetic mechanisms at the basis of HBV carcinogenic potential are not known, and more in-depth studies are needed, considering that a clear correlation between chronic HBV infection and hematological malignancies could benefit both antiviral drugs and vaccines.
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Affiliation(s)
- Valentina Svicher
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Romina Salpini
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Stefano D’Anna
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Marco Iannetta
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Vincenzo Malagnino
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Loredana Sarmati
- Clinical Infectious Diseases, Department of System Medicine, University of Rome Tor Vergata, Rome, Italy
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Muhammad H, Zaffar D, Tehreem A, Ting PS, Simsek C, Gokcan H, Gurakar A, Idilman R. HBV/HDV management after liver transplantation: Review. JOURNAL OF LIVER TRANSPLANTATION 2021. [DOI: 10.1016/j.liver.2021.100046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Coffin CS, Mulrooney-Cousins PM, Michalak TI. Hepadnaviral Lymphotropism and Its Relevance to HBV Persistence and Pathogenesis. Front Microbiol 2021; 12:695384. [PMID: 34421849 PMCID: PMC8377760 DOI: 10.3389/fmicb.2021.695384] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Since the discovery of hepatitis B virus (HBV) over five decades ago, there have been many independent studies showing presence of HBV genomes in cells of the immune system. However, the nature of HBV lymphotropism and its significance with respect to HBV biology, persistence and the pathogenesis of liver and extrahepatic disorders remains underappreciated. This is in contrast to studies of other viral pathogens in which the capability to infect immune cells is an area of active investigation. Indeed, in some viral infections, lymphotropism may be essential, and even a primary mechanism of viral persistence, and a major contributor to disease pathogenesis. Nevertheless, there are advances in understanding of HBV lymphotropism in recent years due to cumulative evidence showing that: (i) lymphoid cells are a reservoir of replicating HBV, (ii) are a site of HBV-host DNA integration and (iii) virus genomic diversification leading to pathogenic variants, and (iv) they play a role in HBV resistance to antiviral therapy and (v) likely contribute to reactivation of hepatitis B. Further support for HBV lymphotropic nature is provided by studies in a model infection with the closely related woodchuck hepatitis virus (WHV) naturally infecting susceptible marmots. This animal model faithfully reproduces many aspects of HBV biology, including its replication scheme, tissue tropism, and induction of both symptomatic and silent infections, immunological processes accompanying infection, and progressing liver disease culminating in hepatocellular carcinoma. The most robust evidence came from the ability of WHV to establish persistent infection of the immune system that may not engage the liver when small quantities of virus are experimentally administered or naturally transmitted into virus-naïve animals. Although the concept of HBV lymphotropism is not new, it remains controversial and not accepted by conventional HBV researchers. This review summarizes research advances on HBV and hepadnaviral lymphotropism including the role of immune cells infection in viral persistence and the pathogenesis of HBV-induced liver and extrahepatic diseases. Finally, we discuss the role of immune cells in HBV diagnosis and assessment of antiviral therapy efficacy.
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Affiliation(s)
- Carla S Coffin
- Liver Unit, Department of Gastroenterology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Patricia M Mulrooney-Cousins
- Molecular Virology and Hepatology Research Group, Division of Basic Medical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of Basic Medical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
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Michalak TI. Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B. Front Immunol 2020; 11:853. [PMID: 32536912 PMCID: PMC7267019 DOI: 10.3389/fimmu.2020.00853] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.
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Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
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VanHuis A, Loy V. Myth: Liver Transplant Provides a Cure for Liver Disease. Clin Liver Dis (Hoboken) 2019; 13:154-157. [PMID: 31316761 PMCID: PMC6605739 DOI: 10.1002/cld.770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 09/27/2018] [Indexed: 02/04/2023] Open
Affiliation(s)
| | - Veronica Loy
- Department of GastroenterologyEdward Hines Junior VA HospitalHinesIL
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Lau KCK, Osiowy C, Giles E, Lusina B, van Marle G, Burak KW, Coffin CS. Deep sequencing shows low-level oncogenic hepatitis B virus variants persists post-liver transplant despite potent anti-HBV prophylaxis. J Viral Hepat 2018; 25:724-732. [PMID: 29316067 DOI: 10.1111/jvh.12860] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/27/2017] [Indexed: 12/17/2022]
Abstract
Recent studies suggest that withdrawal of hepatitis B immune globulin (HBIG) and nucleos(t)ide analogues (NA) prophylaxis may be considered in HBV surface antigen (HBsAg)-negative liver transplant (LT) recipients with a low risk of disease recurrence. However, the frequency of occult HBV infection (OBI) and HBV variants after LT in the current era of potent NA therapy is unknown. Twelve LT recipients on prophylaxis were tested in matched plasma and peripheral blood mononuclear cells (PBMCs) for HBV quasispecies by in-house nested PCR and next-generation sequencing of amplicons. HBV covalently closed circular DNA (cccDNA) was detected in Hirt DNA isolated from PBMCs with cccDNA-specific primers and confirmed by nucleic acid hybridization and Sanger sequencing. HBV mRNA in PBMC was detected with reverse-transcriptase nested PCR. In LT recipients on immunosuppressive therapy (10/12 male; median age 57.5 [IQR: 39.8-66.5]; median follow-up post-LT 60 months; 6 pre-LT hepatocellular carcinoma [HCC]), 9 were HBsAg-. HBV DNA was detected in all plasma and PBMC tested; cccDNA and/or mRNA was detected in the PBMC of 10/12 patients. Significant HBV quasispecies diversity (ie 143-2212 nonredundant HBV species) was noted in both sites, and single nucleotide polymorphisms associated with cirrhosis and HCC were detected at varying frequencies. In conclusion, OBI and HBV variants associated with severe liver disease persist in LT recipients on prophylaxis. Although HBV control and cccDNA transcriptional silencing may occur despite immunosuppression, complete virological eradication does not occur in LT recipients with a history of HBV-related end-stage liver disease.
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Affiliation(s)
- K C K Lau
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - C Osiowy
- Bloodborne Pathogens and Hepatitis, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - E Giles
- Bloodborne Pathogens and Hepatitis, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - B Lusina
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - G van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - K W Burak
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - C S Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Gao S, Duan ZP, Chen Y, van der Meer F, Lee SS, Osiowy C, van Marle G, Coffin CS. Compartmental HBV evolution and replication in liver and extrahepatic sites after nucleos/tide analogue therapy in chronic hepatitis B carriers. J Clin Virol 2017; 94:8-14. [PMID: 28709006 DOI: 10.1016/j.jcv.2017.06.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 06/23/2017] [Accepted: 06/30/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) variants are associated with nucleos/tide analogue (NA) response and liver disease but it is unknown whether NA influences extrahepatic HBV persistence. OBJECTIVES To investigate HBV replication and genetic evolution in hepatic and extrahepatic sites of chronic hepatitis B (CHB) before and after NA therapy. STUDY DESIGN A total of 13 paired plasma, peripheral blood mononuclear cells (PBMC), were collected from chronic HBV carriers at baseline and after a median 53 weeks NA therapy as well as liver biopsy (N=7 baseline, N=5 follow-up). HBV covalently closed circular DNA (cccDNA) and messenger (m) RNA in liver and PBMC were analyzed. HBV polymerase (P)/surface (S), basal core promoter (BCP)/pre-core (PC)/C gene clonal sequencing was done in plasma, peripheral blood mononuclear cells (PBMC), and liver. RESULTS Compare to baseline, at ∼53 weeks follow-up, there was no significant change in HBV cccDNA levels in liver (0.2-0.08 copies/hepatocyte, p>0.05) or in PBMC 0.003-0.02 copies/PBMC, p>0.05), and HBV mRNA remained detectable in both sites. At baseline, BCP variants were higher in PBMC vs. liver and plasma. After therapy, drug resistant (DR) and immune escape (IE) variants increased in liver but IE and PC variants were more frequent in PBMC. HBV P/S diversity was significantly higher in PBMC compared to plasma. CONCLUSION Continuous HBV replication occurs in liver and PBMC and shows compartmentalized evolution under selective pressure of potent NA therapy.
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Affiliation(s)
- Shan Gao
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhong-Ping Duan
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yu Chen
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Frank van der Meer
- Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Samuel S Lee
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carla Osiowy
- Bloodborne Pathogens and Hepatitis Laboratory of the National Microbiology Laboratory, Winnipeg, MB, Canada
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carla S Coffin
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Lee MH, Lin YC, Cheng HT, Chuang WY, Huang HC, Kao HW. Coexistence of hepatoma with mantle cell lymphoma in a hepatitis B carrier. World J Gastroenterol 2015; 21:12981-12986. [PMID: 26668520 PMCID: PMC4671051 DOI: 10.3748/wjg.v21.i45.12981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/24/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
The coexistence of hepatocellular carcinoma (HCC) and non-Hodgkin’s lymphoma (NHL) in the liver is rare. Reports show that these patients have cirrhotic livers or hepatitis virus infections before they develop HCC and NHL. We present a patient with hepatitis B virus infection who was transferred to our hospital with a newly detected liver mass; abdominal computed tomography examination showed one hypodense mass of 7 cm in diameter and multiple mesenteric and mediastinal lymph nodes. A liver tumor biopsy showed a hepatoma, and the pathologic findings from an inguinal lymph node excision showed mantle cell lymphoma. An immunohistochemical stain confirmed that the atypical lymphoid cells within the HCC were positive for the CD20, CD5 and cyclin D1 antigens. Taking these findings into account, the hepatic tumor was determined to be a HCC infiltrated by mantle cell lymphoma.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Biomarkers, Tumor/analysis
- Biopsy
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/virology
- Cyclophosphamide/therapeutic use
- Doxorubicin/therapeutic use
- Hepatitis B/complications
- Hepatitis B/diagnosis
- Humans
- Immunohistochemistry
- Liver Neoplasms/chemistry
- Liver Neoplasms/diagnosis
- Liver Neoplasms/drug therapy
- Liver Neoplasms/virology
- Lymphoma, Mantle-Cell/chemistry
- Lymphoma, Mantle-Cell/diagnosis
- Lymphoma, Mantle-Cell/drug therapy
- Lymphoma, Mantle-Cell/virology
- Male
- Middle Aged
- Neoplasms, Multiple Primary
- Prednisolone/therapeutic use
- Risk Factors
- Tomography, X-Ray Computed
- Treatment Outcome
- Vincristine/therapeutic use
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Makvandi K, Ranjbari N, Makvandi M, Ashraf Teimori A, Neisi N, Rasti M, Alipour V, Albokord M, Kanani M, Ahadi R, Habibian A. Study of the Association of Mutant HBsAg Gene and Hodgkin and Non-Hodgkin Lymphoma. Jundishapur J Microbiol 2015; 8:e25726. [PMID: 26862382 PMCID: PMC4740896 DOI: 10.5812/jjm.25726] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 04/05/2015] [Accepted: 05/23/2015] [Indexed: 01/04/2023] Open
Abstract
Background: Hepatitis B Virus (HBV) is responsible for chronic, acute, and fulminant hepatitis, which are prevalent worldwide. Chronic HBV may lead to cirrhosis and hepatocellular carcinoma. Several epidemiological studies have indicated that hepatitis B virus is involved in B-cell Hodgkin and Non-Hodgkin Lymphoma (NHL). Objectives: The aim of this study was to evaluate the association between hepatitis B infection and Hodgkin and non-Hodgkin Lymphoma. Materials and Methods: Paraffin embedded of 41 block samples including 12 (29.26%) Hodgkin and 29 (70.73%) non-Hodgkin patients were collected. Next, DNA extraction was carried out for all the samples followed by HBV DNA detection by the nested polymerase chain reaction (PCR). The positive HBV DNA samples were sequenced, and HBV genotypes and HBV subtypes were determined. Results: Three out of 12 (25%) Hodgkin samples and seven out of 29 (24.13%) non-Hodgkin showed positive HBV DNA results. The results of sequencing revealed that the D genotype was predominant among the positive HBV patients. Interestingly an unpredictable amino acid proline was detected in position 88 of the HBs gene, which indicates a new mutation in the “S” region of HBV DNA in patients with Hodgkin and non-Hodgkin lymphoma. Conclusions: A high rate of 25% and 24.13% of HBV DNA was detected among patients with Hodgkin and non-Hodgkin lymphoma, respectively.
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Affiliation(s)
- Kamyar Makvandi
- Infectious and Tropical Disease Research Center, Health Research Institute, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Nastaran Ranjbari
- Department of Pathology, Imam Khomeini hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
- Corresponding author: Nastaran Ranjbari, Department of Pathology, Imam Khomeini hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran. Tel: +98-6133354389, Fax: +98-6113361544, E-mail:
| | - Manoochehr Makvandi
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Ali Ashraf Teimori
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Niloofar Neisi
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Mojtaba Rasti
- Infectious and Tropical Disease Research Center, Health Research Institute, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Vida Alipour
- Infectious and Tropical Disease Research Center, Health Research Institute, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Mostafa Albokord
- Infectious and Tropical Disease Research Center, Health Research Institute, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Malek Kanani
- Department of Pathology, Imam Khomeini hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Ramezan Ahadi
- Department of Nuclear Medicine, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
| | - Ala Habibian
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
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Mulrooney-Cousins PM, Michalak TI. Asymptomatic Hepadnaviral Persistence and Its Consequences in the Woodchuck Model of Occult Hepatitis B Virus Infection. J Clin Transl Hepatol 2015; 3:211-9. [PMID: 26623268 PMCID: PMC4663203 DOI: 10.14218/jcth.2015.00020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 07/20/2015] [Accepted: 07/21/2015] [Indexed: 02/06/2023] Open
Abstract
Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV). Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology, where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC). Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model: secondary occult infection (SOI) and primary occult infection (POI). SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure. POI is caused by small amounts of virus and progresses without serological infection markers, but the virus genome and its replication are detectable in the immune system and with time in the liver. SOI can be accompanied by minimal hepatitis, while the hallmark of POI is normal liver morphology. Nonetheless, HCC develops in about 20% of animals with SOI or POI within 3 to 5 years. The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL, causes hepatitis and HCC when concentrated and administered to virus-naïve woodchucks. SOI is accompanied by virus-specific T and B cell immune responses, while only virus-specific T cells are detected in POI. SOI coincides with protection against reinfection, while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions. Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes. Overall, SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics. Here, we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI).
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Affiliation(s)
| | - Tomasz I. Michalak
- Correspondence to: Tomasz I. Michalak, Molecular Virology and Hepatology Research Group, Faculty of Medicine, Health Sciences Centre, Memorial University, St. John’s, NL A1B 3V6, Canada. Tel: +1-709-777-7301, Fax: +1-709-777-8279, E-mail:
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Detection of Hepatitis B Virus (HBV) Genomes and HBV Drug Resistant Variants by Deep Sequencing Analysis of HBV Genomes in Immune Cell Subsets of HBV Mono-Infected and/or Human Immunodeficiency Virus Type-1 (HIV-1) and HBV Co-Infected Individuals. PLoS One 2015; 10:e0137568. [PMID: 26390290 PMCID: PMC4577215 DOI: 10.1371/journal.pone.0137568] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 08/18/2015] [Indexed: 12/14/2022] Open
Abstract
The hepatitis B virus (HBV) and the human immunodeficiency virus type 1 (HIV-1) can infect cells of the lymphatic system. It is unknown whether HIV-1 co-infection impacts infection of peripheral blood mononuclear cell (PBMC) subsets by the HBV. Aims To compare the detection of HBV genomes and HBV sequences in unsorted PBMCs and subsets (i.e., CD4+ T, CD8+ T, CD14+ monocytes, CD19+ B, CD56+ NK cells) in HBV mono-infected vs. HBV/HIV-1 co-infected individuals. Methods Total PBMC and subsets isolated from 14 HBV mono-infected (4/14 before and after anti-HBV therapy) and 6 HBV/HIV-1 co-infected individuals (5/6 consistently on dual active anti-HBV/HIV therapy) were tested for HBV genomes, including replication indicative HBV covalently closed circular (ccc)-DNA, by nested PCR/nucleic hybridization and/or quantitative PCR. In CD4+, and/or CD56+ subsets from two HBV monoinfected cases, the HBV polymerase/overlapping surface region was analyzed by next generation sequencing. Results All analyzed whole PBMC from HBV monoinfected and HBV/HIV coinfected individuals were HBV genome positive. Similarly, HBV DNA was detected in all target PBMC subsets regardless of antiviral therapy, but was absent from the CD4+ T cell subset from all HBV/HIV-1 positive cases (P<0.04). In the CD4+ and CD56+ subset of 2 HBV monoinfected cases on tenofovir therapy, mutations at residues associated with drug resistance and/or immune escape (i.e., G145R) were detected in a minor percentage of the population. Summary HBV genomes and drug resistant variants were detectable in PBMC subsets from HBV mono-infected individuals. The HBV replicates in PBMC subsets of HBV/HIV-1 patients except the CD4+ T cell subpopulation.
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12
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Yan Y, Chen N, Wang Y, Wang K. The application of antitumor drug-targeting models on liver cancer. Drug Deliv 2015; 23:1667-75. [PMID: 26289213 DOI: 10.3109/10717544.2015.1064188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.
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Affiliation(s)
- Yan Yan
- a School of Pharmacy, Xi'an Jiaotong University , Xi'an , Shaanxi , China
| | - Ningbo Chen
- b Surgical Department of Emergency Center, The People's Hospital of Sichuan Province , Sichuan , China and
| | - Yunbing Wang
- c National Engineering Research Center in Biomaterials, Sichuan University , Chengdu , Sichuan , China
| | - Ke Wang
- a School of Pharmacy, Xi'an Jiaotong University , Xi'an , Shaanxi , China
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Au KP, Chan SC, Chok KSH, Sharr WW, Dai WC, Sin SL, Wong TCL, Lo CM. Clinical factors affecting rejection rates in liver transplantation. Hepatobiliary Pancreat Dis Int 2015; 14:367-373. [PMID: 26256080 DOI: 10.1016/s1499-3872(15)60391-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND With improvements in survival, liver transplant recipients now suffer more morbidity from long-term immunosuppression. Considerations were given to develop individualized immunosuppression based on their risk of rejection. METHOD We retrospectively analyzed the data of 788 liver transplants performed during the period from October 1991 to December 2011 to study the relationship between acute cellular rejection (ACR) and various clinical factors. RESULTS Multivariate analysis showed that older age (P=0.04, OR=0.982), chronic hepatitis B virus infection (P=0.005, OR= 0.574), living donor liver transplantation (P=0.02, OR=0.648) and use of interleukin-2 receptor antagonist on induction (P<0.001, OR=0.401) were associated with fewer ACRs. Patients with fulminant liver failure (P=0.004, OR=4.05) were more likely to develop moderate to severe grade ACR. CONCLUSIONS Liver transplant recipients with older age, chronic hepatitis B virus infection, living donor liver transplantation and use of interleukin-2 receptor antagonist on induction have fewer ACR. Patients transplanted for fulminant liver failure are at higher risk of moderate to severe grade ACR. These results provide theoretical framework for developing individualized immunosuppression.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, the University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong SAR, China.
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14
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Loustaud-Ratti V, Wagner A, Carrier P, Marczuk V, Chemin I, Lunel F, Fouchard-Hubert I, Ahmed SS, Abergel A, Rousseau A, Lefebvre A, Debette-Gratien M, Denis F, Alain S. Distribution of total DNA and cccDNA in serum and PBMCs may reflect the HBV immune status in HBsAg+ and HBsAg- patients coinfected or not with HIV or HCV. Clin Res Hepatol Gastroenterol 2013; 37:373-383. [PMID: 23477988 DOI: 10.1016/j.clinre.2012.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 10/07/2012] [Accepted: 11/06/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND The potential reservoir role of serum and peripheral blood mononuclear cells (PBMCs) for total HBV DNA (tDNA) and cccDNA still remains unknown. MATERIAL AND METHODS We analyzed tDNA and cccDNA with a single sensitive and validated standardized real-time PCR method in serum and PBMCs in two populations of chronic HBV infection coinfected or not with HCV and/or HIV viruses: a retrospective cohort of 130 HBsAg-negative (HBsAg-) patients with "anti-HBc alone" or anti-HBc and anti-HBs antibodies (Ab) and a cohort of 70 HBsAg-positive patients, 16 of them being prospectively followed under treatment. RESULTS Among HBsAg- patients, HBV DNA was detected in serum or PBMCs in about half of the cases with various distributions of tDNA and cccDNA: in HIV-negative patients with an "antiHBc alone" profile, tDNA was mostly detected in PBMCs suggesting a possible active role of PBMCs; although cccDNA was not detected in PBMCs in HIV-positive patients, tDNA and cccDNA were mostly observed in serum, suggesting a specific pattern of more "persistent" than "occult" infection in this population. Patients with anti-HBc and anti-HBs Ab harbored tDNA in serum or in PBMCs, regardless of their HIV or HCV status, raising the question of a viral reactivation risk during immunosupression in these patients. Among HBsAg+ patients, tDNA was detected in serum and PBMCs of 88.5% of the cases and cccDNA in 22%. Levels of tDNA in both compartments were highly correlated during treatment, suggesting a passive reservoir role for PBMCs. CONCLUSION The respective distribution of tDNA and cccDNA in serum and PBMCs may reflect the different immune statuses of the host in HBsAg+ and HBsAg- patients. The frequency of HBV DNA in PBMCs from AgHBs- patients suggests a viral reactivation risk during immunodepression in those patients.
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Affiliation(s)
- V Loustaud-Ratti
- Inserm UMR 1092, Faculté de médecine, Université Limoges, 2, rue du Docteur-Marcland, 87025 Limoges cedex, 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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16
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Levitsky J, Doucette K. Viral hepatitis in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:147-68. [PMID: 23465008 DOI: 10.1111/ajt.12108] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- J Levitsky
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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17
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Alavian SM, Lankarani KB, Rizzetto M, Marzano A, Moghadami M, Nik-Eghbolian S, Bahrani A. Management of Hepatitis B Virus Infection in Liver Transplantation Setting; The Rising Concerns and Growing Hopes, Report From 10th Congress of the Iranian Society for Organ Transplantation, 2011, Shiraz, Iran. HEPATITIS MONTHLY 2012; 12:e8094. [PMCID: PMC3580826 DOI: 10.5812/hepatmon.8094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 08/15/2012] [Accepted: 09/08/2012] [Indexed: 02/05/2023]
Abstract
Hepatitis B infection is the main cause of liver related mortality in many countries including Iran. Liver transplantation in cirrhosis due to HBV infection before 1990 was an absolute contraindication. Recurrent infection was a significant event in post liver transplant setting and resulted in increased risk of graft failure and death except successful transplanted individuals. Advances in antiviral prophylaxis have now made graft reinfection majority patients as a rare event. Graft and patient survival have been improved significantly during the past two decades, and consequences of transplantation for hepatitis B virus are now superior to those achieved for most other indications. This has encouraged many centers including the major liver transplantation center of Iran, in Shiraz, to provide liver transplantation to more patients with HBV related end stage liver disease. Management of these patients begins before transplantation along with special care after transplantation. There are some myths and doubts in the management of these patients and one should always balance the cost and efficiency. One of the major concerns is the high economic and social cost of recurrence and all possible efforts should be performed to avoid the ominous consequences of reinfection. Having a clear scientific grasp on the management of HBV cirrhosis before and after liver transplantation, options and protocols, and changing the concept which HBV infected are contraindicated ones for liver transplantation, and future hopes in increasing patients survival after liver transplantation using the new nucleosides analogues and availability of hepatitis B immunoglobulin in the transplantation setting. This scientific report paper outlines the insights communicated at the HBV and liver transplantation symposium during 10th Congress of the Iranian Society for Organ Transplantation, May 2011, Shiraz, Iran.
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Affiliation(s)
- Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Kamran B. Lankarani
- Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Mario Rizzetto
- Department of Gastroenterology, Molinette University of Torino, Torino, Italy
| | - Alfredo Marzano
- Division of Gastroenterology and Hepatology, San Giovanni Battista Hospital, Turin, Italy
| | - Mohsen Moghadami
- HIV/AIDS Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Saman Nik-Eghbolian
- Shiraz Organ Transplant Unit, Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Amin Bahrani
- Shiraz Organ Transplant Unit, Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, IR Iran
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18
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Coffin CS, Mulrooney-Cousins PM, van Marle G, Roberts JP, Michalak TI, Terrault NA. Hepatitis B virus quasispecies in hepatic and extrahepatic viral reservoirs in liver transplant recipients on prophylactic therapy. Liver Transpl 2011; 17:955-62. [PMID: 21462295 DOI: 10.1002/lt.22312] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The characterization of hepatitis B virus (HBV) quasispecies in different compartments in liver transplant (LT) recipients may be helpful in optimizing prophylaxis regimens. The aims of this study were to evaluate liver, peripheral blood mononuclear cells (PBMC), and plasma samples for HBV and to compare the quasispecies in hepatic and extrahepatic sites in LT recipients on long-term prophylaxis. For 12 patients followed for up to 15 years post-LT, liver, plasma, and PBMC samples [all HBV DNA-negative according to conventional polymerase chain reaction (PCR) assays] were evaluated for HBV DNA by a sensitive nested PCR method [covalently closed circular DNA (cccDNA) for liver and PBMC samples] and by the sequencing and phylogenetic analysis of polymerase quasispecies. For the 10 patients on prophylaxis with no clinical recurrence (median time post-LT = 15.5 months, range = 12-96 months), liver samples were HBV DNA-reactive in 9 of 10 cases, plasma samples were HBV DNA-reactive in 3 of 10 cases, and PBMC samples were HBV DNA-reactive in 2 of 7 cases (including 1 case with HBV cccDNA in PBMCs). The sequence analysis showed that all HBV clones had a wild-type (WT) sequence in the liver and PBMCs. In 2 patients with early HBV recurrence post-LT who were treated with nucleosides only, HBV DNA was detected in serum, PBMC, and liver samples, and HBV cccDNA was found in liver samples. An HBV lamivudine-resistant variant with an M204I mutation was identified in liver (70% and 18% of the clones) and plasma samples (100% of the clones), but a WT sequence was found in 70% and 100% of the PBMC clones. In conclusion, despite prophylaxis and the absence of HBV DNA in serum according to conventional assays, HBV is detectable in the serum, liver, and PBMCs of almost all patients, and this supports the use of continued anti-HBV therapy in this group. Antiviral drug-resistant variants are more frequent in the liver versus PBMCs, but both compartments are potential sources of reinfection.
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Affiliation(s)
- Carla S Coffin
- Liver Unit, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
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19
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Coffin CS, Mulrooney-Cousins PM, Peters MG, van Marle G, Roberts JP, Michalak TI, Terrault NA. Molecular characterization of intrahepatic and extrahepatic hepatitis B virus (HBV) reservoirs in patients on suppressive antiviral therapy. J Viral Hepat 2011; 18:415-23. [PMID: 20626626 PMCID: PMC4142495 DOI: 10.1111/j.1365-2893.2010.01321.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hepatitis B virus (HBV) replicates via an error-prone reverse transcriptase generating potential drug-resistant quasispecies. The degree of HBV variability in liver vs peripheral blood mononuclear cells (PBMC) in patients on long-term suppressive antivirals is unclear. We characterized HBV replication, drug resistance and molecular diversity in patients with plasma HBV DNA undetectable by clinical assays. Explant liver (n=9), PBMC (n=6) and plasma (n=7) from nine such patients undergoing liver transplantation were evaluated for HBV genomes by sensitive PCR/nucleic acid hybridization assay. Cases with HBV DNA in liver and PBMC were tested for covalently closed circular DNA (HBV cccDNA). HBV polymerase (P) amplicons were cloned, sequenced and both P and overlapping surface (S) gene sequences were analysed. HBV DNA was detected in 43% (3/7) of plasma, 100% (9/9) of liver and 83% (5/6) of PBMC samples. HBV cccDNA was detected in all liver and one PBMC sample. Four patients had a clinical diagnosis of resistance. HBV P gene sequencing revealed 100% wild type (wt) in plasma (2/2), 83% wt in PBMC (5/6) but livers of 3/9 (33%) contained wt and 6/9 (66%) carried resistance to lamivudine and/or adefovir. The translated S gene revealed no changes affecting HBV antigenicity. Sequences from livers with antiviral resistant mutants revealed greater interpatient quasispecies diversity. Despite apparent HBV suppression, the liver continues to support HBV replication and extrahepatic HBV can be detected. PBMC may be a sanctuary for wt virus during antiviral therapy, while the liver harbours more drug-resistant viruses. Drug resistance correlates with intrahepatic viral diversity.
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Affiliation(s)
- C. S. Coffin
- Liver Unit, Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of Calgary, AB, Canada
| | - P. M. Mulrooney-Cousins
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - M. G. Peters
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - G. van Marle
- Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, AB, Canada
| | - J. P. Roberts
- Department of Surgery, University of California, San Francisco, CA, USA
| | - T. I. Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL, Canada
| | - N. A. Terrault
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
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20
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Affiliation(s)
- J Levitsky
- Division of Hepatology and Organ Transplantation, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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21
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Akay S, Karasu Z. Hepatitis B immune globulin and HBV-related liver transplantation. Expert Opin Biol Ther 2008; 8:1815-22. [DOI: 10.1517/14712598.8.11.1815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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22
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Mulrooney-Cousins PM, Michalak TI. Repeated passage of wild-type woodchuck hepatitis virus in lymphoid cells does not generate cell type-specific variants or alter virus infectivity. J Virol 2008; 82:7540-50. [PMID: 18495768 PMCID: PMC2493328 DOI: 10.1128/jvi.00405-08] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2008] [Accepted: 05/13/2008] [Indexed: 01/12/2023] Open
Abstract
Woodchuck hepatitis virus (WHV), which is closely related to human hepatitis B virus, infects the liver but also invariably establishes persistent infection in the lymphatic system. Although the dose of invading virus appears to be the main factor in determining whether WHV infection is restricted to the lymphatic system or also engages the liver, the nature of WHV lymphotropism remains unclear and a role for a specific lymphotropic variant was not excluded. The availability of woodchuck lymphocyte and hepatocyte cultures susceptible to WHV infection allows investigation of this issue in vitro. We hypothesized that repeated passage of wild-type WHV in lymphoid cells should lead to enrichment of a lymphotropic virus variant, if in fact such a variant exists. For this purpose, wild-type WHV with a homogeneous sequence was used as the inoculum, while lymphoid cells from a single healthy woodchuck donor and a normal woodchuck WCM-260 hepatocyte line served as infection targets. The serial passage of the wild-type virus repeated up to 13 times for both cell types did not lead to the emergence of cell type-specific WHV variants, as revealed by sequence analysis of the virus envelope and the core and X gene sequences. Moreover, the virus passaged in both cell types remained infectious for naive woodchucks, produced infection profiles that depended upon virus dose but not on virus cellular origin, and retained its initial DNA sequence. These results imply that WHV lymphotropism is a natural propensity of the wild-type virus and is not a consequence of infection with a viral variant.
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Affiliation(s)
- Patricia M Mulrooney-Cousins
- Molecular Virology and Hepatology Research Group, Division of BioMedical Science, Faculty of Medicine, Health Science Centre, Memorial University, St. John's, Newfoundland, Canada A1B 3V6
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Abstract
Advances in hepatitis B virus (HBV) antiviral prophylaxis have dramatically improved graft and patient survival for patients undergoing liver transplantation for hepatitis B related end-stage liver disease. In particular, the availability of hepatitis B immune globulin (HBIg) in combination with nucleos(t)ide analogues such as lamivudine and adefovir, have transformed outcomes. The availability of newer antivirals such as adefovir, tenofovir and entecavir either as monotherapy or in combination offer an increasing number of antiviral options. Despite these advances, significant challenges remain. Factors that affect the efficacy of anti-viral therapy include detectable HBV viraemia at the time of transplant and emergence of HBV mutants (especially in patients with prior exposure to lamivudine). HBV prophylaxis protocols are expensive especially with use of high-dose HBIg and newer nucleos(t)ide analogues. This review summarizes current HBV prophylaxis protocols and management of recurrent disease post-transplantation. There is an increasing need for individualization of therapy based on prior drug exposures, level of HBV DNA at time of transplantation and type of prophylaxis used.
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Affiliation(s)
- Carla S Coffin
- Department of Medicine, University of California at San Francisco, San Francisco, CA 94143, USA
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24
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Buti M, Mas A, Prieto M, Casafont F, González A, Miras M, Herrero JI, Jardi R, Esteban R. Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence. Transplantation 2007; 84:650-4. [PMID: 17876280 DOI: 10.1097/01.tp.0000277289.23677.0a] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Lamivudine combined with hepatitis B immune globulin (HBIg) is the standard of care for preventing the recurrence hepatitis B virus after liver transplant. To determine the risk of hepatitis B virus (HBV) recurrence after early withdrawal of HBIg in patients receiving lamivudine maintenance therapy, 20 patients receiving a course of HBIg and lamivudine after transplantation and long-term maintenance therapy with lamivudine and 9 patients receiving HBIg and lamivudine indefinitely were analyzed. The survival rate was 90% after a mean follow-up of 83 months. The HBV recurrence rate was 14% with a mean period of 91 months free from HBV recurrence. Both groups had similar HBV recurrence rates, 15% for the combination and 11% for lamivudine alone. Four patients, 3 of whom were noncompliant with therapy, experienced posttransplant HBV recurrence. Patients who adhere to long-term prophylaxis with lamivudine after early withdrawal of HBIg have a low risk of HBV recurrence, similar to those who receive combination prophylaxis.
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Affiliation(s)
- Maria Buti
- Hospital General Valle de Hebrón and CIBER EHD, Barcelona, Spain. mbuti@vhebronnet
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25
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Samuel D, Roque-Afonso AM. New sensitive tools for hepatitis B virus (HBV) detection in liver transplantation: what will be their impact on the prophylaxis of HBV infection? Liver Transpl 2007; 13:1084-7. [PMID: 17663408 DOI: 10.1002/lt.21156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Eisenbach C, Sauer P, Mehrabi A, Stremmel W, Encke J. Prevention of hepatitis B virus recurrence after liver transplantation. Clin Transplant 2007; 20 Suppl 17:111-6. [PMID: 17100710 DOI: 10.1111/j.1399-0012.2006.00609.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Liver transplantation for hepatitis B virus (HBV)-related liver disease has changed from a contraindication to outcomes comparable with non-HBV-related liver transplantations during the last two decades. Mainly the implementation of immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and the use of nucleoside analogs such as lamivudine and adefovir account for this dramatic change. The standard of care in most centers today consists of lamivudine treatment in replicating hepatitis B pre-orthotopic liver transplantation (OLT) and a combination regimen of lamivudine and HBIG post-OLT. With adefovir, a potent antiviral drug became available in recent years that allows for the treatment of patients with lamivudine-resistant tyrosine-methionine-aspartate-aspartate (YMDD)-mutant HBV. In the transplantation setting, first studies indicate that a triple prophylactic therapy consisting of lamivudine, adefovir, and HBIG will become the standard of care for YMDD-mutant-related hepatitis B. With new drugs emerging for the treatment of chronic HBV, there is optimism for new options also in the transplant setting.
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Affiliation(s)
- Christoph Eisenbach
- Department of Internal Medicine IV, University of Heidelberg, Heidelberg, Germany.
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27
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Eckert V, Struff WG. Hepatitis B: Where Are We Today? Transfus Med Hemother 2006. [DOI: 10.1159/000093298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Lo CM, Liu CL, Chan SC, Lau GK, Fan ST. Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B. J Hepatol 2005; 43:283-7. [PMID: 15964658 DOI: 10.1016/j.jhep.2005.03.013] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2005] [Revised: 02/25/2005] [Accepted: 03/23/2005] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS Lamivudine prophylaxis against hepatitis B virus (HBV) reinfection after liver transplantation is associated with recurrence due to escape mutants. METHODS Fifty-two patients on lamivudine prophylaxis at a median of 412 days (median, 370-2040 days) after transplantation for chronic HBV-related liver disease received two courses of an accelerated schedule of double-dose recombinant HBV vaccine. Before vaccination, all patients were seronegative for HBsAg, anti-HBs and HBV DNA (by qPCR). Three intramuscular doses of vaccine (40 microg each) were administered monthly and another identical course was repeated after 3 months. Lamivudine (100mg/day) was continued throughout the study. RESULTS After the first course, two patients developed a weak response (anti-HBs titre of 12 mIU/mL) that disappeared rapidly. One early responder developed anti-HBs (27 mIU/mL) again after the second course but the other did not. Two other patients developed response (anti-HBs titre of 17 and 103 mIU/mL, respectively) giving an overall response rate of 7.7%. The antibody level declined rapidly. At the end of the study, one patient who did not respond had developed viral breakthrough which was treated with adefovir dipivoxil therapy. CONCLUSIONS Active immunization with two courses of double-dose recombinant HBV vaccine has limited efficacy in patients receiving lamividine prophylaxis after liver transplantation.
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Affiliation(s)
- Chung Mau Lo
- Centre for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
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29
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Samuel D, Shouval D. The questionable role of immunization against hepatitis B in HBV infected liver transplant patients. J Hepatol 2005; 43:203-6. [PMID: 15975686 DOI: 10.1016/j.jhep.2005.05.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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30
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Umeda M, Marusawa H, Seno H, Katsurada A, Nabeshima M, Egawa H, Uemoto S, Inomata Y, Tanaka K, Chiba T. Hepatitis B virus infection in lymphatic tissues in inactive hepatitis B carriers. J Hepatol 2005; 42:806-12. [PMID: 15885350 DOI: 10.1016/j.jhep.2005.01.016] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2004] [Revised: 01/11/2005] [Accepted: 01/27/2005] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Hepatitis B virus (HBV) infection in extrahepatic tissues is controversial. To clarify whether episomal HBV can infect nonhepatic tissues, we investigated the molecular forms of HBV in the lymphatic cells of inactive HBV carriers who lacked viremia, thus avoiding contamination with HBV genomes originating from the viral particles present in the serum. METHODS We assessed HBV genome, replicative forms, and viral integrants in the liver, serum, peripheral blood mononuclear cells (PBMC), and lymph nodes of 21 inactive HBV carriers who tested positive for antibodies against the HBV core antigen (anti-HBc). RESULTS Of the 21 anti-HBc positive individuals, HBV-DNA was detected in liver samples of 15 (71.4%), in the lymph nodes of 11 (52.4%), and in PBMC of three (14.3%). However, none of the detected HBV genomes from lymphatic tissues included the replicative forms of HBV. In one case, integrated HBV was present in the lymphatic tissues and the host-viral junction was present in the intronic sequences of chromosome 17. CONCLUSIONS These data suggest that human lymphatic tissues cannot support viral replication in anti-HBc positive inactive HBV carriers, while retaining the viral genome as an integrated form.
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Affiliation(s)
- Makoto Umeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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31
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Roche B, Samuel D. [Prevention and treatment of hepatitis B virus infection after liver transplantation]. ACTA ACUST UNITED AC 2005; 29:393-404. [PMID: 15864201 DOI: 10.1016/s0399-8320(05)80787-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Bruno Roche
- Centre Hépatobiliaire, EA 3541, Université Paris-Sud, Villejuif, France
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32
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Roche B, Samuel D. Treatment of hepatitis B and C after liver transplantation. Part 1, hepatitis B. Transpl Int 2005; 17:746-58. [PMID: 15688165 DOI: 10.1007/s00147-004-0797-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2002] [Revised: 11/25/2003] [Accepted: 01/05/2004] [Indexed: 12/19/2022]
Abstract
The outcome of OLT for HBV-related liver disease is dependent on the prevention of allograft re-infection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of long-term hepatitis B immune globulin (HBIG) administration as a prophylaxis against HBV recurrence, and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM), were a major breakthrough in the management of these patients. Results of OLT for HBV infection are similar to those achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and thus decrease the risk of re-infection of the graft. Combination prophylaxis with LAM and HBIG after transplantation highly effectively reduces the rate of HBV re-infection, even in HBV replicative cirrhotic patients. The optimal HBIG protocol in the LAM era is yet to be defined: dosing of HBIG, routes of administration, and possibility of stopping HBIG. Several antiviral drugs have been developed for the management of HBV infection on the graft, so outcome is currently good.
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Affiliation(s)
- Bruno Roche
- Centre Hepatobiliaire, UPRES 3541, EPI 99-41, Universite Paris-Sud, Hôpital Paul Brousse, 14 Ave. P.V. Couturier, 94800 Villejuif, France
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Vierling JM. Management of HBV Infection in Liver Transplantation Patients. Int J Med Sci 2005; 2:41-49. [PMID: 15968339 PMCID: PMC1142224 DOI: 10.7150/ijms.2.41] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2004] [Accepted: 01/01/2005] [Indexed: 12/17/2022] Open
Abstract
In the absence of preventative therapy, reinfection of allografts with hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) resulted in dismal allograft and patient survival. Major advances in the management of HBV-infected recipients of OLT during the past 15 years have steadily reduced the rate of reinfection, resulting in improved outcomes. Initially, long-term use of hepatitis B immune globulin (HBIG) as a source of anti-HBs antibodies was effective in preventing or delaying reinfection. Lamivudine monotherapy made it possible to suppress HBV replication prior to OLT, markedly decreasing the risk of reinfection. Although lamivudine monotherapy used before and after OLT could prevent reinfection, its effectiveness was limited by progressive development of lamivudine-resistant mutant infections. Combination therapy with HBIG and lamivudine after OLT reduced both HBV recurrence and the risk of lamivudine resistance even in patients with active HBV replication. Introduction of adefovir provided a safe, alternative oral antiviral able to treat effectively lamivudine-resistant mutants HBV. Available strategies to prevent reinfection have resulted in OLT outcomes for HBV-infected patients comparable to those for patients transplanted for non-HBV indications. In the future, combination therapies of HBIG and both nucleoside and/or nucleotide agents will undoubtedly be optimized. Development of new drugs to treat HBV will increase opportunities to combine agents to enhance safety, efficacy and prevent emergence of HBV escape mutants. New vaccines and adjuvants may make it possible to generate anti-HBs in immunosuppressed patients, eliminating the need for HBIG.
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35
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Seehofer D, Rayes N, Neuhaus P. Prophylaxis and treatment of hepatitis B recurrence after liver transplantation in the antiviral era. Expert Rev Anti Infect Ther 2004; 1:307-18. [PMID: 15482126 DOI: 10.1586/14787210.1.2.307] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Redistribution of virions from extrahepatic reservoirs with resultant reinfection of the graft is a serious complication after liver transplantation for hepatitis B-related liver disease. Prophylaxis of hepatitis B virus recurrence is a major issue in these patients. With the introduction of passive immunoprophylaxis and the development of antiviral drugs, liver transplantation has evolved as an established therapy of hepatitis B-induced end-stage liver failure. However, even under indefinite monoprophylaxis, a significant percentage of patients develop reinfection due to a high mutation rate of the hepatitis B virus. Progress, especially in the field of antiviral therapy, has opened new strategies, including combination prophylaxis and therapy, which further improve outcome. On the other hand, the broad use of antiviral drugs brings about new problems such as resistance formation prior to liver transplantation. In addition, due to the high costs of hepatitis B immunoglobulin alternatives such as prophylaxis with nucleoside analogs or vaccination are increasingly being investigated.
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Affiliation(s)
- Daniel Seehofer
- Department of General-, Visceral-, and Transplant Surgery, Charité Campus Virchov, Berlin, Germany.
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Abstract
1. Long-term prophylaxis with hepatitis B immune globulin (HBIG) significantly reduces the risk for hepatitis B virus (HBV) recurrence and increases survival. Patients with HBV cirrhosis and / or positive HBV DNA at the time of transplantation have a high risk for recurrence despite HBIG prophylaxis. 2. Pre-orthotopic liver transplantation (OLT) antiviral treatment using lamivudine (LAM) can suppress HBV replication before transplantation and may induce clinical improvement in a subset of patients. Adefovir dipivoxil (ADV) may serve as "rescue" therapy for patients with LAM resistance; its place as first-line therapy requires further evaluation. 3. Combination prophylaxis with LAM and HBIG prevents HBV recurrence in 90% to 100% of patients who undergo transplantation for hepatitis B. The optimal HBIG protocol in the "nucleoside-nucleotide analog era" remains to be determined. The place of ADV or LAM as first-line posttransplant antiviral therapy in combination with HBIG requires further studies. 4. Future research should test new protocols using lower HBIG doses given intravenously (IV) or intramuscularly (IM) alone or in combination with antiviral agents and identify patients in whom HBIG prophylaxis can be stopped safely or replaced by antiviral agents or vaccination.
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Affiliation(s)
- Bruno Roche
- Centre Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France
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Beckebaum S, Cicinnati VR, Gerken G, Broelsch CE. Management of chronic hepatitis B in the liver transplant setting. Transplant Rev (Orlando) 2004. [DOI: 10.1016/j.trre.2004.03.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Affiliation(s)
- Christian Trautwein
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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Roche B, Samuel D. Liver transplantation for hepatitis B virus-related liver disease: indications, prevention of recurrence and results. J Hepatol 2004; 39 Suppl 1:S181-9. [PMID: 14708701 DOI: 10.1016/s0168-8278(03)00335-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Bruno Roche
- Centre Hépatobiliary, UPRES 3541, Formation de recherche Claude Bernard Virus et Transplantation, Université Paris-Sud, Hôpital Paul Brousse, Assistance Publique Hôpitaux de Paris, 14 avenue Paul Vaillant Couturier, 94800 Villejuif, France
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41
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Villamil FG. Prophylaxis with anti-HBs immune globulins and nucleoside analogues after liver transplantation for HBV infection. J Hepatol 2003; 39:466-74. [PMID: 12971953 DOI: 10.1016/s0168-8278(03)00396-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Federico G Villamil
- Fundacion Favaloro, Liver Unit, Avenida Belgrano 1782, Piso 5, C1093AAS, Buenos Aires, Argentina.
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Fábrega E, García-Suarez C, Guerra A, Orive A, Casafont F, Crespo J, Pons-Romero F. Liver transplantation with allografts from hepatitis B core antibody-positive donors: a new approach. Liver Transpl 2003; 9:916-920. [PMID: 12942452 DOI: 10.1053/jlts.2003.50190] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The enduring shortfall of organ donors has inspired the widespread utilization of hepatic allografts from donors with hepatitis B core antibodies in spite of the potential risk of transmitting hepatitis B virus (HBV) infection to the recipient. Here we report a protocol of naive recipients receiving livers from hepatitis B core antibody-positive donors. From November, 1999 to March, 2002, 77 liver transplantations were performed in 73 patients at our institution, 7 of whom received livers from hepatitis B core antibody-positive donors. All recipients received 10,000 U/d of intravenous HBIg for 7 days and 100 mg/d of lamivudine until we could obtain the HBV-DNA from the donor samples (serum and liver tissue). If the results of the HBV-DNA from the donor samples were positive, the patient would continue with prophylaxis and if they were negative we would finish the combined prophylaxis. After transplantation, HBV serologic markers and HBV-DNA by polymerase chain reaction (PCR) in serum and lymphocytes were tested in the recipients on the seventh, fifteenth, thirtieth, and ninetieth days as well as every 3 months after transplantation. All seven donor organs were negative for HBV-DNA in serum and liver tissue. Thus, we stopped the combined prophylaxis in all recipients (range, 7 to 10 days). None of the 7 patients developed de novo HBV infection over the 3-year study period (range, 9 to 36 months). Our approach is reasonably safe, and it appears to be very effective in the prevention of de novo HBV infection after liver transplantation.
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Affiliation(s)
- Emilio Fábrega
- Gastroenterology and Hepatology Unit, University Hospital Marqués de Valdecilla, Faculty of Medicine, Santander, Spain.
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Abstract
Hepatitis B immune globulin remains a central component of prophylaxis in HBV-infected patients undergoing liver transplantation. HBIG monotherapy given at a high dosage and indefinitely can prevent recurrence in 65% to 80% of patients. Because treatment failures occur and combination therapy using HBIG plus a nucleoside analog is more uniformly effective, the current standard of care is combination HBIG plus a nucleoside analog. These combination protocols have reduced the rate of virologic breakthrough to 10% or less. Several questions remain. The optimal dose and duration of HBIG use is unclear. Moreover, the development of resistance to lamivudine (and other nucleoside analogs) before transplantation increases the risk for virologic breakthrough post-transplantation. For patients with pre-transplant evidence of active HBV replication caused by the presence of nucleoside analog resistance, HBIG may be the main or only form of prophylaxis. For these patients, HBIG doses sufficient to maintain anti-HBs titers comparable to the days of HBIG monotherapy seem warranted. New HBIG formulations have made anti-HBs therapy more safe and tolerable to patients but the cost of the drug remains significant. The cost factor is particularly important in developing countries or countries with more limited resources for management of liver transplant recipients. Thus, there remains a need to develop and test new forms of anti-HBs therapy, so that effective but less expensive forms of immunoprophylaxis can be made available.
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Affiliation(s)
- Norah A Terrault
- Department of Medicine, University of California, 513 Parnassus Avenue, Room S 537, San Francisco, CA 94143-0538, USA.
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Roche B, Feray C, Gigou M, Roque-Afonso AM, Arulnaden JL, Delvart V, Dussaix E, Guettier C, Bismuth H, Samuel D. HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis. Hepatology 2003; 38:86-95. [PMID: 12829990 DOI: 10.1053/jhep.2003.50294] [Citation(s) in RCA: 171] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) is widely accepted for the prevention of recurrent hepatitis B virus (HBV) infection after liver transplantation in HBV-infected patients without viral replication. We report long-term results of HBIG administration in 284 hepatitis B surface antigen (HBsAg)-positive transplant patients. In protocol 1, 259 patients were given HBIG with the goal of maintaining the anti-HBs antibody (Ab) titer over 100 IU/L. After December 1993, 25 HBV DNA-positive patients received HBIG, with a target anti-HBs Ab titer over 500 IU/L, combined with posttransplantation antiviral therapy (protocol 2). At 10 years, 44 patients without recurrence were tested for the presence of HBV DNA in serum using real-time polymerase chain reaction (PCR); 28 were also tested in liver and peripheral blood mononuclear cells (PBMC). The overall 5- and 10-year posttransplantation actuarial rates of HBV recurrence were 24.2% and 25.4%, respectively. The 5-year recurrence rate in protocol 2 patients was 11.8%. On multivariate analysis, predictors of lower HBV recurrence risk were absence of serum HBV DNA before transplantation (P <.0001), acute liver disease (P =.0037), HDV superinfection (P =.012), and protocol 2 therapy (P <.0001). Low-level HBV DNA was detected by PCR in 45.4% of patients without HBV recurrence at 10 years. Overall actuarial 10-year survival was 74.4%. In conclusion, we confirm the efficacy of long-term HBIG immunoprophylaxis. Combination prophylaxis with HBIG and antiviral therapy is effective in patients with viral replication. Although there were only a few cases of HBV recurrence after 5 years, HBV DNA remained present in 45% of patients at 10 years.
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Affiliation(s)
- Bruno Roche
- Centre Hepato-Biliaire, Hôpital Paul Brousse, Villejuif, France
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Zoulim F. Towards an improved and cost-saving prophylaxis of hepatitis B virus recurrence after liver transplantation? J Hepatol 2003; 38:850-2. [PMID: 12763381 DOI: 10.1016/s0168-8278(03)00151-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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Ben-Ari Z, Mor E, Tur-Kaspa R. Experience with lamivudine therapy for hepatitis B virus infection before and after liver transplantation, and review of the literature. J Intern Med 2003; 253:544-52. [PMID: 12702032 DOI: 10.1046/j.1365-2796.2003.01134.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVES To analyse the results of lamivudine therapy on suppression of hepatitis B virus (HBV) replication before transplantation and on preventing graft reinfection postoperatively. DESIGN Long-term clinical study. SETTING Liver Institute and Department of Transplantation of a tertiary-care university-affiliated centre. SUBJECTS (1) 14 candidates for liver transplantation with decompensated liver disease caused by active replication of HBV; (2) six patients with recurrent HBV infection after transplantation. INTERVENTION Lamivudine 100 mg daily; administered in group 1 before surgery and continued after in nine patients who underwent transplantation; administered in group two postoperatively only. anti-hepatitis B surface antigen immunoglobulin (HBIg) was administered postoperatively in both groups. MAIN OUTCOME MEASURES Immunoassay evaluation of serum hepatitis B surface antigen, serum hepatitis Be antigen and serum HBV DNA (hybridization and PCR); sequencing through the tyrosine-methionine-aspartate-aspartate locus of the HBV polymerase gene in patients with lamivudine breakthrough; inflammation and fibrosis scoring on liver biopsy before and at least 2 years after lamivudine therapy in group 2. RESULTS Pretransplantation therapy (group 1) significantly suppressed HBV replication and enabled nine patients (64.2%) to undergo transplantation. Only one patient (7.1%) had lamivudine breakthrough, and one (7.1%) had recurrent HBV. Lamivudine administration begun after transplantation (mean 48.0 months, range 30-60 months) because of graft reinfection (group 2) was associated, over the long-term, with the emergence of high mutation rates (83.3%), histological disease progression (66.6%), and hepatic failure (33.3%). CONCLUSIONS In patients with chronic HBV infection and active viral replication, lamivudine therapy is effective when started before transplantation. However, its long-term administration after transplantation for recurrent HBV leads to high resistance rates. Combination therapy with lamivudine and HBIg immunoglobulin can substantially reduce the recurrence rate. Further studies on combination antiviral therapy are needed in this patient population.
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Affiliation(s)
- Z Ben-Ari
- Liver Institute and Department of Medicine D, Rabin Medical Center, Beilinson Campus, Sackler School of Medicine, Tel Aviv University, Petah Tikva, Israel.
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Papatheodoridis GV, Sevastianos V, Burroughs AK. Prevention of and treatment for hepatitis B virus infection after liver transplantation in the nucleoside analogues era. Am J Transplant 2003; 3:250-8. [PMID: 12614278 DOI: 10.1034/j.1600-6143.2003.00063.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Post-transplant prophylaxis with hepatitis B immune globulin (HBIG) has significantly reduced hepatitis B virus (HBV) recurrence rates, but it is rather ineffective in patients with pretransplant viremia. Moreover, long-term HBIG administration is very expensive and may be associated with emergence of escape HBV mutants. Lamivudine has been widely used in the management of HBV transplant patients. Pretransplant lamivudine lowers HBV viremia, decreasing the risk of post-transplant HBV recurrence, but to try and minimize development of resistant HBV strains, it should start within the last 6 months of the anticipated transplantation timing. Preemptive post-transplant lamivudine monotherapy is associated with progressively increasing HBV recurrence rates, but combined therapy with lamivudine and HBIG at relatively low dosage is currently the most effective approach in this setting, even in HBV-DNA-positive patients, who also receive lamivudine in the pretransplant period. The most frequent therapy for post-transplant HBV recurrence is lamivudine, but the increasing resistance rates represent a rather challenging problem. Adefovir dipivoxil and entecavir are currently the most promising agents for lamivudine-resistant HBV strains. All these advances in anti-HBV therapy have made HBV liver disease an indication for liver transplantation irrespective of viral replication status, a complete turn around from 10 years ago.
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Lo CM, Fan ST, Liu CL, Lai CL, Wong J. Prophylaxis and treatment of recurrent hepatitis B after liver transplantation. Transplantation 2003; 75:S41-4. [PMID: 12589139 DOI: 10.1097/01.tp.0000047027.68167.07] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is the leading cause of end-stage liver disease in Asia. The results of liver transplantation in these patients have significantly improved to a level comparable to those of other recipients as a result of the rapid evolution in the strategies of prevention and treatment of recurrent hepatitis B over the past decade. Hepatitis B immune globulin (HBIG) and lamivudine, either alone or in combination, are effective in preventing reinfection, but the most cost-effective dosing regimen with optimum efficacy without the prohibitive cost remains to be determined, an issue that is particularly relevant to liver transplant centers with serious financial constraints in Asia. The idea of active immunization is attractive, but the results have been conflicting to date. The newer nucleoside analogs appear most promising, and a combination of two or more antiviral agents is likely to represent the future strategy of choice in the prophylaxis and treatment of recurrent hepatitis B after liver transplantation.
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Affiliation(s)
- Chung-Mau Lo
- Centre for the Study of Liver Disease and the Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong, China.
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Lo CM, Fung JTK, Lau GKK, Liu CL, Cheung ST, Lai CL, Fan ST, Wong J. Development of antibody to hepatitis B surface antigen after liver transplantation for chronic hepatitis B. Hepatology 2003; 37:36-43. [PMID: 12500186 DOI: 10.1053/jhep.2003.50035] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Patients with chronic hepatitis B virus (HBV) infection have a defective HBV-specific immune response, and the spontaneous development of antibody against hepatitis B surface antigen (anti-HBs) after liver transplantation has not been observed. We report the spontaneous production of anti-HBs in 21 of 50 (42%) patients receiving lamivudine monoprophylaxis after liver transplantation. Seroconversion to anti-HBs status (>10 mIU/mL) was found at a median of 8 days (range, 1 to 43 days) after transplantation. In each case, serial serum samples showed a >100% increase in antibody titer as compared with that of day 7 after transplantation in the absence of any blood product transfusion. The anti-HBs titer increased to a maximum within 3 months, and the peak titer was <100 mIU/mL in 10 patients, 100 to 1000 mIU/mL in 5 patients, and >1,000 mIU/mL in 6 patients. In 12 patients, anti-HBs disappeared from serum at a median of 201 days (range, 24 to 414 days), whereas the other 9 patients remained positive for anti-HBs at a median of 221 days (range, 94 to 1,025 days) after transplantation. Patients in whom anti-HBs in serum developed had a more rapid clearance of serum hepatitis B surface antigen (HBsAg) (log rank test, P =.011). Using logistic regression analysis, the only predictor of anti-HBs production was an HBV-immune donor (odds ratio, 18.9; 95% confidence interval, 3.2 to 112.4; P =.001). In conclusion, patients who undergo liver transplantation for chronic hepatitis B using lamivudine prophylaxis may develop anti-HBs spontaneously. The antibody is likely to be of donor origin, suggesting the possibility of adoptive immunity transfer through a liver graft.
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Affiliation(s)
- Chung-Mau Lo
- Department of Surgery, Center for the Study of Liver Disease, University of Hong Kong Medical Center, Queen Mary Hospital, China.
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Abstract
1. Patients undergoing orthotopic liver transplantation (OLT) for hepatitis B without effective prophylaxis have a high risk for recurrent infection and severe graft damage, leading to death or re-OLT. 2. Long-term prophylaxis with hepatitis B immune globulin (HBIg) significantly reduces the risk for hepatitis B virus (HBV) recurrence and increases survival. Patients with detectable HBV DNA at the time of OLT have a high risk for recurrence despite HBIg prophylaxis. 3. Lamivudine (LAM) therapy for patients with decompensated HBV cirrhosis before OLT results in inhibition of viral replication and clinical improvement. Its efficacy is limited by the frequent emergence of LAM-resistant YMDD mutations. The ideal length of therapy with LAM pre-OLT has not yet been defined. 4. Prophylaxis of HBV recurrence with LAM monotherapy is not recommended because of the reappearance of hepatitis B surface antigen after OLT in approximately 50% of patients. 5. LAM is the best available treatment for patients with established recurrent hepatitis B. Long-term therapy is associated with the emergence of drug-resistant mutants in up to 60% of patients. Severe hepatitis and liver failure have been described among liver transplant recipients with YMDD mutations. 6. Combination therapy with HBIg and LAM prevents HBV recurrence in 90% to 100% of patients who undergo OLT for hepatitis B. The optimal HBIg protocol in the LAM era is yet to be defined. 7. Preliminary studies suggest that adefovir dipivoxil inhibits HBV replication in patients infected with LAM-resistant HBV strains. 8. Fifteen years ago, hepatitis B was regarded as a relative or absolute contraindication for OLT. Today, hepatitis B is a universally accepted indication for OLT.
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Affiliation(s)
- Federico G Villamil
- Hepatology and Liver Transplantation Unit, Fundacion Favaloro, Buenos Aires, Argentina.
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