|
1
|
Ding L, Huang J, Huang S. The significance of antibody to hepatitis B surface antigen in infection and clearance of hepatitis B virus. Hum Vaccin Immunother 2025; 21:2445283. [PMID: 39754388 DOI: 10.1080/21645515.2024.2445283] [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: 09/24/2024] [Revised: 11/30/2024] [Accepted: 12/17/2024] [Indexed: 01/06/2025] Open
Abstract
One of the key features of chronic hepatitis B virus (HBV) infection is the inability to mount sufficient and coordinated adaptive immune responses against HBV. Recent studies on HBV-specific B cells and antibody to hepatitis B surface antigen (anti-HBs) have shed light on their role in the pathogenesis of chronic hepatitis B (CHB). Anti-HBs is recognized as a protective immune marker, both for HBV infection clearance and following vaccination, and it is also considered an important indicator of functional cure for CHB. Notably, functional impairment of HBV-specific B cells may be reversible. The restoration of HBV-specific B cell function, along with the induction of an anti-HBs antibody response, is regarded as pivotal for terminating chronic HBV infection and achieving functional cure. This article reviews the significance of anti-HBs in both the infection and clearance of HBV, and discusses the potential of neutralizing antibodies and therapeutic vaccines as promising future strategies.
Collapse
Affiliation(s)
- Ling Ding
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuaiwen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
2
|
Gu S, Tang L, Guo L, Zhong C, Fu X, Ye G, Zhong S, Li X, Wen C, Zhou Y, Wei J, Chen H, Novikov N, Fletcher SP, Moody MA, Hou J, Li Y. Circulating HBsAg-specific B cells are partially rescued in chronically HBV-infected patients with functional cure. Emerg Microbes Infect 2024; 13:2409350. [PMID: 39470771 PMCID: PMC11523254 DOI: 10.1080/22221751.2024.2409350] [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: 07/13/2024] [Revised: 09/09/2024] [Accepted: 09/23/2024] [Indexed: 11/01/2024]
Abstract
It is well established that humoral immunity targeting hepatitis B virus surface antigen (HBsAg) plays a critical role in viral clearance and clinical cure. However, the functional changes in HBsAg-specific B cells before and after achieving functional cure remain poorly understood. In this study, we characterized circulating HBsAg-specific B cells and identified functional shifts and B-cell epitopes directly associated with HBsAg loss. The phenotypes and functions of HBV-specific B cells in patients with chronic HBV infection were investigated using a dual staining method and the ELISpot assay. Epitope mapping was performed to identify B cell epitopes associated with functional cure. Hyperactivated HBsAg-specific B cells in patients who achieved HBsAg loss were composed of enriched resting memory and contracted atypical memory fractions, accompanied by sustained co-expression of multiple inhibitory receptors and increased IL-6 secretion. The frequency of HBsAb-secreting B cells was significantly increased after achieving a functional cure. The rHBsAg displayed a weaker immunomodulatory effect on B cells than rHBeAg and rHBcAg in vitro. Notably, sera from patients with HBsAg loss reacted mainly with peptides S60, S61, and S76, suggesting that these are dominant linear B-cell epitopes relevant for functional cure. Intriguingly, patients reactive with S76 showed a higher frequency of the HLA class II DQB1*05:01 allele. Taken together, HBsAg-specific B cells were partially restored in patients after achieving a functional cure. Functional cure-related epitopes may be promising targets for developing therapeutic vaccines to treat HBV infection and promote functional cure.
Collapse
Affiliation(s)
- Shuqin Gu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Infectious Diseases Division, Department of Pediatrics, Duke University, Durham, NC, USA
| | - Libo Tang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Ling Guo
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, China
| | - Chunxiu Zhong
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Xin Fu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Guofu Ye
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Shihong Zhong
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Xiaoyi Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Chunhua Wen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Department of Hematology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Yang Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- Infectious Diseases Division, Department of Pediatrics, Duke University, Durham, NC, USA
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Jinling Wei
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou, China
| | - Haitao Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Nikolai Novikov
- Department of Biology, Gilead Sciences, Foster City, CA, USA
| | | | - M. Anthony Moody
- Infectious Diseases Division, Department of Pediatrics, Duke University, Durham, NC, USA
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC, USA
| | - Jinlin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Institute of Hepatology, Guangzhoua, China
| |
Collapse
|
|
3
|
Wang Y, Li Q, Li C, Wang C, Wang S, Yuan W, Yu D, Zhang K, Shi B, Chen X, Liu T, Yuan Z, Tong S, Nassal M, Wen YM, Wang YX. Chimeric antigen receptors of HBV envelope proteins inhibit hepatitis B surface antigen secretion. Gut 2024; 73:668-681. [PMID: 37973365 DOI: 10.1136/gutjnl-2023-330537] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVES Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss. DESIGN We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models. RESULTS After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector. CONCLUSION CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.
Collapse
Affiliation(s)
- Yang Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qiqi Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cheng Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cong Wang
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shijie Wang
- Deparment of Infectious Diseases, Changzheng Hospital, Navy Medical University, Shanghai, China
| | - Wenjie Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Demin Yu
- Department of Infectious Diseases, Institute of Infectious and Respiratory Diseases, Sino-French Research Center for Life Science and Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ke Zhang
- SCG Cell Therapy Pte Ltd, Singapore
| | - Bisheng Shi
- Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaomei Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tiantian Liu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuping Tong
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Michael Nassal
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Yu-Mei Wen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yong-Xiang Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| |
Collapse
|
|
4
|
Hildt E, Hu J. New facet of CARs: HBV-specific CARs as inhibitors of virus morphogenesis and release. Gut 2024; 73:566-567. [PMID: 38253479 PMCID: PMC10958327 DOI: 10.1136/gutjnl-2023-331462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 01/24/2024]
Affiliation(s)
- Eberhard Hildt
- Division of Virology, Paul-Ehrlich-Institut, Langen, Germany
- German Center for Infection Research, Gießen-Marburg-Langen, Germany
| | | |
Collapse
|
|
5
|
Qu W, Sui L, Li Y. Vaccine escape challenges virus prevention: The example of two vaccine-preventable oncogenic viruses. J Med Virol 2023; 95:e29184. [PMID: 37943176 DOI: 10.1002/jmv.29184] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/06/2023] [Accepted: 10/09/2023] [Indexed: 11/10/2023]
Abstract
Over the years, the pace of developing vaccines for HBV and HPV has never stopped. After more than 30 years of application, the HBV vaccine has reduced 80% of hepatocellular carcinoma (HCC). However, vaccine escape variants occur under selective pressure induced by widespread vaccination and antiviral therapy, which results in fulminant infection and horizontal transmission. Several mechanisms have been studied to explain HBV vaccine escape, including vaccine escape mutations (VEMs) in the major hydrophilic region, which leads to a decrease in the binding ability to neutralize antibodies and is the primary escape mechanism, protein conformational and N-linked glycosylation sites changes caused by VEMs, differences in genotype distribution, gene recombination, and some temporarily unknown reasons. However, effective solutions are still being explored. The HPV vaccine has also been proven to prevent 70%-90% of cervical cancer worldwide. Cases of HPV infection after being vaccinated have been observed in clinical practice. However, few researchers have paid attention to the mechanism of HPV vaccine escape. Thus, we reviewed the literature on vaccine escape of both HBV and HPV to discuss the mechanism of the virus escaping from vaccine protection and possible solutions to this problem. We analyzed the gap between studies of HPV and HBV and made prospects for further research in HPV vaccine escape.
Collapse
Affiliation(s)
- Wenjie Qu
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Long Sui
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yanyun Li
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| |
Collapse
|
|
6
|
Yoon KC, Seo S, Lee KW, Oh SC, Park MY, Hong SK, Choi Y, Yi NJ, Suh KS. Hepatitis B immunoglobulin inhibits the secretion of HBV via antigen-antibody precipitation in the multivesicular body. Am J Transl Res 2023; 15:5908-5920. [PMID: 37854220 PMCID: PMC10579012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/22/2023] [Indexed: 10/20/2023]
Abstract
BACKGROUND AND AIMS Although the main action of human hepatitis B immunoglobulin (HBIG) is to neutralize hepatitis B virus surface antigen (HBsAg) in serum, HBIG is known to be localized in the cell. However, the effect of intracellularly located HBIG is poorly understood because of the low purity of conventional plasma-derived HBIG (cHBIG). We attempted to elucidate the mechanism of action of internalized HBIG using recombinant HBIG (lenvervimab). METHODS We used HBsAg producing cell lines, non-HBsAg cell lines and human HBsAg-producing hepatocytes. The autophagosome lysis pathway-related proteins Rab5, calnexin, giantin, and Rab7 were used to localize HBsAg and anti-HBs-IgG in the cytoplasm using Western blotting and confocal microscopy. RESULTS Intracellular anti-HBs-IgG (lenvervimab and cHBIG) transported via Fc receptor-mediated endocytosis increased the number of autophagosomes. However, there was no change in autolysis. HBsAg and anti-HBs-IgG co-localized in the multivesicular body and precipitated in the cytoplasm. HBsAg secretion into culture medium decreased after lenvervimab treatment. Simultaneously, the amount of cellular HBsAg increased in the cell lines but decreased in human hepatocytes. Furthermore, intracellular lenvervimab is not easily removed from HBsAg cell lines. CONCLUSIONS Lenvervimab decreases HBsAg secretion, and HBsAg antibody precipitation in the multivesicular body may play an important role.
Collapse
Affiliation(s)
- Kyung Chul Yoon
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
- Department of Surgery, Seoul National University Boramae Medical CenterSeoul, Republic of Korea
| | - Sooin Seo
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - Seung Cheol Oh
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - Min Young Park
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of MedicineSeoul, Republic of Korea
| |
Collapse
|
|
7
|
Zheng H, Zhu Z, Wang N, Qin J, Guo Y, Xu Z, Li X, Qi C, Yuan X, Wu W, Wang J, Liu L, Nashan B. Entecavir Combined With Short-term Hepatitis B Immunoglobulin in Preventing Hepatitis B Virus Recurrence in Liver Transplant Recipients. Transplant Proc 2023; 55:408-412. [PMID: 36907782 DOI: 10.1016/j.transproceed.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/02/2023] [Indexed: 03/12/2023]
Abstract
BACKGROUND The combination of nucleoside analogs and long-term hepatitis B immunoglobulin (HBIG) is considered to be the standard regimen for preventing hepatitis B virus (HBV) recurrence after liver transplant (LT). However, long-term use of HBIG causes many adverse effects. The aim of this study was to evaluate the effect of nucleoside analogs entecavir combined with short-term HBIG in preventing HBV recurrence after LT. METHODS This retrospective study assessed the effect a combination of entecavir and short-term HBIG in prophylaxis of HBV recurrence among 56 LT recipients who had undergone the procedure because of HBV-associated liver disease at our center between December 2017 and December 2021. All patients received entecavir treatment combined with HBIG for the prevention of hepatitis B recurrence, and HBIG treatment was withdrawn within 1 month. The patients were followed up to determine levels of hepatitis B surface antigen, antibody to hepatitis B surface antigen (HBsAb), and HBV-DNA and the recurrence rate of HBV. RESULTS Only 1 patient appeared positive for hepatitis B surface antigen at 2 months post-LT. The overall HBV recurrence rate was 1.8%. The HBsAb titers of all patients gradually decreased over time, with a median of 376.6 IU/L at 1 month post-LT and a median of 13.47 IU/L at 12 months post-LT. During the follow-up period, the HBsAb titer of the preoperative HBV-DNA-positive patients remained at a lower level than that of HBV-DNA-negative patients. CONCLUSIONS Entecavir combined with short-term HBIG can exert a good effect for the prevention of HBV reinfection post-LT.
Collapse
Affiliation(s)
- Hao Zheng
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Zebin Zhu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Ning Wang
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Jiwei Qin
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Yafei Guo
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Zhijun Xu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Xuefeng Li
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Can Qi
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Xiaodong Yuan
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Wei Wu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Jizhou Wang
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Lianxin Liu
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China
| | - Björn Nashan
- Department of Organ Transplantation Center, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China.
| |
Collapse
|
|
8
|
Burm R, Van Houtte F, Verhoye L, Mesalam AA, Ciesek S, Roingeard P, Wedemeyer H, Leroux-Roels G, Meuleman P. A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection. JHEP Rep 2023; 5:100646. [PMID: 36748051 PMCID: PMC9898450 DOI: 10.1016/j.jhepr.2022.100646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/17/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Background & Aims Elimination of chronic HBV/HDV infection remains a major global health challenge. Targeting excessive hepatitis B surface antigen (HBsAg) release may provide an interesting window of opportunity to break immune tolerance and to achieve a functional cure using additional antivirals. Methods We evaluated a HBsAg-specific human monoclonal antibody, as part of either a prophylactic or therapeutic strategy, against HBV/HDV infection in cell culture models and in human-liver chimeric mice. To assess prophylactic efficacy, mice were passively immunized prior to infection with HBV or HBV/HDV (coinfection and superinfection setting). Therapeutic efficacy was assessed in HBV and HBV/HDV-coinfected mice receiving 4 weeks of treatment. Viral parameters (HBV DNA, HDV RNA and HBsAg) were assessed in mouse plasma. Results The antibody could effectively prevent HBV/HDV infection in a dose-dependent manner with IC50 values of ∼3.5 ng/ml. Passive immunization showed complete protection of mice from both HBV and HBV/HDV coinfection. Moreover, HDV superinfection was either completely prevented or at least attenuated in HBV-infected mice. Finally, antibody treatment in mice with established HBV/HDV infection resulted in a significant decline in viremia and a concomitant drop in on-treatment HBsAg, with a moderate viral rebound following treatment cessation. Conclusion We present data on a valuable antibody candidate that could complement other antivirals in strategies aimed at achieving functional cure of chronic HBV and HDV infection. Impact and implications Patients chronically infected with HBV may eventually develop liver cancer and are at great risk of being superinfected with HDV, which worsens and accelerates disease progression. Unfortunately, current treatments can rarely eliminate both viruses from chronically infected patients. In this study, we present data on a novel antibody that is able to prevent chronic HBV/HDV infection in a mouse model with a humanized liver. Moreover, antibody treatment of HBV/HDV-infected mice strongly diminishes viral loads during therapy. This antibody is a valuable candidate for further clinical development.
Collapse
Affiliation(s)
- Rani Burm
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Freya Van Houtte
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Ahmed Atef Mesalam
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), Dokki, Cairo 12622, Egypt
| | - Sandra Ciesek
- Institute for Medical Virology, University Hospital, Goethe University, Frankfurt am Main, Germany
- German Center for Infection Research, DZIF, External Partner Site, Frankfurt am Main, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Theodor Stern Kai 7, Frankfurt am Main, Germany
| | - Philippe Roingeard
- INSERM U966, Université François Rabelais and CHRU de Tours, Tours, France
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Geert Leroux-Roels
- Center for Vaccinology, Faculty of Medicine and Health Sciences, Ghent University and University Hospital, Ghent, Belgium
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| |
Collapse
|
|
9
|
Gao N, Yu H, Zhang J, Mo Z, Chu J, Xie C, Peng L, Gao Z. Role of hepatitis B surface antibody in seroreversion of hepatitis B surface antigen in patients achieving hepatitis B surface antigen loss with pegylated interferon-based therapy. J Viral Hepat 2022; 29:899-907. [PMID: 35871534 DOI: 10.1111/jvh.13734] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/29/2022] [Indexed: 12/09/2022]
Abstract
It is unclear whether hepatitis B surface antibody (HBsAb) confers clinical benefits after HBsAg seroclearance, especially in hepatitis B surface antigen (HBsAg) seroreversion and maintenance of HBsAb. We evaluated this in patients (n = 222) with HBsAg loss following treatment with pegylated interferon (PEG-IFN)-based therapy who completed a 48-week follow-up period. Serum hepatitis B virus (HBV) markers and biochemical indicators were evaluated every 3 months. The primary endpoint was HBsAg seroreversion. Factors associated with HBsAg seroreversion were also investigated. HBsAb ≥100 mIU/ml resulted in a lower HBsAg seroreversion rate than an HBsAb-negative status (5.5% vs. 29.5%, p < .001); however, the seroreversion rate was not significantly different between patients with HBsAb 10-100 mIU/ml and those in the HBsAb-negative group. Patients with HBsAb ≥100 mIU/ml had a lower HBsAb loss rate than those with HBsAb 10-100 mIU/ml (7.3% vs. 21.7%, p = .005). The final HBsAg seroreversion and HBV DNA relapse rates were 13.5% and 1.8%, respectively. HBsAb ≥100 mIU/ml at the off-treatment time (odds ratio [OR] 0.110, 95% confidence interval [CI]: 0.034-0.353, p < .001) and treatment time to attain HBsAg loss >28 weeks (OR 2.508, 95% CI: 1.068-5.890, p = .035) were predictors of HBsAg seroreversion. Consolidation therapy for 12-24 weeks resulted in higher HBsAb titres than consolidation therapy for ≤12 weeks in HBsAb-negative patients at the off-treatment time (p < .001). HBsAg seroconversion with HBsAb ≥100 mIU/ml decreases HBsAg seroreversion and provides an efficient maintenance rate of HBsAb. HBsAg seroconversion with high HBsAb titres may be clinically beneficial for chronic hepatitis B treated with PEG-IFN-based therapy.
Collapse
Affiliation(s)
- Na Gao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huiying Yu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jing Zhang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhishuo Mo
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
| | - Junhao Chu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chan Xie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
| |
Collapse
|
|
10
|
Konopleva MV, Borisova VN, Sokolova MV, Semenenko TA, Suslov AP. Recombinant HBsAg of the Wild-Type and the G145R Escape Mutant, included in the New Multivalent Vaccine against Hepatitis B Virus, Dramatically Differ in their Effects on Leukocytes from Healthy Donors In Vitro. Vaccines (Basel) 2022; 10:235. [PMID: 35214692 PMCID: PMC8880183 DOI: 10.3390/vaccines10020235] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
Immune-escape hepatitis B virus (HBV) mutants play an important role in HBV spread. Recently, the multivalent vaccine Bubo®-Unigep has been developed to protect against both wild-type HBV and the most significant G145R mutant. Here, we compared the effects of recombinant HBsAg antigens, wild-type and mutated at G145R, both included in the new vaccine, on activation of a human high-density culture of peripheral blood mononuclear cells (PBMC) in vitro. The antigens were used either alone or in combination with phytohemagglutinin (PHA). None of the antigens alone affected the expression of CD40, HLA-DR or CD279. Wild-type HBsAg enhanced CD86 and CD69 expression, and induced TNF-α, IL-10, and IFN-γ, regardless of the anti-HBsAg status of donor. In the presence of PHA, wild-type HBsAg had no effect on either of the tested surface markers, but increased IFN-γ and IL-10 and inhibited IL-2. In contrast, the G145R mutant alone did not affect CD86 expression, it induced less CD69, and stimulated IL-2 along with lowering levels of TNF-α, IL-10, and IFN-γ. The G145R mutant also suppressed PHA-induced activation of CD69. The dramatic differences in the immune responses elicited by wild-type HBsAg and the G145R mutant HBsAg suggest distinct adaptive capabilities of the G145R mutant HBV.
Collapse
Affiliation(s)
- Maria V. Konopleva
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| | | | - Maria V. Sokolova
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| | - Tatyana A. Semenenko
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| | - Anatoly P. Suslov
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| |
Collapse
|
|
11
|
Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100398. [PMID: 35059620 PMCID: PMC8760517 DOI: 10.1016/j.jhepr.2021.100398] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/15/2022]
Abstract
Insights into the immunopathogenesis of chronic HBV infections are fundamental in the quest for novel treatment approaches aimed at a functional cure. While much is known about the ineffective HBV-specific T-cell responses that characterise persistent HBV replication, B cells have been left largely understudied. However, an important role for humoral immunity during the natural history of HBV infections, as well as after functional cure, has been inadvertently revealed by the occurrence of HBV flares following B cell-depleting treatments. Herein, we review our current understanding of the role of the humoral immune response in chronic HBV, both at the level of HBV-specific antibody production and at the phenotypic and broader functional level of B cells. The recent development of fluorescently labelled HBV proteins has given us unprecedented insights into the phenotype and function of HBsAg- and HBcAg-specific B cells. This should fuel novel research into the mechanisms behind dysfunctional HBsAg-specific and fluctuating, possibly pathogenic, HBcAg-specific B-cell responses in chronic HBV. Finally, novel immunomodulatory treatments that partly target B cells are currently in clinical development, but a detailed assessment of their impact on HBV-specific B-cell responses is lacking. We plead for a rehabilitation of B-cell studies related to both the natural history of HBV and treatment development programmes.
Collapse
|
|
12
|
Schemmer P, Burra P, Hu R, Hüber CM, Loinaz C, Machida K, Vogel A, Samuel D. State of the art treatment of hepatitis B virus hepatocellular carcinoma and the role of hepatitis B surface antigen post-liver transplantation and resection. Liver Int 2022; 42:288-298. [PMID: 34846790 PMCID: PMC9300017 DOI: 10.1111/liv.15124] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 11/17/2021] [Accepted: 11/28/2021] [Indexed: 01/27/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is the major aetiology of hepatocellular carcinoma (HCC). The optimal goal of therapy, hepatitis B surface antigen (HBsAg) loss and anti-HBs production, is achieved rarely and HBsAg-associated HCC risk is well recognized. Here we review the role of HBsAg in HCC, the link between HBsAg and HCC recurrence post-liver transplantation or resection, and the implications for therapy. HBV-associated carcinogenesis is a multifactorial process. The observation that HBV-related HCC can occur in the absence of cirrhosis is compatible with a direct oncogenic effect of the virus, which may occur via multiple mechanisms, including those mediated by both mutated and unmutated HBsAg. HCC recurrence in HBsAg-positive patients post-liver transplantation has been reported in 10%-15% of patients and is likely to be because of expansion of residual HCC tumour cell populations containing integrated HBV DNA, which expand and independently replicate HBV, leading to the recurrence of both HCC and HBV. The direct role of HBsAg in HCC recurrence post-liver resection is less clear. Cirrhosis is the most important risk factor for HCC development, and precancerous cirrhotic liver remains after resection, with the potential to undergo malignant transformation regardless of the existence of HBV-derived oncogenic drivers. The role of HBsAg in the development of HCC and its recurrence post-surgical intervention has multiple implications for therapy and suggests a potential role for immunotherapy in the future management of HCC, in particular post-liver transplantation. Use of hepatitis B immunoglobulins that target HBsAg directly, alongside immune-oncology therapies, may be relevant in this setting.
Collapse
Affiliation(s)
- Peter Schemmer
- General, Visceral and Transplant SurgeryDepartment of SurgeryMedical University of GrazGrazAustria
| | - Patrizia Burra
- Department of Surgery, Oncology, and GastroenterologyPadua University HospitalPaduaItaly
| | - Rey‐Heng Hu
- Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
| | | | - Carmelo Loinaz
- Department of General and Digestive SurgeryUniversity Hospital 12 de OctubreMadridSpain
| | - Keigo Machida
- Keck Hospital of University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and EndocrinologyMedizinische Hochschule HannoverHannoverGermany
| | - Didier Samuel
- Centre HepatobiliaireUniversity Hospital Paul BrousseUniversity Paris‐Saclay and Inserm‐Paris Saclay Research Unit 1193VillejuifFrance
| |
Collapse
|
|
13
|
Li Y, Yin S, Issa R, Tong X, Wang G, Xia J, Huang R, Chen G, Weng D, Chen C, Wu C, Chen Y. B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection. J Clin Transl Hepatol 2021; 9:592-597. [PMID: 34447690 PMCID: PMC8369012 DOI: 10.14218/jcth.2021.00051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/24/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.
Collapse
Affiliation(s)
- Yang Li
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rahma Issa
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guangmei Chen
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dan Weng
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Chen Chen
- Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
| |
Collapse
|
|
14
|
Li MS, Hou ZH, Yao GZ, Tan DM. The strategy and efficacy of prophylaxis against hepatitis B virus recurrence after liver transplantation for HBV-related diseases in the era of potent nucleos(t)ide analogues: A meta-analysis. J Dig Dis 2021; 22:91-101. [PMID: 33128339 DOI: 10.1111/1751-2980.12959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/04/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This meta-analysis aimed to evaluate the clinical outcome of liver transplant (LT) recipients under potent nucleoside or nucleotide analogue (NA)-based regimens and investigate different prophylactic schemes. METHODS We followed PRISMA statement to conduct this study. Two reviewers independently searched relevant literature via PubMed, Embase, Ovid MEDLINE, Web of Science and Insightmeme. Studies were included if they evaluated hepatitis B virus (HBV) recurrence under potent NA-based regimens in patients who received HBV-related LT. Primary and secondary outcomes were HBV recurrence, hepatocellular carcinoma (HCC) recurrence, all-cause and HBV recurrence-related mortality. Incidences with 95% confidence intervals were calculated and assessed by fixed and random effects models. Subgroup analyses were used to examine the impact of different treatment strategies. RESULTS Altogether 25 studies (N = 2327) were included, with a pooled HBV recurrence rate of 1.01% (95% CI 0.53%-1.59%). HBV viremia or hepatitis D virus superinfection did not influence HBV recurrence significantly (P = 0.23 and 0.71, respectively). The recurrence rate under an indefinite combination of potent NA and hepatitis B immunoglobulin (HBIG) was lower than that under potent NA monotherapy (P = 0.000) and similar to that under NA plus a finite course of HBIG (P = 0.48). The pooled HCC recurrence rate was 5.34% (95% CI 0.78%-12.48%). HBV recurrence-related mortality and all-cause mortality were 0% and 6.95% (95% CI 4.30%-10.08%), respectively. CONCLUSIONS Potent NA-based regimens provide satisfactory HBV antiviral prophylaxis and improve long-term outcomes for LT recipients. A finite combination of potent NA and HBIG is an alternative to life-long dual therapy.
Collapse
Affiliation(s)
- Ming Shu Li
- Xiangya School of Public Health, Central South University, Changsha, Hunan Province, China
| | - Zhou Hua Hou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Guo Zhu Yao
- School of Mathematics and Statistics, Changsha University of Science and Technology, Changsha, Hunan Province, China
| | - De Ming Tan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
Nasir M, Wu GY. Prevention of HBV Recurrence after Liver Transplant: A Review. J Clin Transl Hepatol 2020; 8:150-160. [PMID: 32832395 PMCID: PMC7438351 DOI: 10.14218/jcth.2020.00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/16/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022] Open
Abstract
Globally, hepatitis B virus (HBV) infection is recognized as a major risk factor for the development of hepatocellular carcinoma, and HBV-induced liver failure is one of the leading indications for liver transplantation. Until about two decades ago, liver transplantation in patients with chronic HBV infection was a relative contraindication, due to high risk of viral replication with the use of immunosuppressants which could result in graft infection. In the 1990s, hepatitis B immunoglobulin (HBIg) use significantly reduced the risk of graft infection, improving outcomes of liver transplant in patients with chronic HBV infection. However, very high costs, especially with the need for long-term use, became a major concern. With the advent of nucleos(t)ide analogs (NAs), there was less need for high-dose, long-term HBIg use to prevent HBV recurrence. Lamivudine was initially used but resistance soon became a major issue. This was followed by more potent NAs, such as entecavir and tenofovir, emerging as the more preferred agents. Additionally, the use of these antiviral agents (HBIg and/or NAs) have made it possible to use the grafts from donors with positivity for hepatitis B core antibody, allowing for expansion of the donor pool. Nevertheless, there is no consensus on management protocols, which vary significantly amongst centers. In this review, we appraise studies on management strategies used and the role of active vaccination in the prevention of HBV recurrence in post-liver transplant patients.
Collapse
Affiliation(s)
- Myra Nasir
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| |
Collapse
|
|
17
|
Chen T, Liu J, Yu Q, Yao N, Yang Y, Wu Y, Ren D, Tian Z, Zhao Y, Wang J. Tenofovir plus hepatitis B immunoglobulin treatment resulted in a rapid HBV DNA load decline in high-risk pregnant women who missed the optimal time window of antiviral prophylaxis. Antivir Ther 2020; 24:125-131. [PMID: 30570488 DOI: 10.3851/imp3284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2018] [Indexed: 10/27/2022]
Abstract
BACKGROUND Tenofovir disoproxil fumarate (TDF) administration in the third trimester for pregnant women with high HBV DNA load has been accepted as a wise practice to prevent mother-to-infant transmission (MTIT). However, for those women who missed the optimal time window of antiviral prophylaxis, this treatment is lacking in the current clinical guidelines. METHODS Forty-eight pregnant women who did not receive antiviral prophylaxis before 28 weeks of gestation were screened and were administrated with TDF plus hepatitis B immunoglobulin (HBIG; TDF+HBIG group) or TDF alone (TDF group). HBV DNA inhibition and the safety profile were compared between two groups. RESULTS A decline of HBV DNA load was observed in both groups after a short period of treatment, and no infant had MTIT. However, compared with the TDF group, the speed of HBV DNA load decline was more rapid (P=0.002) and a much more striking HBV DNA load decline in the first 4 weeks of treatment was exhibited in the TDF+HBIG group (P=0.001). The percentages of mothers with HBV DNA <4 log10 IU/ml and 3 log10 IU/ml at delivery were both much higher in the TDF+HBIG group than the TDF group (P=0.034 and 0.024, respectively). TDF and HBIG were found to be well-tolerated with no safety concerns in the mothers and their infants. CONCLUSIONS TDF plus HBIG treatment resulted in a rapid HBV DNA load decline in high-risk women who missed the optimal time window of antiviral prophylaxis in pregnancy, which potentially protected infants from HBV infection.
Collapse
Affiliation(s)
- Tianyan Chen
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Jinfeng Liu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Qiang Yu
- Department of Pediatric Surgery, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Naijuan Yao
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Yuan Yang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Yuchao Wu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Danfeng Ren
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Zhen Tian
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Yingren Zhao
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| | - Jing Wang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China.,Department of Rheumatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an City, China
| |
Collapse
|
|
18
|
Warner N, Locarnini S, Xu H. The role of hepatitis B surface antibodies in HBV infection, disease and clearance. Future Virol 2020. [DOI: 10.2217/fvl-2019-0147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The clinical sequelae associated with chronic HBV infection is generally regarded as a consequence of an inadequate and inappropriate immune response to active viral replication, predominantly at the T-cell level. However, recent studies on hepatitis B surface antigen (HBsAg)-specific B cells and hepatitis B surface antibody (anti-HB) responses have identified their previously unrecognized role in the pathogenesis of chronic hepatitis B (CHB). These studies have also uncovered novel therapeutic approaches to more effectively target HBsAg loss and seroconversion, an important end point and regarded as a functional cure. Anti-HBs IgG has also been shown to have multiple direct acting antiviral roles with the Fab component directly blocking viral entry, and release while the Fc component has been linked to antibody dependent cellular cytotoxicity. Likewise, the HBsAg-specific B-cell dysfunctionality can be reversed providing new therapeutic opportunities to achieve functional cure in CHB.
Collapse
Affiliation(s)
- Nadia Warner
- Molecular Research & Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, Victoria, Australia
| | - Stephen Locarnini
- Molecular Research & Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, Victoria, Australia
| | - Hui Xu
- Molecular Research & Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, Victoria, Australia
| |
Collapse
|
|
19
|
Elalfy H, Besheer T, Elhammady D, Mesery AE, Shaltout SW, El-Maksoud MA, Amin AI, Bekhit AN, Aziz MAE, El-Bendary M. Pathological characterization of occult hepatitis B virus infection in hepatitis C virus-associated or non-alcoholic steatohepatitis-related hepatocellular carcinoma. World J Meta-Anal 2020; 8:67-77. [DOI: 10.13105/wjma.v8.i2.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/08/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
|
|
20
|
Maini MK, Burton AR. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat Rev Gastroenterol Hepatol 2019; 16:662-675. [PMID: 31548710 DOI: 10.1038/s41575-019-0196-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2019] [Indexed: 02/06/2023]
Abstract
Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies.
Collapse
Affiliation(s)
- Mala K Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
| | - Alice R Burton
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
| |
Collapse
|
|
21
|
Chen Y, Kong Y, Shi L, Zhang X, Yang X, Liu X, Lin S, Ye F. Study of the distribution of hepatitis B immunoglobulin in pregnant mice using small-animal imaging technology. J Med Virol 2019; 91:1811-1817. [PMID: 31209906 DOI: 10.1002/jmv.25521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 06/09/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND The safety and necessity of hepatitis B immunoglobulin (HBIG) in preventing the mother-to-child transmission of hepatitis B virus (HBV) are still controversial because of its unclear mechanism of action and the inconsistent injection programs used during gestation. OBJECTIVES This study aimed to show the dynamic transportation and distribution of HBIG in the maternal body and to provide evidence for its clinical efficacy in preventing mother-to-child HBV transmission. STUDY DESIGN Pregnant mice were injected with Cy7-labeled mouse anti-human monoclonal hepatitis B surface antibodies through the tail vein. In vivo imaging technology was used to observe the dynamic transportation and distribution of HBIG in the pregnant mice. RESULTS HBIG fluorescence signals were higher in the uterus than in the liver, spleen, and kidneys. Fluorescence signals in the uterine region were obviously higher at the third trimester than at early and mid pregnancy. CONCLUSIONS HBIG is gradually deposited in the mouse placenta during pregnancy, with the phenomenon being more significant in the third trimester.
Collapse
Affiliation(s)
- Yunru Chen
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Kong
- Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lei Shi
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xi Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xueliang Yang
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaojing Liu
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shumei Lin
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Feng Ye
- Department of Infectious Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| |
Collapse
|
|
22
|
Li C, Wang Y, Liu T, Niklasch M, Qiao K, Durand S, Chen L, Liang M, Baumert TF, Tong S, Nassal M, Wen YM, Wang YX. An E. coli-produced single-chain variable fragment (scFv) targeting hepatitis B virus surface protein potently inhibited virion secretion. Antiviral Res 2019; 162:118-129. [DOI: 10.1016/j.antiviral.2018.12.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 12/06/2018] [Accepted: 12/28/2018] [Indexed: 01/14/2023]
|
|
23
|
Salimzadeh L, Le Bert N, Dutertre CA, Gill US, Newell EW, Frey C, Hung M, Novikov N, Fletcher S, Kennedy PT, Bertoletti A. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest 2018; 128:4573-4587. [PMID: 30084841 PMCID: PMC6159957 DOI: 10.1172/jci121957] [Citation(s) in RCA: 205] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022] Open
Abstract
Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as "baits" for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti-PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell-maturing cytokines and PD-1 blockade.
Collapse
Affiliation(s)
- Loghman Salimzadeh
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Microbiology and Immunology, National University of Singapore, Singapore
| | - Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Charles-A. Dutertre
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
| | - Upkar S. Gill
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Evan W. Newell
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
| | - Christian Frey
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Magdeleine Hung
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Nikolai Novikov
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Simon Fletcher
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Patrick T.F. Kennedy
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
| |
Collapse
|
|
24
|
Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L, Alberts E, Davidson BR, Kennedy PT, Gill US, Mauri C, Blair PA, Pelletier N, Maini MK. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest 2018; 128:4588-4603. [PMID: 30091725 PMCID: PMC6159997 DOI: 10.1172/jci121960] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/26/2018] [Indexed: 12/15/2022] Open
Abstract
B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21-CD27- atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.
Collapse
Affiliation(s)
- Alice R. Burton
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Laura J. Pallett
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Laura E. McCoy
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Kornelija Suveizdyte
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Oliver E. Amin
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Leo Swadling
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Elena Alberts
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Brian R. Davidson
- Department of Surgery, University College London, London, United Kingdom
| | | | - Upkar S. Gill
- Centre for Immunobiology, Barts and the London, London, United Kingdom
| | - Claudia Mauri
- Division of Medicine, University College London, London, United Kingdom
| | - Paul A. Blair
- Division of Medicine, University College London, London, United Kingdom
| | | | - Mala K. Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| |
Collapse
|
|
25
|
Ajayi T, Luu H, Saberi B, Hamilton JP, Konduk BT, Özşeker B, Al Khalloufi K, Pustavoitau A, Philosophe B, Cameron AM, Gürakar A. Role of nucleoside/nucleotide analogues and low-dose hepatitis B immune globülin in prophylaxis of hepatitis B recurrence among cadaveric liver transplant recipients. TURKISH JOURNAL OF GASTROENTEROLOGY 2018; 29:61-66. [PMID: 29391309 DOI: 10.5152/tjg.2018.17595] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Hepatitis B core antibody (HBcAb) positivity of the donor or the recipient may pose a risk of hepatitis B virus (HBV) reactivation following liver transplantation (LT). We retrospectively investigated patient survival and reactivation among recipients who were given low-dose Hepatitis B Immune Globulin (HBIG) plus antiviral agent (AV) versus AV only. MATERIALS AND METHODS Records of cadaveric LT recipients, between 2013 and 2016, with positive Hepatitis B surface Antigen (HBsAg) and/or HBcAb and recipients who had received LT from HBcAb-positive donors were reviewed. Patient characteristics and clinical data were extracted. Donor variables were retrieved from the United Network of Organ Sharing (UNOS) database. HBIG (1560 IU/mL) Intravenous (IV) was intraoperatively administered with three daily doses. Entecavir 1 mg daily was also given. STATA was used for statistical analysis. RESULTS There were 53 recipients; 39 (73.6%) were male with a median age of 59 y. HCV was the major indication in 30 (55.6%) patients. There were 28 recipients (52.8%) who received HBIG plus AV and 25 (47.2%) received AV only. The Model of End Stage Liver Disease (MELD) score between the groups were similar. Survival rates at 6, 12, and 24 months were 100% (n=53), 93.2% (n=44), and 100.0% (n=26), respectively. There was no reactivation; two recipients in the AV group and one in the HBIG plus AV group died within 12 months. CONCLUSION This study supports the use of low-dose HBIG and AV for post-LT prophylaxis to be as effective as conventionally used high-dose HBIG (9600 IU) plus AV. Future prospective larger studies are warranted to examine the potential benefits of using AV alone without HBIG.
Collapse
Affiliation(s)
- Tokunbo Ajayi
- Department of Internal Medicine, Johns Hopkins Howard County General Hospital, Columbia, MD; Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Harry Luu
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Behnam Saberi
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - James P Hamilton
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Bugra Tolga Konduk
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Burak Özşeker
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kawtar Al Khalloufi
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Aliaksei Pustavoitau
- Department of Anesthesiology and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Benjamin Philosophe
- Transplant Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew M Cameron
- Transplant Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ahmet Gürakar
- Division of Gastroenterology and Hepatology, Transplant Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD
| |
Collapse
|
|
26
|
Chang CY, Chang FL, Chiang CW, Lo YN, Lin TY, Chen WC, Tsai KC, Lee YC. Interaction of S17 Antibody with the Functional Binding Region of the Hepatitis B Virus Pre-S2 Epitope. Viral Immunol 2018; 31:492-499. [PMID: 29847243 DOI: 10.1089/vim.2017.0200] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
To understand the mechanism for inhibition of hepatitis B virus (HBV) infection is important. In this study, single-chain variable fragment (scFv) antibodies were generated and directed to the pre-S2 epitope of HBV surface antigen (HBsAg). These human scFvs were isolated from a person with history of HBV infection by phage display technology. An evaluation of panning efficiency revealed that the eluted phage titer was increased, indicating that specific clones were enriched after panning. Selected scFvs were characterized with the recombinant HBsAg through Western blotting and enzyme-linked immunosorbent assay to confirm the binding ability. Flow cytometry analysis and immunocytochemical staining revealed that one scFv, S17, could recognize endogenous HBsAg expressed on the HepG2215 cell membrane. Moreover, the binding affinity of scFv S17 to the pre-S2 epitope was determined to be 4.2 × 10-8 M. Two ion interactions were observed as the major driving forces for scFv S17 interacting with pre-S2 by performing a rational molecular docking analysis. This study provides insights into the structural basis to understand the interactions between an antibody and the pre-S2 epitope. The functional scFv format can potentially be used in future immunotherapeutic applications.
Collapse
Affiliation(s)
- Chang-Yu Chang
- 1 Department of Medical Technology, Jen-Teh Junior College of Medicine , Nursing and Management, Miaoli, Taiwan
| | - Fu-Ling Chang
- 2 The Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University , Taipei, Taiwan
| | - Chen-Wei Chiang
- 3 Research Center of Cancer Translational Medicine, Taipei Medical University , Taipei, Taiwan
| | - Yan-Ni Lo
- 3 Research Center of Cancer Translational Medicine, Taipei Medical University , Taipei, Taiwan
| | - Tsai-Yu Lin
- 3 Research Center of Cancer Translational Medicine, Taipei Medical University , Taipei, Taiwan
| | - Wang-Chuan Chen
- 4 The School of Chinese Medicine for Post Baccalaureate, I-Shou University , Kaohsiung, Taiwan .,5 Department of Chinese Medicine, E-Da Hospital , Kaohsiung, Taiwan
| | - Keng-Chang Tsai
- 6 The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University , Taipei, Taiwan .,7 National Research Institute of Chinese Medicine , Ministry of Health and Welfare, Taipei, Taiwan
| | - Yu-Ching Lee
- 2 The Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University , Taipei, Taiwan .,3 Research Center of Cancer Translational Medicine, Taipei Medical University , Taipei, Taiwan
| |
Collapse
|
|
27
|
Corti D, Benigni F, Shouval D. Viral envelope-specific antibodies in chronic hepatitis B virus infection. Curr Opin Virol 2018; 30:48-57. [PMID: 29738926 DOI: 10.1016/j.coviro.2018.04.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/26/2018] [Accepted: 04/02/2018] [Indexed: 12/20/2022]
Abstract
While the cellular immune response associated with acute and chronic HBV infection has been thoroughly studied, the B cell response in chronic hepatitis B and the role of antibodies raised against the HBV envelope antigens in controlling and prevention of infection requires further investigation. The detection of anti-HBs antibodies is considered as one of the biomarkers for functional cure of chronic hepatitis B virus infection, as well as for protective immunity. Indeed, vaccine-induced neutralizing anti-HBs antibodies have been shown to protect against HBV challenge. Yet, the therapeutic potential of viral envelope-specific antibodies and the mechanism involved in protection and prevention of cell-to-cell transmission warrants additional investigative efforts. In this review, we will provide a critical overview of the available preclinical and clinical literature supporting the putative role of active and passive vaccination and neutralizing envelope-specific antibodies for therapeutic intervention in combination regimens intended to cure persistent HBV infection.
Collapse
Affiliation(s)
- Davide Corti
- Humabs BioMed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
| | - Fabio Benigni
- Humabs BioMed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
| | - Daniel Shouval
- Liver Unit, Institute for Gastroenterology and Hepatology, Hadassah-Hebrew University Hospital, P.O. Box 12000, 91120 Jerusalem, Israel.
| |
Collapse
|
|
28
|
Datta S, Chakravarty R. Role of RNA secondary structure in emergence of compartment specific hepatitis B virus immune escape variants. World J Virol 2016; 5:161-169. [PMID: 27878103 PMCID: PMC5105049 DOI: 10.5501/wjv.v5.i4.161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/09/2016] [Accepted: 08/29/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the role of subgenotype specific RNA secondary structure in the compartment specific selection of hepatitis B virus (HBV) immune escape mutations.
METHODS This study was based on the analysis of the specific observation of HBV subgenotype A1 in the serum/plasma, while subgenotype A2 with G145R mutation in the peripheral blood leukocytes (PBLs). Genetic variability found among the two subgenotypes was used for prediction and comparison of the full length pregenomic RNA (pgRNA) secondary structure and base pairings. RNA secondary structures were predicted for 37 °C using the Vienna RNA fold server, using default parameters. Visualization and detailed analysis was done using RNA shapes program.
RESULTS In this analysis, using similar algorithm and conditions, entirely different pgRNA secondary structures for subgenotype A1 and subgenotype A2 were predicted, suggesting different base pairing patterns within the two subgenotypes of genotype A, specifically, in the HBV genetic region encoding the major hydrophilic loop. We observed that for subgenotype A1 specific pgRNA, nucleotide 358U base paired with 1738A and nucleotide 587G base paired with 607C. However in sharp contrast, in subgenotype A2 specific pgRNA, nucleotide 358U was opposite to nucleotide 588G, while 587G was opposite to 359U, hence precluding correct base pairing and thereby lesser stability of the stem structure. When the nucleotides at 358U and 587G were replaced with 358C and 587A respectively (as observed specifically in the PBL associated A2 sequences), these nucleotides base paired correctly with 588G and 359U, respectively.
CONCLUSION The results of this study show that compartment specific mutations are associated with HBV subgenotype specific alterations in base pairing of the pgRNA, leading to compartment specific selection and preponderance of specific HBV subgenotype with unique mutational pattern.
Collapse
|
|
29
|
Saab S, Chen PY, Saab CE, Tong MJ. The Management of Hepatitis B in Liver Transplant Recipients. Clin Liver Dis 2016; 20:721-736. [PMID: 27742010 DOI: 10.1016/j.cld.2016.06.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver transplant (LT) is now an established indication for patients with chronic hepatitis B, mainly because of the development and use of hepatitis B immunoglobulin (HBIG) and oral antivirals for prophylaxis. The combination of low-dose HBIG and antivirals has been considered the standard prophylaxis regimen to prevent post-LT recurrence of hepatitis B. The important remaining issues are related to the long-term cost of HBIG and the risk of escape hepatitis B virus (HBV) mutants. Strategies for prevention of HBV after LT are constantly improving. With the availability of new nucleoside/nucleotide analogues, new post-LT strategies also should emerge.
Collapse
Affiliation(s)
- Sammy Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Ping-Yu Chen
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Clara E Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
| | - Myron J Tong
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA; Huntington Medical Research Institutes, Pasadena, CA, USA
| |
Collapse
|
|
30
|
Makvandi M. Update on occult hepatitis B virus infection. World J Gastroenterol 2016; 22:8720-8734. [PMID: 27818588 PMCID: PMC5075547 DOI: 10.3748/wjg.v22.i39.8720] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/13/2016] [Accepted: 07/20/2016] [Indexed: 02/06/2023] Open
Abstract
The event of mutations in the surface antigen gene of hepatitis B virus (HBV) results in undetectable hepatitis B surface antigen with positive/negative anti-hepatitis B core (anti-HBc) antibody status in serum and this phenomenon is named occult hepatitis B infection (OBI). The presence of anti-HBc antibody in serum is an important key for OBI tracking, although about 20% of OBI cases are negative for anti-HBc antibody. The diagnosis of OBI is mainly based on polymerase chain reaction (PCR) and real-time PCR assays. However, real-time PCR is a more reliable method than PCR. OBI is a great issue for the public health problem and a challenge for the clinical entity worldwide. The persistence of OBI may lead to the development of cirrhosis and hepatocellular carcinoma. With regard to OBI complications, the screening of HBV DNA by the highly sensitive molecular means should be implemented for: (1) patients with a previous history of chronic or acute HBV infection; (2) patients co-infected with hepatitis C virus/human immunodeficiency virus; (3) patients undergoing chemotherapy or anti-CD20 therapy; (4) recipients of organ transplant; (5) blood donors; (6) organ transplant donors; (7) thalassemia and hemophilia patients; (8) health care workers; (9) patients with liver related disease (cryptogenic); (10) hemodialysis patients; (11) patients undergoing lamivudine or interferon therapy; and (12) children in time of HBV vaccination especially in highly endemic areas of HBV. Active HBV vaccination should be implemented for the close relatives of patients who are negative for OBI markers. Thus, the goal of this review is to evaluate the rate of OBI with a focus on status of high risk groups in different regions of the world.
Collapse
|
|
31
|
Stapleton NM, Einarsdóttir HK, Stemerding AM, Vidarsson G. The multiple facets of FcRn in immunity. Immunol Rev 2016; 268:253-68. [PMID: 26497526 DOI: 10.1111/imr.12331] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The neonatal Fc receptor, FcRn, is best known for its role in transporting IgG in various tissues, providing newborns with humoral immunity, and for prolonging the half-life of IgG. Recent findings implicate the involvement of FcRn in a far wider range of biological and immunological processes, as FcRn has been found to bind and extend the half-life of albumin; to be involved in IgG transport and antigen sampling at mucosal surfaces; and to be crucial for efficient IgG-mediated phagocytosis. Herein, the function of FcRn will be reviewed, with emphasis on its recently documented significance for IgG polymorphisms affecting the half-life and biodistribution of IgG3, on its role in phagocyte biology, and the subsequent role for the presentation of antigens to lymphocytes.
Collapse
Affiliation(s)
- Nigel M Stapleton
- Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, Amsterdam, The Netherlands
| | - Helga K Einarsdóttir
- Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, Amsterdam, The Netherlands
| | | | - Gestur Vidarsson
- Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, Amsterdam, The Netherlands
| |
Collapse
|
|
32
|
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.
Collapse
|
|
33
|
Lee EC, Kim SH, Lee SD, Park H, Lee SA, Park SJ. High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation. World J Gastroenterol 2016; 22:3803-3812. [PMID: 27076765 PMCID: PMC4814743 DOI: 10.3748/wjg.v22.i14.3803] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 12/13/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impact of high-dose hepatitis B immunoglobulin (HBIG) on hepatocellular carcinoma (HCC) and hepatitis B virus (HBV) recurrence and overall survival after living donor liver transplantation (LDLT).
METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen (HBeAg) -positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose.
RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively (P = 0.042). In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose (P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met (P = 0.317 and 0.190, respectively) and did not meet (P = 0.350 and 0.987, respectively) the Milan criteria.
CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBeAg-positive patients after LDLT.
Collapse
|
|
34
|
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.
Collapse
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
| |
Collapse
|
|
35
|
Revill P, Locarnini S. The Basis for Antiviral Therapy: Drug Targets, Cross-Resistance, and Novel Small Molecule Inhibitors. MOLECULAR AND TRANSLATIONAL MEDICINE 2016. [DOI: 10.1007/978-3-319-22330-8_14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
36
|
Oh IS, Park SH. Immune-mediated Liver Injury in Hepatitis B Virus Infection. Immune Netw 2015; 15:191-8. [PMID: 26330805 PMCID: PMC4553257 DOI: 10.4110/in.2015.15.4.191] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 07/26/2015] [Accepted: 08/02/2015] [Indexed: 12/29/2022] Open
Abstract
Hepatitis B virus (HBV) is responsible for approximately 350 million chronic infections worldwide and is a leading cause of broad-spectrum liver diseases such as hepatitis, cirrhosis and liver cancer. Although it has been well established that adaptive immunity plays a critical role in viral clearance, the pathogenetic mechanisms that cause liver damage during acute and chronic HBV infection remain largely known. This review describes our current knowledge of the immune-mediated pathogenesis of HBV infection and the role of immune cells in the liver injury during hepatitis B.
Collapse
Affiliation(s)
- In Soo Oh
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea. ; Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06973, Korea
| | - Su-Hyung Park
- Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
| |
Collapse
|
|
37
|
Chen Y, Chernyavsky A, Webber RJ, Grando SA, Wang PH. Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris. J Biol Chem 2015; 290:23826-37. [PMID: 26260795 DOI: 10.1074/jbc.m115.668061] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Indexed: 01/23/2023] Open
Abstract
Pemphigus vulgaris (PV) is a life-long, potentially fatal IgG autoantibody-mediated blistering disease targeting mucocutaneous keratinocytes (KCs). PV patients develop pathogenic anti-desmoglein (Dsg) 3 ± 1 and antimitochondrial antibodies (AMA), but it remained unknown whether and how AMA enter KCs and why other cell types are not affected in PV. Therefore, we sought to elucidate mechanisms of cell entry, trafficking, and pathogenic action of AMA in PV. We found that PVIgGs associated with neonatal Fc receptor (FcRn) on the cell membrane, and the PVIgG-FcRn complexes entered KCs and reached mitochondria where they dissociated. The liberated AMA altered mitochondrial membrane potential, respiration, and ATP production and induced cytochrome c release, although the lack or inactivation of FcRn abolished the ability of PVIgG to reach and damage mitochondria and to cause detachment of KCs. The assays of mitochondrial functions and keratinocyte adhesion demonstrated that although the pathobiological effects of AMA on KCs are reversible, they become irreversible, leading to epidermal blistering (acantholysis), when AMA synergize with anti-Dsg antibodies. Thus, it appears that AMA enter a keratinocyte in a complex with FcRn, become liberated from the endosome in the cytosol, and are trafficked to the mitochondria, wherein they trigger pro-apoptotic events leading to shrinkage of basal KCs uniquely expressing FcRn in epidermis. During recovery, KCs extend their cytoplasmic aprons toward neighboring cells, but anti-Dsg antibodies prevent assembly of nascent desmosomes due to steric hindrance, thus rendering acantholysis irreversible. In conclusion, FcRn is a common acceptor protein for internalization of AMA and, perhaps, for PV autoantibodies to other intracellular antigens, and PV is a novel disease paradigm for investigating and elucidating the role of FcRn in this autoimmune disease and possibly other autoimmune diseases.
Collapse
Affiliation(s)
- Yumay Chen
- From the Irvine Diabetes Center, Department of Medicine, and
| | | | | | - Sergei A Grando
- Departments of Dermatology and Biological Chemistry, and the Institute for Immunology, University of California at Irvine, Irvine, California 92967 and
| | - Ping H Wang
- From the Irvine Diabetes Center, Department of Medicine, and Biological Chemistry, and
| |
Collapse
|
|
38
|
Molecular Mechanisms to Control Post-Transplantation Hepatitis B Recurrence. Int J Mol Sci 2015; 16:17494-513. [PMID: 26263973 PMCID: PMC4581205 DOI: 10.3390/ijms160817494] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B often progresses to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). Although newer nucleos(t)ide analogues result in >90% viral and hepatitis activity control, severely decompensated patients still need OLT because of drug-resistant virus, acute exacerbation, or hepatocellular carcinoma. Acute hepatitis B is also an indication for OLT, because it can progress to fatal acute liver failure. After OLT, the hepatitis B recurrence rate is >80% without prevention, while >90% of transplant recipients are clinically controlled with combined hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogue treatment. However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost; therefore, several treatment protocols with low-dose HBIG, combined with nucleos(t)ide analogues, have been investigated. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using an HBV envelope (HBs) antigen vaccine. Patients who are not HBV carriers, such as those with acutely infected liver failure, are good candidates for vaccination. For chronic HBV carrier liver cirrhosis patients, a successful vaccine response can only be achieved in selected patients, such as those treated with experimentally reduced immunosuppression protocols. The present protocol for post-OLT HBV control and the future prospects of newer treatment strategies are reviewed.
Collapse
|
|
39
|
Choudhary NS, Saraf N, Saigal S, Mohanka R, Rastogi A, Goja S, Menon PB, Soin AS. Low-dose short-term hepatitis B immunoglobulin with high genetic barrier antivirals: the ideal post-transplant hepatitis B virus prophylaxis? Transpl Infect Dis 2015; 17:329-33. [PMID: 25682715 DOI: 10.1111/tid.12369] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 12/02/2014] [Accepted: 01/28/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Low-dose hepatitis B immunoglobulin (HBIG) and nucleos(t)ides analogs (lamivudine/adefovir) used for the prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) are associated with some risk of HBV recurrence and antiviral resistance. METHODS The study cohort included 176 patients (at least >12 months follow-up) with HBV cirrhosis/hepatocellular carcinoma who received secondary prophylaxis with indefinite entecavir/tenofovir after living-donor LT (LDLT). All patients received 10,000 IU intravenous HBIG in anhepatic phase followed by 600-1000 IU intramuscularly daily for 7 days, weekly for 3 weeks, and then monthly, to keep antiHBs levels >100 mIU/mL for 1 year. Hepatitis B surface antigen (HBsAg) and HBV DNA were tested every 6 months. RESULTS The study cohort is composed of 157 men and 19 women, mean age 47.9 ± 10.1 years, all HBsAg positive, 35 (19.8%) had HBV DNA >2000 IU/mL before LT. After LT, patients received entecavir (n = 126, 71.5%), tenofovir (n = 20, 11.3%), or a combination of entecavir and tenofovir (n = 30, 17% for 3 months), followed by entecavir alone. During follow-up of 43 (12-117) months, 2 patients (including 1 with non-compliance) had HBV recurrence. CONCLUSION In a large cohort of LDLT recipients for HBV-related liver disease, use of low-dose short-term HBIG with high genetic barrier drugs results in a substantially lower incidence of HBV recurrence, even in high-risk patients.
Collapse
Affiliation(s)
- N S Choudhary
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - N Saraf
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - S Saigal
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - R Mohanka
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - A Rastogi
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - S Goja
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - P B Menon
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| | - A S Soin
- Medanta Liver Institute, Medanta The Medicity, Gurgaon, Haryana, India
| |
Collapse
|
|
40
|
Cerino A, Bremer CM, Glebe D, Mondelli MU. A Human Monoclonal Antibody against Hepatitis B Surface Antigen with Potent Neutralizing Activity. PLoS One 2015; 10:e0125704. [PMID: 25923526 PMCID: PMC4414269 DOI: 10.1371/journal.pone.0125704] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 03/17/2015] [Indexed: 12/11/2022] Open
Abstract
We describe the production and characterization of human monoclonal antibodies (mAb) specific for the major hepatitis B virus (HBV) S protein. The mAbs, two IgG1κ and one IgG1λ, were secreted by B-cell clones obtained from peripheral blood mononuclear cells (PBMC) of one person convalescent from acute hepatitis B and one vaccinated individual. The former recognized a denaturation-insensitive epitope within the p24 protein whereas the latter recognized a denaturation-sensitive, conformational epitope located within the HBsAg common "a" determinant. This mAb, denominated ADRI-2F3, displayed a very high protective titer of over 43,000 IU/mg mAb and showed an extremely potent neutralizing activity in the in vitro model of HBV infection using primary hepatocytes from Tupaia belangeri as target. Recombinant variable heavy and light domain sequences derived from mAb ADRI-2F3 were cloned into eukaryotic expression vectors and showed identical fine specificity and 1 log10 higher titer than the original IgG1λ. It is envisaged that such mAb will be able to efficiently prevent HBV reinfection after liver transplantation for end-stage chronic HBV infection or infection after needle-stick exposure, providing an unlimited source of valuable protective anti-HBs antibody.
Collapse
Affiliation(s)
- Antonella Cerino
- Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Corinna M. Bremer
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, German Center for Infection Research, Justus-Liebig University of Giessen, Giessen, Germany
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, German Center for Infection Research, Justus-Liebig University of Giessen, Giessen, Germany
| | - Mario U. Mondelli
- Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- * E-mail:
| |
Collapse
|
|
41
|
Morel A, Passot C, Arnoult C, Dumans A, Beaumont E, Gouilleux-Gruart V, Roingeard P, Blanchard E. The neonatal Fc receptor does not modulate hepatitis C virus neutralization. J Gen Virol 2015; 96:1062-1066. [PMID: 25614590 DOI: 10.1099/vir.0.000060] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/15/2015] [Indexed: 12/19/2022] Open
Abstract
The neonatal Fc receptor (FcRn) is the only receptor known to be able to transport IgG across cell barriers and may therefore modulate virus infection. FcRn is expressed efficiently in hepatocytes. We therefore investigated the possible involvement of an FcRn-dependent mechanism in hepatitis C virus (HCV) neutralization. Our study, in both HCV pseudoparticles and HCV in cell-culture models, showed that FcRn was not involved in the intracellular neutralization of HCV, in contrast to the situation observed for influenza A virus.
Collapse
Affiliation(s)
- Anthony Morel
- INSERM U966, Université François Rabelais and CHRU de Tours, France
| | - Christophe Passot
- UMR CNRS 7292, Université François Rabelais and CHRU de Tours, France
| | | | - Amélie Dumans
- INSERM U966, Université François Rabelais and CHRU de Tours, France
| | - Elodie Beaumont
- INSERM U966, Université François Rabelais and CHRU de Tours, France
| | | | | | | |
Collapse
|
|
42
|
Tan W, Meng Y, Li H, Chen Y, Han S, Zeng J, Huang A, Li B, Zhang Y, Guo Y. A bispecific antibody against two different epitopes on hepatitis B surface antigen has potent hepatitis B virus neutralizing activity. MAbs 2015; 5:946-55. [PMID: 24492346 DOI: 10.4161/mabs.26390] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Treatment of chronic hepatitis B virus (HBV) infection with interferon and viral reverse transcriptase inhibitor regimens results in poor viral clearance, loss of response, and emergence of drug-resistant mutant virus strains. These problems continue to drive the development of new therapeutic approaches to combat HBV. Here, we engineered a bispecific antibody using two monoclonal antibodies cloned from hepatitis B surface antigen (HBsAg)-specific memory B cells from recombinant HBsAg-vaccinated healthy volunteers. Next, we evaluated its efficacy in neutralizing HBV in HepaRG cells. This bispecific antibody, denoted as C4D2-BsAb, had superior HBV-neutralizing activity compared with the combination of both parental monoclonal antibodies, possibly through steric hindrance or induction of HBsAg conformational changes. Moreover, C4D2-BsAb has superior endocytotic characteristics into hepatocytes, which inhibits the secretion of HBsAg. These results suggest that the anti-HBsAg bispecific antibody may be an effective treatment method against HBV infection.
Collapse
Affiliation(s)
- Wenlong Tan
- Shanghai Institute of Immunology; Institutes of Medical Sciences; Shanghai Jiao Tong University School of Medicine; Shanghai, China
| | - Yanchun Meng
- International Joint Cancer Institute; Second Military Medical University; Shanghai, China
| | - Hui Li
- PLA General Hospital Cancer Center; PLA School of Medical Sciences; Beijing, China
| | - Yang Chen
- PLA General Hospital Cancer Center; PLA School of Medical Sciences; Beijing, China
| | - Siqi Han
- PLA General Hospital Cancer Center; PLA School of Medical Sciences; Beijing, China
| | - Jing Zeng
- PLA General Hospital Cancer Center; PLA School of Medical Sciences; Beijing, China
| | - Ang Huang
- PLA General Hospital Cancer Center; PLA School of Medical Sciences; Beijing, China
| | - Bohua Li
- International Joint Cancer Institute; Second Military Medical University; Shanghai, China
| | - Yanyun Zhang
- Shanghai Institute of Immunology; Institutes of Medical Sciences; Shanghai Jiao Tong University School of Medicine; Shanghai, China
| | - Yajun Guo
- Shanghai Institute of Immunology; Institutes of Medical Sciences; Shanghai Jiao Tong University School of Medicine; Shanghai, China; International Joint Cancer Institute; Second Military Medical University; Shanghai, China; PLA General Hospital Cancer Center; PLA School of Medical Sciences; Beijing, China
| |
Collapse
|
|
43
|
Takaki A, Yagi T, Yamamoto K. Safe and cost-effective control of post-transplantation recurrence of hepatitis B. Hepatol Res 2015; 45:38-47. [PMID: 24905970 PMCID: PMC4309460 DOI: 10.1111/hepr.12368] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 05/18/2014] [Accepted: 06/02/2014] [Indexed: 12/14/2022]
Abstract
A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence.
Collapse
Affiliation(s)
- Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan,Correspondence: Dr Akinobu Takaki, Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| | - Takahito Yagi
- Department of Gastroenterological Surgery Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| |
Collapse
|
|
44
|
Contradictory immune response in post liver transplantation hepatitis B and C. Int J Inflam 2014; 2014:814760. [PMID: 25215259 PMCID: PMC4158295 DOI: 10.1155/2014/814760] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 08/10/2014] [Accepted: 08/10/2014] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV) reinfects transplanted livers at a rate of >90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C.
Collapse
|
|
45
|
Feng Z, Hirai-Yuki A, McKnight KL, Lemon SM. Naked Viruses That Aren't Always Naked: Quasi-Enveloped Agents of Acute Hepatitis. Annu Rev Virol 2014; 1:539-60. [PMID: 26958733 DOI: 10.1146/annurev-virology-031413-085359] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Historically, viruses were considered to be either enveloped or nonenveloped. However, recent work on hepatitis A virus and hepatitis E virus challenges this long-held tenet. Whereas these human pathogens are shed in feces as naked nonenveloped virions, recent studies indicate that both circulate in the blood completely masked in membranes during acute infection. These membrane-wrapped virions are as infectious as their naked counterparts, although they do not express a virally encoded protein on their surface, thus distinguishing them from conventional enveloped viruses. The absence of a viral fusion protein implies that these quasi-enveloped virions have unique mechanisms for entry into cells. Like true enveloped viruses, however, these phylogenetically distinct viruses usurp components of the host ESCRT system to hijack host cell membranes and noncytolytically exit infected cells. The membrane protects these viruses from neutralizing antibodies, facilitating dissemination within the host, whereas nonenveloped virions shed in feces are stable in the environment, allowing for epidemic transmission.
Collapse
Affiliation(s)
- Zongdi Feng
- Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, and Departments of Medicine and Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292;
| | - Asuka Hirai-Yuki
- Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, and Departments of Medicine and Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292;
| | - Kevin L McKnight
- Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, and Departments of Medicine and Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292;
| | - Stanley M Lemon
- Lineberger Comprehensive Cancer Center, Inflammatory Diseases Institute, and Departments of Medicine and Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292;
| |
Collapse
|
|
46
|
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]
|
|
47
|
Varghese J, Reddy MS, Cherian T, Vijaya S, Jayanthi V, Rela M. Anti-HBs response to hepatitis B immunoglobulin prophylaxis in liver transplant recipients. Indian J Gastroenterol 2014; 33:226-30. [PMID: 24760685 DOI: 10.1007/s12664-014-0457-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Accepted: 10/13/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) recurrence after a liver transplant (LT) is a global issue. Several strategies have been adopted to prevent this recurrence. Most strategies recommend a combination of hepatitis B immunoglobulin (HBIG) and or nucleos(t)ide analogue. AIM OF THE STUDY The aim of the study is to determine the anti-HBs response to HBIG among Indian patients who had undetectable pre-transplant HBV DNA. METHODS Seven adult HBV-related LT recipients of Indian origin with low pre-transplant HBV titres who had a liver transplant between August 2009 and June 2012 were included in the study. The protocol followed for post-liver transplant HBIG dose was titrated to achieve an anti-HBs titre of at least 100 IU/L. All recipients were on entecavir. Anti-HBs titre, and HBsAg status was checked at regular intervals. A retrospective analysis of the anti-HBs response to a loading and maintenance dose of HBIG was done. RESULTS Seven adult HBV-related LT recipients on post-transplant prophylaxis with HBIG and nucleoside analogue (entecavir) fulfilled the criteria for the study. The median anti-HBs response to the anhepatic and loading dose of HBIG was high at 555 IU/L. In two, the response was less than 100 IU/L. The median dose of HBIG reduced at end of 1 month to 800 IU, and the median titre was 223 IU/L. For the next 11 months, the median requirement of HBIG was 3,000 and 4,000 IU, and the titre was low at 53.8 and 60.9 IU/L at end of 6 and 12 months, respectively. CONCLUSIONS The anti-HBs response to HBIG was variable, and titres even below 100 IU/L did not result in HBV recurrence when HBIG was given in combination with entecavir.
Collapse
Affiliation(s)
- Joy Varghese
- Department of Hepatology and Liver Transplantation, Global Hospitals and Health City, Perumbakkam, Chennai, 600 100, India,
| | | | | | | | | | | |
Collapse
|
|
48
|
Yi NJ, Lee KW, Kong SY, Park KU, Lee KB, Hong G, Han SS, Park SJ, Suh KS. Outcome of various treatments for posttransplant hepatitis B virus recurrence. World J Surg 2013; 37:812-9. [PMID: 23344522 DOI: 10.1007/s00268-013-1914-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Currently, no treatment guidelines are available for posttransplant hepatitis B virus (HBV) recurrence. We retrospectively evaluated the rate of clearance of hepatitis B surface antigen (HBsAg) from serum according to various treatment regimens in two large Korean liver transplantation centers. METHODS Between 1996 and 2008, HBV recurred in 59 patients among 933 HBV liver recipients (6.3 %). Patients with HBV recurrence were divided into four groups according to their treatment: group L (lamivudine-based therapy n = 21) and group N [new nucleos(t)ide analogue (NA)-based therapy, n = 38]. Intravenous hepatitis B immunoglobulin (ivHBIG) had been simultaneously administered to 10 patients in group L and 26 patients in group N. The mean posttransplant follow-up duration and time to HBV recurrence were 69 (14-152) months and 37 (3-120) months. RESULTS Overall, 22 patients (37.3 %) showed seronegative conversion of HBsAg for a median 8 months after treatment (range 1-15 months). The seroclearance rate was significantly higher in group N (n = 20, 52.6 %) than in group L (n = 2, 9.5 %) (p < 0.000). The time to seroconversion did not differ between group L (7 months, range 5-16) and group N (7 months, range 1-15) (p = 0.428). Subgroup analysis showed that the HBsAg seroconversion rate was much higher for patients given combined ivHBIG and new NAs (15/26 patients, 58.0 %) than the others (p = 0.006). CONCLUSIONS Seroclearance of HBsAg could be achieved using new NAs in half of the patients after posttransplant HBV recurrence. Combined ivHBIG may add a synergistic effect to new NAs for clearing HBsAg.
Collapse
Affiliation(s)
- Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Chongro-gu, Seoul, 110-744, South Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
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.
Collapse
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)
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Berdichevski T, Kumar S, Katz LH. Hepatitis B immune globulin for preventing hepatitis B recurrence after liver transplantation. Hippokratia 2012. [DOI: 10.1002/14651858.cd010174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
| | - Sushil Kumar
- University of Minnesota; Division of Basic and Translational Research, Department of Surgery; 420 Delaware Street SE Mayo Mail Code 195 Minneapolis USA 55455
| | - Lior H Katz
- MD Anderdson Cancer Center; Gastroenterology, Hepatology and Nutrition Department; 1515 Holcombe st. Houston Texas USA 77030
| |
Collapse
|