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Wang JW, Zhu HX, Zhang F, Wang H, Fan YC, Han LY, Wang K. Reduced murine double minute-2 methylation from peripheral blood mononuclear cells correlates with enhanced oxidative stress in hepatitis b virus-related hepatocellular carcinoma. Front Microbiol 2025; 16:1590492. [PMID: 40432974 PMCID: PMC12106469 DOI: 10.3389/fmicb.2025.1590492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Background Hepatitis B virus-related hepatocarcinogenesis (HBV-related HCC) involves a variety of causes including oncogene hypomethylation, oxidative stress and HBV itself. Oxidative stress induces an alternation in the DNA methylation status. We aimed to study the relationship between oxidative stress and murine double minute-2 (MDM2) methylation status in HBV-related HCC patients and healthy controls (HCs). Methods A total of 135 patients with HBV-related HCC and 26 healthy controls (HCs) were recruited. The MDM2 methylation status was detected by methylation-specific PCR. The expression of MDM2 mRNA was assessed using quantitative real-time PCR. The plasma malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), nuclear factor erythroid 2-related factor 2 (NRF2), heme Oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) were measured by enzyme-linked immunosorbent assay (ELISA). Thirty-six patients with HBV-related HCC and 11 HCs were selected and the serum metabolism was analyzed by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Results Compared with HCs, the MDM2 promoter methylation frequency was significantly decreased in HBV-related HCC. The MDA levels were increased, whereas the GSH, SOD, NRF2, HO-1, and GPX4 levels were decreased in the HBV-related HCC patients relative to HCs. There were 216 differential metabolites between HBV-related HCC and HCs in plasma, which belongs to amino acids, bile acids, fatty acids, phospholipids, and other compounds. The cysteine and methionine metabolism were the most significant metabolic pathways associated with differential metabolites between MDM2 methylated group and MDM2 unmethylated group in HBV-related HCC. Conclusion Our results suggested that oxidative stress may cause MDM2 hypomethylation, in which cysteine and methionine pathway might play an important role in.
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Affiliation(s)
- Jing-Wen Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Han-Xu Zhu
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Feng Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - He Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
| | - Li-Yan Han
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Institute of Hepatology, Shandong University, Jinan, China
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Wang Y, Guan X, Lv F, Rong Y, Meng X, Tong Y, Ma X, Zheng H, Chen C, Xie S, Zhang H, Dong F, Guo L, Lu R. HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis. Tumour Virus Res 2024; 18:200290. [PMID: 39032828 PMCID: PMC11331954 DOI: 10.1016/j.tvr.2024.200290] [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: 01/11/2024] [Revised: 07/04/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and hepatitis B X (HBx) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of HBx integration in DLBCL. The data showed that clinical DLBCL cells demonstrated HBx integration, and the sequencing analysis of integrated sites validated HBx integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the HBx-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the HBx-negative samples. Therefore, HBx integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.
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Affiliation(s)
- Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaolin Guan
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fangfang Lv
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yi Rong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xin Meng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ying Tong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaolu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Cuncun Chen
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Heng Zhang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Feng Dong
- Department of Outpatient Office, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Choi WM, Choi J, Lim YS. Hepatitis B: epidemiology, natural history, and diagnosis. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:183-203. [DOI: 10.1016/b978-0-323-98368-6.00007-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Bilajac E, Mahmutović L, Lundstrom K, Glamočlija U, Šutković J, Sezer A, Hromić-Jahjefendić A. Viral Agents as Potential Drivers of Diffuse Large B-Cell Lymphoma Tumorigenesis. Viruses 2022; 14:2105. [PMID: 36298660 PMCID: PMC9610751 DOI: 10.3390/v14102105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/19/2022] [Indexed: 04/22/2025] Open
Abstract
Among numerous causative agents recognized as oncogenic drivers, 13% of total cancer cases occur as a result of viral infections. The intricacy and diversity of carcinogenic processes, however, raise significant concerns about the mechanistic function of viruses in cancer. All tumor-associated viruses have been shown to encode viral oncogenes with a potential for cell transformation and the development of malignancies, including diffuse large B-cell lymphoma (DLBCL). Given the difficulties in identifying single mechanistic explanations, it is necessary to combine ideas from systems biology and viral evolution to comprehend the processes driving viral cancer. The potential for more efficient and acceptable therapies lies in targeted medicines that aim at viral proteins or trigger immune responses to either avoid infection or eliminate infected or cancerous cells. In this review, we aim to describe the role of viral infections and their mechanistic approaches in DLBCL tumorigenesis. To the best of our knowledge, this is the first review summarizing the oncogenic potential of numerous viral agents in DLBCL development.
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Affiliation(s)
- Esma Bilajac
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Lejla Mahmutović
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | | | - Una Glamočlija
- Department of Pharmaceutical Biochemistry and Laboratory Diagnostics, University of Sarajevo, Faculty of Pharmacy, Zmaja od Bosne 8, 71 000 Sarajevo, Bosnia and Herzegovina
- School of Medicine, University of Mostar, Zrinskog Frankopana 34, 88 000 Mostar, Bosnia and Herzegovina
- Scientific-Research Unit, Bosnalijek JSC, Jukićeva 53, 71 000 Sarajevo, Bosnia and Herzegovina
| | - Jasmin Šutković
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Abas Sezer
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
| | - Altijana Hromić-Jahjefendić
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnička cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
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Detectability of Hepatitis B Virus in Peripheral Blood Mononuclear Cells Among Naive Chronic Hepatitis B Patients With Negative Viremia. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2022. [DOI: 10.1097/ipc.0000000000001153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Molecular characteristics of the full-length genome of occult hepatitis B virus from blood donors in China. Sci Rep 2022; 12:8194. [PMID: 35581341 PMCID: PMC9114411 DOI: 10.1038/s41598-022-12288-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/06/2022] [Indexed: 11/22/2022] Open
Abstract
The characteristics of a large sample size of the full-length genome of occult hepatitis B virus (HBV) infection (OBI) have not been extensively explored in China. Voluntary blood donors who were HBsAg-negative/HBV NAT-positive (HBsAg−/HBV NAT+) were identified by blood screening and recruited. Blood samples were tested for HBV serologic markers, viral loads, and PCR to identify OBI. HBV full-length genomes were obtained by amplifying two fragments using nested PCR. The characterization of OBI strains was based on sequence analyses compared with HBsAg+ strains obtained from the same donor population. Of the 50 full-length genomes of 172 identified OBI strains, 33 were classified as genotype B (OBIB) and 17 strains as genotype C (OBIC). Significantly higher nucleotide variabilities were observed in the Pre-S2/S promoter region (SP2) and core upstream regulatory sequence (CURS) in OBIB than in their HBsAg+ controls (P < 0.05). Both OBIB and OBIC showed higher amino acid (aa) variabilities in Pol and Pre-S/S regions than their controls (P < 0.05). In addition, 19 novel OBI-related mutations were found spanning the four open reading frames (ORFs) of the HBV genome. Four novel deletions and one novel insertion were also found in OBIC strains. Several novel OBI-related mutations spanning the four ORFs of the virus were identified by characterizing a large sample size of the full-length OBI genome, which may affect the production of HBsAg and contribute to the occult infection of HBV.
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7
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Hu S, Chen N, Lu K, Zhen C, Sui X, Fang X, Li Y, Luo Y, Zhou X, Wang X. The prognostic roles of hepatitis B virus antibody in diffuse large B-cell lymphoma patients. Leuk Lymphoma 2021; 62:1335-1343. [PMID: 33399486 DOI: 10.1080/10428194.2020.1867726] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) has been correlated with virus infection and immunity status. We retrospectively analyzed the association between HBV antibody and DLBCL development in HBsAg- patients. Compared with HBeAb- patients, HBeAb+ patients displayed unique clinical features. HBV antibody-negative patients had better therapeutic efficiency (p < .05). The media progression-free survival (PFS) and overall survival (OS) of HBV antibody-positive group were shorter than the negative group (p < .05). Furthermore, we found positive association between CD21 and HBsAb and their synergistic effect for prognostic predication. Interestingly, the effect of Rituximab in prognostic improvement was more significant in HBV antibody-positive group than negative group. Univariate analysis showed that HBV antibody was independent risk factor for disease prognosis. Altogether, our investigations identified for the first time the close association between HBV antibody and clinical prognosis in DLBCL patients. These findings provide potential biomarker to predict the effect of Rituximab and prognosis in DLBCL patients.
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Affiliation(s)
- Shunfeng Hu
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Na Chen
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Kang Lu
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Changqing Zhen
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaohui Sui
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaosheng Fang
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Hematology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, China.,School of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, China.,Branch of National Clinical Research Center for Hematologic Diseases, Jinan, China.,National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ying Li
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yingshu Luo
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiangxiang Zhou
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Hematology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, China.,School of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, China.,Branch of National Clinical Research Center for Hematologic Diseases, Jinan, China.,National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Hematology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, China.,School of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, China.,Branch of National Clinical Research Center for Hematologic Diseases, Jinan, China.,National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China
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8
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Lee HL, Bae SH, Lee J, Sung PS, Lee SW, Jang JW, Lee J, Choi JY, Han NI, Yoon SK. Effects of Positive Hepatitis B Core Antibody and Metabolic Disorders in Hepatocellular Carcinoma in an Endemic Area of Hepatitis B Virus. Cancer Control 2021; 28:10732748211039758. [PMID: 34569320 PMCID: PMC8481710 DOI: 10.1177/10732748211039758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND AND AIMS This retrospective study aimed to investigate the impact of positive hepatitis B core antibody (anti-HBc) and metabolic disorders on clinical characteristics of hepatocellular carcinoma (HCC) patients in an HBV-endemic area. METHODS A total of 1950 consecutive patients newly diagnosed with HCC between 2002 and 2015 were included. Patient records were reviewed. We compared non-viral and non-alcoholic HCC patients with other etiological groups for HCC. In addition, we compared HCC patients with negative hepatitis B surface antigen (HBsAg) and positive anti-HBc to those with negative HBsAg and negative anti-HBc, and to those with HBV. RESULTS The prevalence of non-viral and non-alcoholic HCC increased from 7% in 2002-2011 to 12% in 2012-2015. The proportion of non-viral and non-alcoholic HCC gradually increased with age. Patients with non-viral and non-alcoholic HCC exhibited higher rates of metabolic disorders and preserved liver function. The rate of anti-HBc positivity was similarly high in all HCC etiological groups. The clinical features of HCC patients with negative HBsAg and positive anti-HBc were similar to those with negative HBsAg and negative anti-HBc, but significantly different from those with HBV HCC. Regarding tumor characteristics, patients in the non-viral and non-alcoholic HCC group had more advanced stages of tumors (mUICC stage III-V and BCLC stage C/D). There was no significant difference in overall survival among the patient groups. The presence of anti-HBc did not affect patient survival. CONCLUSION Patients with non-viral and non-alcoholic HCC had a relatively high prevalence of metabolic disorders and preserved liver function. However, they had advanced tumor stage compared to patients from other etiological groups. Anti-HBc positivity did not affect the clinical characteristics or prognosis of non-HBV HCC patients in this study.
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Affiliation(s)
- Hae Lim Lee
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jaejun Lee
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Won Lee
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jungmin Lee
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Nam Ik Han
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Michalak TI. Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B. Front Immunol 2020; 11:853. [PMID: 32536912 PMCID: PMC7267019 DOI: 10.3389/fimmu.2020.00853] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.
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Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
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10
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Sinha M, Sundar K, Premalata CS, Asati V, Murali A, Bajpai AK, Davuluri S, Acharya KK, Lakshmaiah KC, Babu K G, Jacob LA, Nandan D, Velayutham D, Datta S, Jayshree RS. Pro-oncogenic, intra host viral quasispecies in Diffuse large B cell lymphoma patients with occult Hepatitis B Virus infection. Sci Rep 2019; 9:14516. [PMID: 31601912 PMCID: PMC6787061 DOI: 10.1038/s41598-019-51157-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 09/26/2019] [Indexed: 02/08/2023] Open
Abstract
Non Hodgkin lymphoma, predominantly Diffuse Large B-cell Lymphoma (DLBCL) has been reported to have a significant association with Hepatitis B virus (HBV). We investigated the presence of different gene segments of HBV in plasma, B-cells and tumor tissues from DLBCL patients and explored the genetic variability of HBV within and across different compartments in a host using Next Generation Sequencing. Despite all 40 patients being HBV seronegative, 68% showed evidence of occult HBV. Sequencing of these gene segments revealed inter-compartment viral variants in 26% of them, each with at least one non-synonymous mutation. Between compartments, core gene variants revealed Arg94Leu, Glu86Arg and Ser41Thr while X gene variants revealed Phe73Val, Ala44Val, Ser146Ala and Ser147Pro. In tumor compartments per se, several mis-sense mutations were detected, notably the classic T1762A/A1764G mutation in the basal core promoter. In addition, a virus surface antigen mis-sense mutation resulting in M125T was detected in all the samples and could account for surface antigen negativity and occult HBV status. It would be interesting to further explore if a temporal accumulation of viral variants within a favored niche, like patients’ lymphocytes, could bestow survival advantage to the virus, and if certain pro-oncogenic HBV variants could drive lymphomagenesis in DLBCL.
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Affiliation(s)
- Mahua Sinha
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India.
| | - Keerthana Sundar
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India
| | - C S Premalata
- Department of Pathology, Kidwai Cancer Institute, Bengaluru, India
| | - Vikas Asati
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Alka Murali
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India.,Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India
| | | | | | - Kshitish K Acharya
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India.,Shodhaka Life Sciences Pvt. Ltd., Bengaluru, India
| | - K C Lakshmaiah
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Govind Babu K
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Linu A Jacob
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | | | | | - Sibnarayan Datta
- Molecular Virology Laboratory, Defence Research Laboratory, Tezpur, Assam, India
| | - R S Jayshree
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India
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11
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Muche M, Berg T, Rimpler S, Staedtler A, Böhm S, Nickel P, Baid-Agrawal S. Low prevalence of occult hepatitis B virus infection in chronic haemodialysis and kidney transplant patients. Liver Int 2019; 39:263-270. [PMID: 30171739 DOI: 10.1111/liv.13951] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 08/09/2018] [Accepted: 08/12/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Occult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in serum and/or liver in HBsAg-negative patients. We investigated the prevalence of OBI in large chronic haemodialysis (CHD) and kidney transplant recipients (KTxR) cohorts, including determination of HBV DNA in peripheral blood mononuclear cells (PBMCs). METHODS HBV DNA was determined in both serum and PBMCs in 417 CHD patients, 417 KTxR, 20 HBsAg-positive non-CHD non-KTx patients (positive controls) and 40 HBsAg-negative healthy subjects (negative controls). RESULTS Chronic haemodialysis group: two of 376 patients were HBsAg-positive. The 374 HBsAg-negative patients tested negative for HBV DNA in both serum and PBMCs. KTxR group: 14 of 417 patients were HBsAg-positive. One of 403 HBsAg-negative patients tested positive for HBV DNA in serum but not in PBMCs. Positive controls: six of 20 patients were under antiviral therapy and had negative HBV DNA in both serum and PBMCs. In 11 of 14 remaining patients, HBV DNA was detected in serum and in both serum and PBMCs in 3 patients. Negative controls: All 34 patients were anti-HBc-negative and HBV DNA-negative in both serum and PBMCs. In the long term, the only case of anti-HBc-negative OBI lost anti-HBs 5 years after inclusion in the study and showed HBV reactivation with HBsAg re-seroconversion. CONCLUSIONS We found nil prevalence of OBI in CHD patients and a very low prevalence (<1%) in KTxR suggesting that routine screening for HBV DNA is not required in CHD population in our region. However, in KTxR, pretransplant screening with HBV DNA should be considered. Testing for HBV DNA in PBMCs does not seem to be of additional value.
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Affiliation(s)
- Marion Muche
- Department of Gastroenterology and Hepatology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Thomas Berg
- Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Sunda Rimpler
- Department of Nephrology and Medical Intensive Care, Charite Universitaetsmedizin Berlin, Berlin, Germany
| | - Adrienne Staedtler
- Department of Nephrology and Medical Intensive Care, Charite Universitaetsmedizin Berlin, Berlin, Germany
| | - Stefan Böhm
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Peter Nickel
- Department of Nephrology and Medical Intensive Care, Charite Universitaetsmedizin Berlin, Berlin, Germany
| | - Seema Baid-Agrawal
- Department of Nephrology and Medical Intensive Care, Charite Universitaetsmedizin Berlin, Berlin, Germany.,Department of Nephrology and Transplant Center, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
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12
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Samiee S, Kanavi MR, Javadi MA, Bagheri A, Balagholi S, Hashemi MS. Real Time Polymerase Chain Reaction for Hepatitis B Screening in Donor Corneas in the Central Eye Bank of Iran. J Ophthalmic Vis Res 2018; 13:392-396. [PMID: 30479707 PMCID: PMC6210878 DOI: 10.4103/jovr.jovr_157_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 01/31/2018] [Indexed: 01/13/2023] Open
Abstract
PURPOSE The aim of this study was to report the results of the use of real-time polymerase chain reaction (PCR) for the diagnosis of hepatitis B virus (HBV) infection in cornea donors at the Central Eye Bank of Iran. METHODS Between 2014 and 2016, all cornea donors that had negative screening serologic results for hepatitis B (HB) surface antigen, HB surface antibody (Ab), hepatitis C virus Ab, human immune deficiency virus Ab, human T-cell leukemia virus Ab, and syphilis, and positive serology for HB core Ab were subjected to real-time PCR with a detection limit of 400 IU/mL to identify HBV DNA. Positive results for HBV DNA were considered occult HBV infections in these donors. RESULTS Over the 3-year period, 122 out of 10448 cornea donors had negative screening serologic tests outside of HB core Ab. Of which, 90 cases were subjected to real-time PCR. Occult HBV was detected in 11 cases (12.2%), resulting in the rejection of the corresponding corneas. The remaining 79 cases (87.8%) had negative results for HBV DNA and the corresponding corneas were used for transplantation. CONCLUSION Implementation of PCR for the detection of occult HBV in cornea donors is necessary to not only increase the security level of cornea donation but also minimize the rejection rate of donors that have isolated HB core Ab reactivity.
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Affiliation(s)
- Shahram Samiee
- Iranian Blood Transfusion Organization Research Center, Tehran, Iran
| | - Mozhgan Rezaei Kanavi
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Central Eye Bank of Iran, Tehran, Iran
| | - Mohammad Ali Javadi
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abouzar Bagheri
- Department of Clinical Biochemistry and Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sahar Balagholi
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Influential Factors of Hepatitis B Virus cccDNA in Peripheral Blood Mononuclear Cells Among HBsAg-Positive Pregnant Females Neonates. HEPATITIS MONTHLY 2018. [DOI: 10.5812/hepatmon.55064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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14
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Wang Y, Wang H, Pan S, Hu T, Shen J, Zheng H, Xie S, Xie Y, Lu R, Guo L. Capable Infection of Hepatitis B Virus in Diffuse Large B-cell Lymphoma. J Cancer 2018; 9:1575-1581. [PMID: 29760795 PMCID: PMC5950586 DOI: 10.7150/jca.24384] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 02/08/2018] [Indexed: 01/05/2023] Open
Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma (NHL). It is strongly correlated to the host immunity and infection status. Aim: This study tested the hypothesis that hepatitis B virus (HBV) infection is also associated with DLBCL. Methods: Clinical analysis of the correlation between DLBCL and HBV infection, detection of HBV in situ of DLBCL tissue, and biological experiments that determined whether HBV infects B lymphocytes were conducted. Results: Our long-term clinical data showed that the positive rate of serum HBV was significantly increased in DLBCL patients (23.6%) compared to that in the general Chinese population (7.2%, P<0.001), especially in advanced stage lymphoma patients (P=0.003). In addition, HBV could infect B lymphocytes in vitro and the HBV antigen and nucleic acid could be detected intracellularly. Hepatitis B x protein (HBx) was also strongly expressed in tissues from DLBCL patients that were serum HBV surface antigen (HBsAg) positive. These patients responded less well to therapy with an odds ratio (OR) of 3.04. Conclusions: HBV can infect B lymphocytes. It might be related to the development of DLBCL and may also impact the efficacy of treatment.
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Affiliation(s)
- Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huijie Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shaokun Pan
- Department of Pathogen Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tao Hu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jiabin Shen
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Youhua Xie
- Department of Pathogen Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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15
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Impact of HBV replication in peripheral blood mononuclear cell on HBV intrauterine transmission. Front Med 2017; 11:548-553. [PMID: 29170913 DOI: 10.1007/s11684-017-0597-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 10/10/2017] [Indexed: 02/06/2023]
Abstract
This study determined the effect of hepatitis B virus (HBV) replication in peripheral blood mononuclear cell (PBMC) from HBsAg-positive mothers on HBV intrauterine transmission. A total of 150 HBsAg-positive mothers and their neonates were recruited in this study. Within 24 h after birth, HBV serological markers, serum HBV DNA, PBMC HBV relaxed circular DNA (rcDNA), and covalently closed circular DNA (cccDNA) were measured in the HBsAg-positive mothers and their neonates before passive-active immune prophylaxis. The relationship between HBV replication in PBMC and HBV intrauterine transmission was examined through Chisquare test and logistic regression. The rate of HBV intrauterine transmission was 8.00% (12/150) in the 150 neonates born to HBsAg-positive mothers. The positivities of PBMC HBV rcDNA and cccDNA in the HBsAg-positive mothers were 36.67% (55/150) and 10% (15/150), respectively. Maternal PBMC HBV cccDNA was a risk factor of HBV intrauterine transmission (OR = 6.003, 95% CI: 1.249-28.855). Maternal serum HBeAg was a risk factor of PBMC HBV rcDNA (OR = 3.896, 95% CI: 1.929-7.876) and PBMC HBV cccDNA (OR = 3.74, 95% CI: 1.186-11.793) in the HBsAg-positive mothers. Administration of hepatitis B immune globulin was a protective factor of PBMC HBV cccDNA (OR = 0.312, 95%CI: 0.102-0.954) during pregnancy. The positivity of PBMC HBV rcDNA was related to that of cccDNA in the HBsAg-positive mothers (χ 2= 5.087, P = 0.024). This study suggests that PBMC is a reservoir of HBV and an extrahepatic site for virus replication and plays a critical role in HBV intrauterine transmission.
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16
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Gao S, Duan ZP, Chen Y, van der Meer F, Lee SS, Osiowy C, van Marle G, Coffin CS. Compartmental HBV evolution and replication in liver and extrahepatic sites after nucleos/tide analogue therapy in chronic hepatitis B carriers. J Clin Virol 2017; 94:8-14. [PMID: 28709006 DOI: 10.1016/j.jcv.2017.06.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 06/23/2017] [Accepted: 06/30/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) variants are associated with nucleos/tide analogue (NA) response and liver disease but it is unknown whether NA influences extrahepatic HBV persistence. OBJECTIVES To investigate HBV replication and genetic evolution in hepatic and extrahepatic sites of chronic hepatitis B (CHB) before and after NA therapy. STUDY DESIGN A total of 13 paired plasma, peripheral blood mononuclear cells (PBMC), were collected from chronic HBV carriers at baseline and after a median 53 weeks NA therapy as well as liver biopsy (N=7 baseline, N=5 follow-up). HBV covalently closed circular DNA (cccDNA) and messenger (m) RNA in liver and PBMC were analyzed. HBV polymerase (P)/surface (S), basal core promoter (BCP)/pre-core (PC)/C gene clonal sequencing was done in plasma, peripheral blood mononuclear cells (PBMC), and liver. RESULTS Compare to baseline, at ∼53 weeks follow-up, there was no significant change in HBV cccDNA levels in liver (0.2-0.08 copies/hepatocyte, p>0.05) or in PBMC 0.003-0.02 copies/PBMC, p>0.05), and HBV mRNA remained detectable in both sites. At baseline, BCP variants were higher in PBMC vs. liver and plasma. After therapy, drug resistant (DR) and immune escape (IE) variants increased in liver but IE and PC variants were more frequent in PBMC. HBV P/S diversity was significantly higher in PBMC compared to plasma. CONCLUSION Continuous HBV replication occurs in liver and PBMC and shows compartmentalized evolution under selective pressure of potent NA therapy.
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Affiliation(s)
- Shan Gao
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhong-Ping Duan
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yu Chen
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Frank van der Meer
- Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Samuel S Lee
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carla Osiowy
- Bloodborne Pathogens and Hepatitis Laboratory of the National Microbiology Laboratory, Winnipeg, MB, Canada
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Carla S Coffin
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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17
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Yuan BH, Li RH, Yuan WP, Xiang BD, Zheng MH, Yang T, Zhong JH, Li LQ. Perioperative entecavir for patients with HBV-related hepatocellular carcinoma and low levels of viral DNA: analysis using propensity score matching. Oncotarget 2017; 8:51810-51816. [PMID: 28881690 PMCID: PMC5584291 DOI: 10.18632/oncotarget.15395] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 01/27/2017] [Indexed: 01/27/2023] Open
Abstract
The safety and efficacy of perioperative antiviral therapy for patients with hepatitis B virus related hepatocellular carcinoma and low serum levels of hepatitis B virus DNA are unknown. This retrospective study compared serum levels of hepatitis B virus DNA, liver function, morbidity, and length of hospital stay between patients who underwent hepatic resection alone and patients who received entecavir therapy before and after resection (n = 44 in each group). Propensity score matching was used to reduce confounding due to baseline differences between the groups. Hepatitis B virus reactivation during follow-up, which lasted a median of 6.1 months, occurred in one patient in the entecavir group (2.3%) and 11 patients in the resection-only group (25%; P = 0.02). Liver function, especially alanine aminotransferase levels, recovered much faster in the entecavir group. This group also showed a slightly lower rate of morbidity (P = 0.081) as well as significantly shorter overall hospital stay (20.1 ± 4.9 vs 24.9 ± 13.2 days; P = 0.028) and postoperative hospital stay (11.4 ± 1.9 vs 16.8 ± 13.1 days; P = 0.008). These results from this pilot study suggest that patients with hepatitis B virus related hepatocellular carcinoma and low levels of hepatitis B virus DNA are at risk of hepatitis B virus reactivation following resection, and that perioperative entecavir therapy can safely and effectively reduce this risk. Such therapy also appears to improve liver function and shorten hospitalization.
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Affiliation(s)
- Bao-Hong Yuan
- Department of General Surgery, Yan’An Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Ru-Hong Li
- Department of General Surgery, Yan’An Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Wei-Ping Yuan
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Ming-Hua Zheng
- Department of Hepatology, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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18
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Omar HH, Taha SA, Hassan WH, Omar HH. Impact of schistosomiasis on increase incidence of occult hepatitis B in chronic hepatitis C patients in Egypt. J Infect Public Health 2017; 10:761-765. [PMID: 28196636 DOI: 10.1016/j.jiph.2016.11.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 10/27/2016] [Accepted: 11/18/2016] [Indexed: 02/07/2023] Open
Abstract
Co-infection of schistosomiasis, HBV and HCV is common in countries where schistosomiasis is endemic. Occult hepatitis B occurs in patients at high risk for HBV infection (e.g., patients on hemodialysis, patients receiving blood transfusions). Schistosomal infection is a risk factor of HBV infection that can increase the incidence of occult hepatitis B. We aimed to determine the prevalence of occult hepatitis B in chronic hepatitis C patients with and without schistosomiasis and to assess the effect of schistosomal infection on the increased risk of exposure to HBV infection and to occult hepatitis B. Two hundred chronic hepatitis C patients who were negative for HBsAg participated. All patients were tested for the following: Anti-schistosome antibodies, Anti-HBc, serum HBV DNA, CBC and liver function. The prevalence of occult hepatitis B in CHC patients with/without schistosomiasis were 12.8% and 8.5% (P=0.042), respectively. Next, 63.8% of CHC patients with schistosomiasis were exposed to HBV infection (Anti-HBc +ve) during their lifetime. In conclusion, the prevalence of occult hepatitis B is higher in CHC patients with schistosomiasis compared to those without schistosomiasis. Periodic laboratory investigations of Schistosoma mansoni, HBV and HCV are recommended for the early detection of the infection and, especially in endemic areas, to avoid infection complications.
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Affiliation(s)
- Hanan H Omar
- Clinical Pathology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Samaa A Taha
- Microbiology and Immunology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Wafaa H Hassan
- Infectious and Endemic Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Hamdy H Omar
- Internal Medicine Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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19
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Kalantari H, Ferdowsi F, Yaran M. Prevalence of occult hepatitis B virus infection in hemodialysis patients in Isfahan, Iran. Adv Biomed Res 2016; 5:151. [PMID: 27713872 PMCID: PMC5046800 DOI: 10.4103/2277-9175.188487] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 03/09/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The absence of a detectable hepatitis B surface antigen (HBsAg) with or without hepatitis B core antibody (anti-HBc) or hepatitis B surface antibody (anti-HBs) in the presence of hepatitis B virus-DNA (HBV-DNA) is defined as occult HBV infection. This study was aimed to evaluate the prevalence of occult HBV infection in patients receiving hemodialysis (HD) in Isfahan, Iran. MATERIALS AND METHODS This cross sectional study was done on 400 patients without acute or chronic HBV infection with end-stage renal disease undergoing regular HD. Blood samples were collected prior to the HD session, and serological markers of viral hepatitis B included HBsAg, anti-HBs and anti-HBc were measured using standard third generation commercially available enzyme immunoassays kit, then samples of positive anti-HBc and negative anti-HBs were tested for HBV DNA using quantitative real-time polymerase chain reaction techniques. Data were analyzed by SPSS using t-test and Chi-square test. RESULTS The mean age of patients was 51.6 ± 11.2 years. Anti-HBc positive was observed in 32 (8%) of 400 studied patients with negative HBsAg. Of 32 patients with anti-HBc positive, 15 were males and 17 were females with mean age of 49.7 ± 12.6 years. Among 32 patients with anti-HBc positive, 10 patients were negative for anti-HBs. All of 10 patients were negative for HBV DNA. The prevalence of occult HBV infection was 0%. CONCLUSIONS The prevalence of occult HBV infection in HBsAg negative patients undergoing HD was 0% and look to be among the lowest worldwide. So, occult HBV infection is not a significant health problem in HD patients in this region.
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Affiliation(s)
- Hamid Kalantari
- Department of Gastroenterology, Isfahan Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Faezeh Ferdowsi
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Majid Yaran
- Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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20
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Hudu SA, Harmal NS, Saeed MI, Alshrari AS, Malik YA, Niazlin MT, Hassan R, Sekawi Z. Molecular and serological detection of occult hepatitis B virus among healthy hepatitis B surface antigen-negative blood donors in Malaysia. Afr Health Sci 2016; 16:677-683. [PMID: 27917199 DOI: 10.4314/ahs.v16i3.6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Occult hepatitis B infections are becoming a major global threat, but the available data on its prevalence in various parts of the world are often divergent. OBJECTIVE This study aimed to detect occult hepatitis B virus in hepatitis B surface antigen-negative serum using anti-HBc as a marker of previous infection. PATIENT AND METHODS A total of 1000 randomly selected hepatitis B surface antigen-negative sera from blood donors were tested for hepatitis B core antibody and hepatitis B surface antibody using an ELISA and nested polymerase chain reaction was done using primers specific to the surface gene (S-gene). RESULTS Of the 1000 samples 55 (5.5%) were found to be reactive, of which 87.3% (48/55) were positive for hepatitis B surface antibody, indicating immunity as a result of previous infection however, that does not exclude active infection with escaped mutant HBV. Nested PCR results showed the presence of hepatitis B viral DNA in all the 55 samples that were positive for core protein, which is in agreement with the hepatitis B surface antibody result. CONCLUSION This study reveals the 5.5% prevalence of occult hepatitis B among Malaysian blood donors as well as the reliability of using hepatitis B core antibody in screening for occult hepatitis B infection in low endemic, low socioeconomic settings.
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Affiliation(s)
- Shuaibu A Hudu
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia; Medical Microbiology and Parasitology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University Sokoto, 840232 Sokoto State, Nigeria
| | - Nabil S Harmal
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia; Department of Medical Microbiology, Faculty of Medicine and Health Sciences, Sana'a University, Sana'a, Yemen
| | - Mohammed I Saeed
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia
| | - Ahmad S Alshrari
- Department of Basic Health Sciences, Faculty of Pharmacy, Northern Border Universiti, 91911 Rafha, Saudi Arabia
| | - Yasmin A Malik
- Department of Clinical Science, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Malaysia
| | - Mohd T Niazlin
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia
| | - Roshida Hassan
- National Blood Centre Malaysia, Jalan Tun Razak Kuala Lumpur, 504000 Malaysia
| | - Zamberi Sekawi
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia
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21
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Zhu HL, Li X, Li J, Zhang ZH. Genetic variation of occult hepatitis B virus infection. World J Gastroenterol 2016; 22:3531-3546. [PMID: 27053845 PMCID: PMC4814639 DOI: 10.3748/wjg.v22.i13.3531] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/13/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Occult hepatitis B virus infection (OBI), characterized as the persistence of hepatitis B virus (HBV) surface antigen (HBsAg) seronegativity and low viral load in blood or liver, is a special form of HBV infection. OBI may be related mainly to mutations in the HBV genome, although the underlying mechanism of it remains to be clarified. Mutations especially within the immunodominant "α" determinant of S protein are "hot spots" that could contribute to the occurrence of OBI via affecting antigenicity and immunogenicity of HBsAg or replication and secretion of virion. Clinical reports account for a large proportion of previous studies on OBI, while functional analyses, especially those based on full-length HBV genome, are rare.
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22
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Hepatitis B virus replication is upregulated in proliferated peripheral blood lymphocytes. Mol Med Rep 2016; 13:3581-7. [PMID: 26936285 DOI: 10.3892/mmr.2016.4973] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 01/26/2016] [Indexed: 01/19/2023] Open
Abstract
Increasing evidence indicates that the hepatitis B virus (HBV) replicates in peripheral blood mononuclear cells (PBMCs), but at a low level. The present study aimed to establish a reliable and sensitive method that effectively detects HBV viral products for monitoring antiviral therapy, organ transplantation screening, and diagnosing occult HBV infection. In the present study, PBMCs (obtained from six healthy volunteers) were inoculated with HBV, and cultured with phytohemagglutinin (PHA) and interleukin‑2 (IL‑2) to stimulate cell proliferation. PBMCs were harvested, and quantitative detection of HBV DNA in cell suspension and intracellular hepatitis B surface antigen (HBsAg) was conducted on days 0, 1, 6 and 12, respectively. In situ hybridization, immunohistochemistry and reverse transcription‑polymerase chain reaction (RT‑PCR) were performed to analyze the HBV infection. The results demonstrated that HBV DNA increased concurrently with proliferation of PBMCs isolated from three of six healthy volunteers, and the mean number of PBMCs on day 12 was 13.61 times higher than the initially seeded cell number (P<0.01). The mean copies of HBV DNA at day 12 were 2.98 times higher compared with initial levels (P<0.05). Furthermore, intracellular HBsAg levels increased concurrently with proliferation of PBMCs in one group of cultured PBMCs, which was accompanied by increased HBV DNA levels. In addition, HBV nucleic acids were detected in PBMCs using in situ hybridization. Intracellular HBsAg was observed in PBMCs and HBV RNA was also detected by RT‑PCR. The present study demonstrated that HBV replicates in proliferating PBMCs, which were induced by PHA and IL‑2. This method offers a novel investigative tool to detect HBV infection in PBMCs and to monitor the course of HBV infection.
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23
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Karimi G, Zadsar M, Vafaei N, Sharifi Z, FalahTafti M. Prevalence of antibody to Hepatitis B core antigen and Hepatitis B virus DNA in HBsAg negative healthy blood donors. Virol J 2016; 13:36. [PMID: 26944046 PMCID: PMC4779215 DOI: 10.1186/s12985-016-0492-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 02/22/2016] [Indexed: 01/05/2023] Open
Abstract
Background Hepatitis B virus is one of the most important blood born viruses. Although the sensitivity of screening tests has been considerably increased, transmission may still occur due to window period or occult hepatitis B infections (OBIs). This study was aimed at evaluating the prevalence of the anti-HBc and identifying the HBV DNA in HBsAg negative blood donors. Methods The Blood samples from 2031 HBsAg-negative blood donors were divided into three aliquots and tested for anti-HBc, anti-HBs and HBV DNA. Serologic screening including anti-HBc and anti-HBs was performed. As a confirmatory test, all positive results for anti-HBc were retested with another kit. Two positive results were considered for anti-HBc positivity. All HBsAg negative selected donations were tested by PCR assay on pooled specimens (five samples per pool), plasma samples found to be HBsAg negative but anti-HBc positive were selected for a single-unit specimen Real-Time assay. Results The study population had a mean age of 33.25 ± 10.09 years were mainly composed of males (94.8 %). The seroprevalance rate was 4.9 % for Anti-HBc and 31.9 % for HBsAb. The majority (58.6 %) of Anti-HBc positive cases were regular blood donors with 42–49 years being the largest age group (41.4 %). Neither individual NAT nor pooled NAT test detected any HBV DNA. Conclusion However, Screening of anti-HBc Ab is proposed as a method to identify previous contact with HBV, but there is controversy in literature data regarding the cost-benefit of exclusion of positive anti-HBc Ab in blood donors. Our data does not suggest HBc-Ab test as a screening tool in the study setting.
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Affiliation(s)
- Gharib Karimi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Hemmat Exp. Way, Next to the Milad Tower, Tehran, Iran.
| | - Maryam Zadsar
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Hemmat Exp. Way, Next to the Milad Tower, Tehran, Iran.
| | - Nasrin Vafaei
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Hemmat Exp. Way, Next to the Milad Tower, Tehran, Iran.
| | - Zohreh Sharifi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Hemmat Exp. Way, Next to the Milad Tower, Tehran, Iran.
| | - Mohammad FalahTafti
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Hemmat Exp. Way, Next to the Milad Tower, Tehran, Iran.
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Minosse C, Coen S, Visco Comandini U, Lionetti R, Montalbano M, Cerilli S, Vincenti D, Baiocchini A, Capobianchi MR, Menzo S. Simple and Reliable Method to Quantify the Hepatitis B Viral Load and Replicative Capacity in Liver Tissue and Blood Leukocytes. HEPATITIS MONTHLY 2016; 16:e28751. [PMID: 27882060 PMCID: PMC5111393 DOI: 10.5812/hepatmon.28751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 07/17/2015] [Accepted: 08/12/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND A functional cure of chronic hepatitis B (CHB) is feasible, but a clear view of the intrahepatic viral dynamics in each patient is needed. Intrahepatic covalently closed circular DNA (cccDNA) is the stable form of the viral genome in infected cells, and represents the ideal marker of parenchymal colonization. Its relationships with easily accessible peripheral parameters need to be elucidated in order to avoid invasive procedures in patients. OBJECTIVES The goal of this study was to design, set up, and validate a reliable and straightforward method for the quantification of the cccDNA and total DNA of the hepatitis B virus (HBV) in a variety of clinical samples. PATIENTS AND METHODS Clinical samples from a cohort of CHB patients, including liver biopsies in some, were collected for the analysis of intracellular HBV molecular markers using novel molecular assays. RESULTS A plasmid construct, including sequences from the HBV genome and from the human gene hTERT, was generated as an isomolar multi-standard for HBV quantitation and normalization to the cellular contents. The specificity of the real-time assay for the cccDNA was assessed using Dane particles isolated on a density gradient. A comparison of liver tissue from 6 untreated and 6 treated patients showed that the treatment deeply reduced the replicative capacity (total DNA/cccDNA), but had limited impact on the parenchymal colonization. The peripheral blood mononuclear cells (PBMCs) and granulocytes from the treated and untreated patients were also analyzed. CONCLUSIONS A straightforward method for the quantification of intracellular HBV molecular parameters in clinical samples was developed and validated. The widespread use of such versatile assays could better define the prognosis of CHB, and allow a more rational approach to time-limited tailored treatment strategies.
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Affiliation(s)
- Claudia Minosse
- Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Sabrina Coen
- Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | | | - Raffaella Lionetti
- Liver Unit, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Marzia Montalbano
- Liver Unit, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Stefano Cerilli
- Liver Unit, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Donatella Vincenti
- Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Andrea Baiocchini
- Laboratory of Pathology, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Maria R. Capobianchi
- Laboratory of Virology, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy
| | - Stefano Menzo
- Laboratory of Virology, Marche Polytechnic University, Ancona, Italy
- Corresponding Author: Stefano Menzo, Laboratory of Virology, Marche Polytechnic University, Ancona, Italy. Tel: +39-715964044, E-mail:
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Mortensen E, Kamali A, Schirmer PL, Lucero-Obusan C, Winston CA, Oda G, Winters MA, Durfee J, Martinello RA, Davey VJ, Holodniy M. Are current screening protocols for chronic hepatitis B virus infection adequate? Diagn Microbiol Infect Dis 2015; 85:159-67. [PMID: 27009896 DOI: 10.1016/j.diagmicrobio.2015.12.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 11/30/2015] [Accepted: 12/14/2015] [Indexed: 12/15/2022]
Abstract
Chronic hepatitis B virus (HBV) infection screening usually includes only HBV surface antigen (HBsAg) testing; HBV core and surface antibody (anti-HBc, anti-HBs) assays, indicating resolved infection and immunity, are not routinely performed. Yet, serum HBV DNA is measurable in approximately 10% of HBsAg-negative/anti-HBc-positive cases, representing occult HBV infection (OBI). Patient blood samples from 2 Veterans Affairs medical center look-back investigations were screened for HBV infection using HBsAg enzyme immunoassays. Supplementary testing included anti-HBc and anti-HBs enzyme immunoassays. For anti-HBc-positive samples, HBV DNA testing was performed. Background OBI prevalence was further estimated at these 2 facilities based on HBV serology testing results from 1999-2012. Finally, a literature review was performed to determine OBI prevalence in the published literature. Of 1887 HBsAg-negative cohort patients, 98 (5.2%) were anti-HBc positive/anti-HBs negative; and 175 (9.3%), anti-HBc positive/anti-HBs positive. Six of 273 were HBV DNA positive, representing 0.3% of the total tested and 2.2% who were anti-HBc positive/anti-HBs negative or anti-HBc positive/anti-HBs positive. Among 32,229 general population veterans at these 2 sites who had any HBV testing, 4/108 (3.7%) were HBV DNA positive, none of whom were part of the cohort. In 129 publications with HBsAg-negative patients, 1817/1,209,426 (0.15%) had OBI. However, excluding blood bank studies with greater than 1000 patients, the OBI rate increased to 1800/17,893 (10%). OBI is not rare and has implications for transmission and disease detection. HBsAg testing alone is insufficient for detecting all chronic HBV infections. These findings may impact blood donation, patient HBV screening, follow-up protocols for patients assumed to have cleared the infection, and initiation of immunosuppression in patients with distant or undetected HBV.
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Affiliation(s)
- Eva Mortensen
- VA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University, Stanford, CA, USA
| | - Amanda Kamali
- VA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University, Stanford, CA, USA
| | - Patricia L Schirmer
- Office of Public Health, Department of Veterans Affairs, Washington, DC, USA
| | | | | | - Gina Oda
- Office of Public Health, Department of Veterans Affairs, Washington, DC, USA
| | - Mark A Winters
- VA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University, Stanford, CA, USA
| | - Janet Durfee
- Office of Public Health, Department of Veterans Affairs, Washington, DC, USA
| | - Richard A Martinello
- Office of Public Health, Department of Veterans Affairs, Washington, DC, USA; Yale University School of Medicine, New Haven, CT, USA
| | - Victoria J Davey
- Office of Public Health, Department of Veterans Affairs, Washington, DC, USA
| | - Mark Holodniy
- VA Palo Alto Health Care System, Palo Alto, CA, USA; Stanford University, Stanford, CA, USA; Office of Public Health, Department of Veterans Affairs, Washington, DC, USA.
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Jiang L, Hu S, Tian D, Zou X, He M. α-Mannosidase I Protein Expression in Peripheral Blood Mononuclear Cells Is Upregulated During Hepatitis B Virus Infection. Viral Immunol 2015; 29:33-9. [PMID: 26569026 DOI: 10.1089/vim.2015.0079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B virus (HBV) has been reported to be recognized by dendritic cell-specific ICAM-3-grabbing nonintegrin in the presence of the α-mannosidase I inhibitor kifunensine, whereas native HBV is not. The aim of our study was to determine whether changes in α-mannosidase I expression in peripheral blood mononuclear cells (PBMCs) occur in patients with HBV infection. Peripheral blood was collected from 90 HBV-infected patients (grouped into immune tolerance, chronic hepatitis B, or inactive carrier group based on their clinical states) and 30 healthy donors. Expression of the three α-mannosidase I subtypes, MAN1A1, MAN1A2, and MAN1C1, was measured using western blot analyses. Compared with the healthy controls, significant increases in the MAN1A1, MAN1A2, and MAN1C1 expression levels were observed in the three HBV-infected groups, among whom the immune tolerance group showed the largest increase. For the patients in the immune tolerance phase, the expression levels of both MAN1A1 and MAN1A2 were linearly and positively correlated with the hepatitis B e antigen (HBeAg) titer and HBV DNA level, although a positive correlation was only found between MAN1C1 expression and the HBeAg titer. These results indicate that increased α-mannosidase I expression in PBMCs may play an important role in HBV immune escape and that its expression level is closely related to viral replication activity.
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Affiliation(s)
- Libin Jiang
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Song Hu
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Deying Tian
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Xiaojing Zou
- 2 Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
| | - Man He
- 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
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Mori S, Fujiyama S. Hepatitis B virus reactivation associated with antirheumatic therapy: Risk and prophylaxis recommendations. World J Gastroenterol 2015; 21:10274-10289. [PMID: 26420955 PMCID: PMC4579875 DOI: 10.3748/wjg.v21.i36.10274] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 06/20/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Accompanying the increased use of biological and non-biological antirheumatic drugs, a greater number of cases of hepatitis B virus (HBV) reactivation have been reported in inactive hepatitis B surface antigen (HBsAg) carriers and also in HBsAg-negative patients who have resolved HBV infection. The prevalence of resolved infection varies in rheumatic disease patients, ranging from 7.3% to 66%. Through an electronic search of the PubMed database, we found that among 712 patients with resolved infection in 17 observational cohort studies, 12 experienced HBV reactivation (1.7%) during biological antirheumatic therapy. Reactivation rates were 2.4% for etanercept therapy, 0.6% for adalimumab, 0% for infliximab, 8.6% for tocilizumab, and 3.3% for rituximab. Regarding non-biological antirheumatic drugs, HBV reactivation was observed in 10 out of 327 patients with resolved infection from five cohort studies (3.2%). Most of these patients received steroids concomitantly. Outcomes were favorable in rheumatic disease patients. A number of recommendations have been established, but most of the supporting evidence was derived from the oncology and transplantation fields. Compared with patients in these fields, rheumatic disease patients continue treatment with multiple immunosuppressants for longer periods. Optimal frequency and duration of HBV-DNA monitoring and reliable markers for discontinuation of nucleoside analogues should be clarified for rheumatic disease patients with resolved HBV infection.
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Detection of Hepatitis B Virus (HBV) Genomes and HBV Drug Resistant Variants by Deep Sequencing Analysis of HBV Genomes in Immune Cell Subsets of HBV Mono-Infected and/or Human Immunodeficiency Virus Type-1 (HIV-1) and HBV Co-Infected Individuals. PLoS One 2015; 10:e0137568. [PMID: 26390290 PMCID: PMC4577215 DOI: 10.1371/journal.pone.0137568] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 08/18/2015] [Indexed: 12/14/2022] Open
Abstract
The hepatitis B virus (HBV) and the human immunodeficiency virus type 1 (HIV-1) can infect cells of the lymphatic system. It is unknown whether HIV-1 co-infection impacts infection of peripheral blood mononuclear cell (PBMC) subsets by the HBV. Aims To compare the detection of HBV genomes and HBV sequences in unsorted PBMCs and subsets (i.e., CD4+ T, CD8+ T, CD14+ monocytes, CD19+ B, CD56+ NK cells) in HBV mono-infected vs. HBV/HIV-1 co-infected individuals. Methods Total PBMC and subsets isolated from 14 HBV mono-infected (4/14 before and after anti-HBV therapy) and 6 HBV/HIV-1 co-infected individuals (5/6 consistently on dual active anti-HBV/HIV therapy) were tested for HBV genomes, including replication indicative HBV covalently closed circular (ccc)-DNA, by nested PCR/nucleic hybridization and/or quantitative PCR. In CD4+, and/or CD56+ subsets from two HBV monoinfected cases, the HBV polymerase/overlapping surface region was analyzed by next generation sequencing. Results All analyzed whole PBMC from HBV monoinfected and HBV/HIV coinfected individuals were HBV genome positive. Similarly, HBV DNA was detected in all target PBMC subsets regardless of antiviral therapy, but was absent from the CD4+ T cell subset from all HBV/HIV-1 positive cases (P<0.04). In the CD4+ and CD56+ subset of 2 HBV monoinfected cases on tenofovir therapy, mutations at residues associated with drug resistance and/or immune escape (i.e., G145R) were detected in a minor percentage of the population. Summary HBV genomes and drug resistant variants were detectable in PBMC subsets from HBV mono-infected individuals. The HBV replicates in PBMC subsets of HBV/HIV-1 patients except the CD4+ T cell subpopulation.
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Stratta P, Bruschetta E, Minisini R, Barbè MC, Cornella C, Tognarelli G, Cena T, Magnani C, Fenoglio R, Toffolo K, Airoldi A, Pirisi M. Prevalence and clinical relevance of occult hepatitis B virus infection in patients on the waiting list for kidney transplantation. Transplant Proc 2015; 41:1132-7. [PMID: 19460498 DOI: 10.1016/j.transproceed.2009.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Occult hepatitis B virus (HBV) infection can be defined as the long-lasting persistence of viral genomes in the liver tissue, and sometimes also in the serum at low levels of viremia in individuals with undetectable HBV surface antigen (HBsAg). Viral replication can be reactivated by immunosuppressive therapies or immunologic diseases, leading to the development of typical hepatitis B. METHODS All patients on the waiting list for renal transplantation at the only 2 transplant centers in our region (Piemonte, Italy) were checked for the presence of occult HBV infection by an highly sensitive quantitative HBV-DNA polymerase chain reaction (PCR) assay (nested PCR); the only exclusion criterion was HBsAg-positivity. The enrollment lasted from October 1, 2006, to May 31, 2007. The prospective follow-up will continue for 5 years. RESULTS HBV-DNA sequences were detected in blood samples from 10 of 300 cases examined (3.3%), being more frequent among Asian (1/3; 33.3%) and African (1/16; 6.25%) subjects as compared with the Caucasians (8/281; 2.8%; P = .011), among anti-hepatitis C virus (HCV) positive versus HCV negative patients (3/32 [9.3%] vs 7/268 [2.6%]; P = .004) and mainly among patients with a previous history of overt liver diseases (3/22 [14%] vs 7/278 [2.5%]; P = .019). HBV-DNA sequences became undetectable at 1 month after renal transplantation in 3 patients; the follow-up is in progress for these and the other patients. CONCLUSION Occult HBV infection occurs in patients undergoing renal transplantation. Longer observation and prospective studies will clarify the clinical impact of this occult infection on transplant outcomes and the possibility of viral reactivation related to immunosuppressive therapy.
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Affiliation(s)
- P Stratta
- Department of Clinical and Experimental Medicine, Amedeo Avogadro University, Novara, Italy.
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Abstract
Hepatitis outbreaks in hemodialysis (HD) patients and staff were reported in the late 1960s, and a number of hepatotropic viruses transmitted by blood and other body fluids have been identified. Hepatitis B virus (HBV) was the first significant hepatotropic virus to be identified in HD centers. HBV infection has been effectively controlled by active vaccination, screening of blood donors, the use of erythropoietin and segregation of HBV carriers. Hepatitis delta virus is a defective virus that can only infect HBV-positive individuals. Hepatitis C virus (HCV) is the most significant cause of non-A, non-B hepatitis and is mainly transmitted by blood transfusion. The introduction in 1990 of routine screening of blood donors for HCV contributed significantly to the control of HCV transmission. An effective HCV vaccine remains an unsolved challenge; however, pegylation of interferon-alfa has made it possible to treat HCV-positive dialysis patients. Unexplained sporadic outbreaks of hepatitis by the mid-1990s prompted the discovery of hepatitis G virus, hepatitis GB virus C and the TT virus. The vigilant observation of guidelines on universal precaution and regular virologic testing are the cornerstones of the effective control of chronic hepatitis in the setting of HD. Major recent advances in the viral diagnosis technology and the development of new oral, direct-acting antiviral agents allow early diagnosis and better therapeutic response. The current update will review the recent developments, controversies and new treatment of viral hepatitis in HD patients.
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Affiliation(s)
- Bassam Bernieh
- Consultant and Chief of Nephrology, Tawam Hospital in Affiliation with Johns Hopkins Medicine, Clinical Professor of Medicine, COMHS, UAE University, Al Ain, UAE
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31
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Gao S, Duan ZP, Coffin CS. Clinical relevance of hepatitis B virus variants. World J Hepatol 2015; 7:1086-1096. [PMID: 26052397 PMCID: PMC4450185 DOI: 10.4254/wjh.v7.i8.1086] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/28/2015] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B virus (HBV) is a global public health problem with more than 240 million people chronically infected worldwide, who are at risk for end-stage liver disease and hepatocellular carcinoma. There are an estimated 600000 deaths annually from complications of HBV-related liver disease. Antiviral therapy with nucleos/tide analogs (NA) targeting the HBV polymerase (P) can inhibit disease progression by long-term suppression of HBV replication. However, treatment may fail with first generation NA therapy due to the emergence of drug-resistant mutants, as well as incomplete medication adherence. The HBV replicates via an error-prone reverse transcriptase leading to quasispecies. Due to overlapping open reading frames mutations within the HBV P can cause concomitant changes in the HBV surface gene (S) and vice versa. HBV quasispecies diversity is associated with response to antiviral therapy, disease severity and long-term clinical outcomes. Specific mutants have been associated with antiviral drug resistance, immune escape, liver fibrosis development and tumorgenesis. An understanding of HBV variants and their clinical relevance may be important for monitoring chronic hepatitis B disease progression and treatment response. In this review, we will discuss HBV molecular virology, mechanism of variant development, and their potential clinical impact.
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Wei J, Xue S, Zhang J, Wang S, Wang B. Study of the relationship in pregnant women between hepatitis B markers and a placenta positive for hepatitis B surface antigen. J Perinat Med 2015; 43:191-9. [PMID: 25014515 DOI: 10.1515/jpm-2014-0056] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/13/2014] [Indexed: 12/25/2022]
Abstract
AIMS A placenta with hepatitis B virus (HBV) is one of the main reasons for transplacental transmission during pregnancy. This study aims to explore the factors influencing the presence of hepatitis B surface antigen (HBsAg) in the placenta and the synergistic effect of these factors. METHODS A total of 155 placentae and blood specimens were collected from HBsAg-positive mothers and their newborns. HBsAg in placenta was detected using the immunohistochemistry method. HBV serum markers were detected using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods. RESULTS The results showed that hepatitis B e antigen (HBeAg) positive, or HBV DNA positive status, is significantly associated with an HBsAg-positive placenta. A synergistic effect was present. The hazard ratio for a HBsAg-positive placenta in mothers with HBeAg and HBV DNA was 1.97 times higher than the sum of the independent relative risk of each separate effect (synergy index, S=1.97). There was a statistically significant association between HBsAg in newborns and HBsAg in placenta, and the risk of newborns with HBsAg was greater (odds ratio values 3.33 and 5.31, respectively) when placental cells close to the fetal side were HBsAg positive. CONCLUSIONS Being positive for HBeAg and/or HBV DNA are significant risk factors for HBsAg in the placenta. HBsAg can pass through the placenta via cellular transfer, possibly contributing to transplacental transmission.
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Liu T, Yang S, Yue Z, Kuang Y, Guan W, Sun L. Clinical and pathological characteristics of 5 children with HBV surface antigen (HBsAg)-negative hepatitis B virus-associated glomerulonephritis. J Clin Virol 2015; 66:1-5. [PMID: 25866326 DOI: 10.1016/j.jcv.2015.02.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 02/11/2015] [Accepted: 02/19/2015] [Indexed: 11/28/2022]
Abstract
BACKGROUND Hepatitis B virus-associated glomerulonephritis (HBV-GN) mainly occurs in children. Patients with HBV-GN are frequently positive for serum HBV surface antigen (HBsAg), but they are rarely negative. OBJECTIVE To explore the clinical and pathological characteristics of patients with HBV-GN who are serum HBsAg negative. STUDY DESIGN Five children with HBV-GN who are negative for HBsAg were included in this study. Their clinical and pathological characteristics were collected and analyzed. RESULTS All 5 children presented with different levels of proteinuria and microscopic hematuria. Renal biopsies showed membranous nephropathy accompanied by HBsAg and/or HBcAg deposits in glomeruli in all of the children. Steroids and/or other immunosuppressants were administered in all cases without antiviral therapy during the early stages of treatment. Two children achieved complete remission but relapsed after the drugs were tapered down. The other 3 children were initially non-responsive but achieved remission after lamivudine was added. CONCLUSIONS Treatment of HBsAg-negative HBV-GN patients with immunosuppressants alone could not achieve satisfactory effects. Antiviral treatment is effective and may be necessary in this type of patient.
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Affiliation(s)
- Ting Liu
- Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shicong Yang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhihui Yue
- Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Kuang
- Department of Clinical Laboratory, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiming Guan
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liangzhong Sun
- Children's Kidney Disease Center, Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Zhang X, Liu L, Xu W, Wang Y, Gao S, Chen S, DU Y. Intracellular levels of hepatitis B virus DNA and mutational patterns of the polymerase gene of hepatitis B virus in peripheral blood mononuclear cells of patients with lamivudine or telbivudine resistance. Exp Ther Med 2015; 9:885-890. [PMID: 25667647 PMCID: PMC4316898 DOI: 10.3892/etm.2014.2156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 08/29/2014] [Indexed: 12/26/2022] Open
Abstract
Studies are limited regarding the association between the quantity of hepatitis virus B (HBV) DNA loads in serum and peripheral blood mononuclear cells (PBMCs) in patients with drug resistance and few studies focus on the mutational pattern of the polymerase gene of HBV in PBMCs of patients with drug resistance. The aim of the present study was to investigate the association between the quantity of HBV DNA loads in serum and PBMCs in patients with lamivudine (LAM) or telbivudine (LdT) resistance and to explore the mutational pattern of the polymerase gene of HBV in PBMCs of these patients. A total of 51 patients underwent antiviral therapy with LAM or LdT for at least half a year. The present study applied quantitative polymerase chain reaction for the quantification of total HBV DNA, and direct sequencing was used to detect the mutation. In total, 31 patients (60.78%) were detected to have drug resistance. The mean serum HBV DNA levels were significantly higher than the HBV DNA levels of PBMCs, whether in patients with LAM or LdT resistance. The PBMCs HBV DNA loads were correlated with the serum HBV DNA loads in the two groups. Three and two mutational patterns were found in the serum of patients with LAM and LdT resistant, respectively. In total, 85.71% of patients with LAM resistance and 75.00% of patients with LdT resistance presented the same mutational pattern in paired PBMCs and serum. The HBV DNA levels in the PBMCs of patients with LAM or LdT resistance were significantly lower than those in serum and there were positive correlations between them. The majority of the mutational patterns of the polymerase gene of HBV DNA in PBMCs were the same as those in the paired serum. These findings may help to increase knowledge regarding HBV drug resistance.
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Affiliation(s)
- Xiaoguo Zhang
- Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Shandong 250021, P.R. China
| | - Lu Liu
- Shandong University School of Medicine, Jinan, Shandong 250021, P.R. China
| | - Wansu Xu
- Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Shandong 250021, P.R. China
| | - Yun Wang
- Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Shandong 250021, P.R. China
| | - Shuchun Gao
- Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Shandong 250021, P.R. China
| | - Shijun Chen
- Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Shandong 250021, P.R. China
| | - Yizhen DU
- Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Shandong 250021, P.R. China
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Pal A, Sarkar N, Saha D, Guha SK, Saha B, Chakrabarti S, Chakravarty R. High incidence of lamivudine-resistance-associated vaccine-escape HBV mutants among HIV-coinfected patients on prolonged antiretroviral therapy. Antivir Ther 2015; 20:545-54. [PMID: 25654813 DOI: 10.3851/imp2942] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Worldwide, frequent emergence of lamivudine (3TC)-resistant HBV mutants has been reported in HIV-HBV-coinfected patients during long-term antiretroviral therapy (ART) that contains 3TC as the sole anti-HBV drug. Three major patterns of mutations in HBV polymerase gene, namely single (rtM204V), double (rtL180M+rtM204V) and triple (rtV173L+rtL180M+rtM204V) mutations, are associated with 3TC-resistance; additionally, the triple mutation has vaccine-escape potential due to a corresponding change in overlapping surface gene. Data from India, a major reservoir for HIV and HBV infection, is lacking. Here we investigated the effect of long-term 3TC treatment on virological response for HBV and characterized the 3TC-resistant HBV mutations in a cohort of HIV-HBV-coinfected patients from eastern India. METHODS A cross-sectional study was performed in HIV-infected patients (n=563) receiving 3TC-containing ART for ≥6 months from the major ART centre of eastern India during 2011-2012. The hepatitis B surface antigen-positive HIV-infected patients (n=62) were categorized into four groups with comparable sample size according to the 3TC exposure for ≥6-<12 months (group I; n=15), ≥12-<24 months (group II; n=20), ≥24-<48 months (group III; n=13) and ≥48 months (group IV; n=14). Patients' plasma samples were examined for hepatitis B e antigen (HBeAg), HBV DNA, viral load and covalently closed circular DNA (cccDNA). HBV reverse transcriptase region was sequenced. RESULTS With a longer period of 3TC exposure, the frequency of HIV-HBV-coinfected patients having HBV DNA suppression decreased. The prevalence of HBeAg-positivity, serum HBV DNA load >2,000 IU/ml and 3TC-resistant mutations simultaneously increased. Remarkably, the 3TC-resistant triple mutation predominated over the double mutation in this cohort (32.26% versus 19.34%) and prevailed in significantly higher frequency among HBV viraemic patients experiencing 3TC for ≥48 months (60% versus 10%; P=0.03). Patients with 3TC-resistant triple mutants had HBV genotype-D, high serum HBV DNA load and elevated alanine aminotransferase level, and presence of cccDNA in their serum. CONCLUSIONS Considering this alarmingly high incidence of 3TC-resistant triple mutation and its possible clinical/public health implications, proper management of 3TC-resistance among HIV-HBV-coinfected patients is an urgent necessity in India.
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Affiliation(s)
- Ananya Pal
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, India
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Xu YY, Liu HH, Zhong YW, Liu C, Wang Y, Jia LL, Qiao F, Li XX, Zhang CF, Li SL, Li P, Song HB, Li Q. Peripheral blood mononuclear cell traffic plays a crucial role in mother-to-infant transmission of hepatitis B virus. Int J Biol Sci 2015; 11:266-73. [PMID: 25678845 PMCID: PMC4323366 DOI: 10.7150/ijbs.10813] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 12/16/2014] [Indexed: 12/18/2022] Open
Abstract
The role of peripheral blood mononuclear cells (PBMCs) in HBV intrauterine infection is not fully defined. Particularly the origin of PBMCs in HBV-infected neonates remains to be addressed. We carried out a population-based nested case-control study by enrolling 312 HBsAg-positive mothers and their babies. PBMC HBV DNA as well as serum HBsAg and HBV DNA was tested in cohort entry samples. Totally, 45.5% (142/312) of the newborns were found to be infected with HBV in perinatal transmission. 119 mother-infant pairs were identified to be different in the genetic profile of maternal and fetal PBMCs by AS-PCR and hemi-nested PCR. Among them, 57.1% (68/119) of the maternal PBMCs in index cases were positive for HBV DNA while 83.8% (57/68) of the HBV DNA positive maternal PBMCs passed the placental barrier and entered the fetus. Furthermore, maternal PBMC HBV infection was significantly associated with newborn infants HBV infection. PBMC traffic from mother to fetus resulted in a 9.5-fold increased risk of HBV infection in PBMC HBV DNA positive newborn infants. These data indicate that maternal PBMCs infected with HBV contribute to HBV intrauterine infection of newborn infants via PBMC traffic from mother to fetus.
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Affiliation(s)
- Yuan-Yong Xu
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Hui-Hui Liu
- 2. Department of Epidemiology, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yan-Wei Zhong
- 3. Pediatric Liver Disease Therapy Research Laboratory, 302 Hospital, Beijing, China
| | - Chang Liu
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Yong Wang
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Lei-Li Jia
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Fei Qiao
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China; ; 4. Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Xin-Xin Li
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Chuan-Fu Zhang
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Shen-Long Li
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Peng Li
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Hong-Bin Song
- 1. Institute of Disease Control and Prevention, Academy of Military Medical Science, Beijing, China
| | - Qiao Li
- 5. Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
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Ramezani A, Aghasadeghi MR, Ahmadi F, Razeghi E, Eslamifar A, Banifazl M, Sofian M, Bahramali G, Hekmat S, Aghakhani A. Isolated anti-hbc and occult HBV infection in dialysis patients. Nephrourol Mon 2015; 7:e22674. [PMID: 25738121 PMCID: PMC4330694 DOI: 10.5812/numonthly.22674] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 09/01/2014] [Accepted: 09/02/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Occult Hepatitis B virus (HBV) infection (OBI) is defined as the presence of HBV-DNA in the liver or serum with undetectable hepatitis B surface antigen (HBsAg). Hemodialysis (HD) patients are at risk of acquiring parenterally transmitted infections. OBJECTIVES The aim of this study was to assess the prevalence of OBI in HD patients. PATIENTS AND METHODS A hundred HBsAg negative HD patients were included in this study from main dialysis units in Tehran, Iran. HBsAg, hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc) and liver enzymes levels were examined in all subjects. The presence of HBV-DNA was determined in plasma samples using real-time PCR. RESULTS A hundredpatients with a mean age of 58.5 ± 16.1 years were enrolled in this study. In total, 56.7% were male and 43.3% female. Anti-HBs, anti-HBc, anti-HCV and anti-HIV were detected in 56.7%, 2%, 5.2% and 1% of patients, respectively. Isolated anti-HBc was detected in 2% of cases. HBV-DNA was detected in 1% of HBsAg negative patients. CONCLUSIONS This study showed a low rate of isolated anti-HBc and occult HBV infection in HD patients. It can be due to improvement of people's knowledge about HBV transmission routes, HBV vaccination of HD patients and regular surveillance of HBV infection.
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Affiliation(s)
- Amitis Ramezani
- Department of Clinical Research, Pasteur Institute of Iran, Tehran, IR Iran
| | | | - Farrokhlagha Ahmadi
- Nephrology Research Center, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Effat Razeghi
- Nephrology Research Center, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Ali Eslamifar
- Department of Clinical Research, Pasteur Institute of Iran, Tehran, IR Iran
| | - Mohammad Banifazl
- Iranian Society for Support Patients With Infectious Diseases, Tehran, IR Iran
| | - Masoomeh Sofian
- TPIRC (Tuberculosis and Pediatric Infectious Research Center), Arak University of Medical Sciences, Arak, IR Iran
| | - Golnaz Bahramali
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
| | - Soheila Hekmat
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
| | - Arezoo Aghakhani
- Department of Clinical Research, Pasteur Institute of Iran, Tehran, IR Iran
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Dumaidi K, Al-Jawabreh A. Prevalence of occult HBV among hemodialysis patients in two districts in the northern part of the West Bank, Palestine. J Med Virol 2014; 86:1694-9. [PMID: 24992542 DOI: 10.1002/jmv.24008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2014] [Indexed: 01/01/2023]
Abstract
Occult hepatitis B infection is the case with undetectable HBsAg, but positive for HBV DNA in liver tissue and/or serum. Occult hepatitis B infection among hemodialysis patients in Palestine has been understudied. In this study, 148 hemodialysis patients from 2 northern districts in Palestine, Jenin (89) and Tulkarem (59), were investigated for occult hepatitis B, HBV, HCV infections with related risk factors. ELISA and PCR were used for the detection of anti-HBc and viral DNA, respectively. The overall prevalence of occult hepatitis B infection among the study group was 12.5% (16/128). Occult hepatitis B infection is more prevalent among males with most cases (15/16) from Jenin District. About one-third (42/132) of the hemodialysis patients were anti-HBc positive. Approximately 27% of the hemodialysis patients were infected with HCV. Around 20% (28/140) were positive for HBV DNA, but only 8.2% (12/146) of the hemodialysis patients were positive for HBsAg. The comparison between hemodialysis patients with occult hepatitis B infection and those without occult hepatitis B infection for selected risk factors and parameters as liver Enzyme, age, sex, HCV infection, blood transfusion, kidney transplant, anti-HBc, and vaccination showed no statistical significance between both categories. Duration of hemodialysis significantly affected the rate of HCV infection. HCV is significantly higher in hemodialysis patients with both Diabetes mellitus and hypertension. The prevalence of occult hepatitis B infection among hemodialysis patients is high; requiring stringent control policies. HBsAg assay is insufficient test for accurate diagnosis of HBV infection among hemodialysis patients.
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Affiliation(s)
- Kamal Dumaidi
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Arab American University, Jenin, Palestine
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39
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Singla B, Chakraborti A, Sharma BK, Kapil S, Chawla YK, Arora SK, Das A, Dhiman RK, Duseja A. Levels of hepatitis B virus replicative intermediate in serum samples of chronic hepatitis B patients. Mol Biol Rep 2014; 41:4689-96. [PMID: 24706057 DOI: 10.1007/s11033-014-3339-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 03/21/2014] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) cccDNA levels is an absolute marker of HBV replication in the liver of HBV infected patients. This study aimed to quantify the HBV cccDNA levels in sera and liver tissue samples of treatment naïve patients with chronic hepatitis B. Eighty one chronic hepatitis B (CHB) treatment naïve patients were enrolled from January 2009 to June 2011. Total HBV DNA and HBV cccDNA levels were quantified using sensitive real time PCR assay. The mean age of recruited patients was 34 ± 11.5 years. Fifty four (66.7%) patients were HBeAg negative. Liver tissue samples were available from 2 HBeAg positive and 21 HBeAg negative CHB patients. The amount of total intrahepatic HBV DNA ranged from 0.09 to 1508.92 copies/cell. The median intrahepatic HBV cccDNA was 0.31 and 0.20 copies/cell in HBeAg positive and HBeAg negative cases, respectively. Serum HBV cccDNA was detectable in 85.2 % HBeAg positive and 48.1% HBeAg negative CHB patients. Median serum HBV cccDNA was 46,000 and 26,350 copies/mL in HBeAg positive and HBeAg negative subjects, respectively. There was a significant positive correlation between the levels of intrahepatic total HBV DNA and intrahepatic HBV cccDNA (r = 0.533, p = 0.009). A positive correlation was also seen between serum HBV cccDNA levels and serum HBV DNA levels (r = 0.871, p < 0.001). It was concluded that serum HBV cccDNA could be detectable in higher proportion of HBeAg positive patients compared to HBeAg negative patients. Moreover, the median level of serum HBV cccDNA was significantly higher in HBeAg positive patients in contrast to HBeAg negative subjects.
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Affiliation(s)
- Bhupesh Singla
- Department of Hepatology, Nehru Hospital, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
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40
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Anvari FA, Alavian SM, Norouzi M, Mahabadi M, Jazayeri SM. Prevalence and molecular analysis of occult hepatitis B virus infection isolated in a sample of cryptogenic cirrhosis patients in iran. Oman Med J 2014; 29:92-96. [PMID: 24715933 PMCID: PMC3976723 DOI: 10.5001/omj.2014.23] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Accepted: 12/19/2013] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVES The aims of this study are to investigate the prevalence of occult hepatitis B virus infection among patients with cryptogenic cirrhosis and to analyze the relationship between surface protein variability and occult hepatitis B virus infection, which may be related to the pathogenesis of occult hepatitis B virus infection in cryptogenic cirrhosis. Occult hepatitis B virus infection is a well-recognized clinical entity characterized by the detection of hepatitis B virus DNA in serum and/or liver in the absence of detectable hepatitis B virus surface antigen, with or without any serological markers of a past infection. METHODS Sera from patients with cryptogenic chronic liver disease were tested for hepatitis B virus DNA using both real-time and nested PCR. In the detected hepatitis B virus DNA samples, the surface gene was analyzed for mutations. RESULTS Hepatitis B virus DNA was detected in 38% of patients, all of whom had a viral load below 10,000 copies/mL. All hepatitis B virus belonged to genotype D. There were no significant associations between occult hepatitis B virus infection status and age, gender, ALT/AST levels, viral load or serologic markers of previous hepatitis B virus infection. There were 14 mutations found in 5 patients; 6 were in the major hydrophilic region, of which 4 were Y134F assigning for the "a" determinant region. All patients who acquired Y134F contained S207R (within HLA-A2-restricted CTL epitope) as a combination. CONCLUSION Hepatitis B virus surface antigen variants may arise as a result of natural selection to evade the immune surveillance of the infected host, and subsequently may go undetected by conventional hepatitis B virus surface antigen screening tests. Etiological diagnosis of cryptogenic cirrhosis is significantly underestimated with current serology testing methods alone.
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Affiliation(s)
- Fatemeh Akhavan Anvari
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, PO Box: 15155-6446, Tehran, Iran. Tel/Fax: +98-21-8899-2660
| | - Seyed Moayyed Alavian
- Baqiyatallah University of Medical Sciences, Baqiyatallah Research Center for Gastroenterology and Liver Disease, P.O. Box: 15155-6446, Tehran, Iran
| | - Mehdi Norouzi
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, PO Box: 15155-6446, Tehran, Iran. Tel/Fax: +98-21-8899-2660
| | - Mostafa Mahabadi
- Baqiyatallah University of Medical Sciences, Baqiyatallah Research Center for Gastroenterology and Liver Disease, P.O. Box: 15155-6446, Tehran, Iran
| | - Seyed Mohammad Jazayeri
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, PO Box: 15155-6446, Tehran, Iran. Tel/Fax: +98-21-8899-2660
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41
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Characterization of the occult hepatitis B virus variants circulating among the blood donors from eastern India. ScientificWorldJournal 2013; 2013:212704. [PMID: 24302857 PMCID: PMC3834618 DOI: 10.1155/2013/212704] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 09/23/2013] [Indexed: 12/18/2022] Open
Abstract
A previous study from West Bengal documented very high rate of occult HBV infection (OBI) among the HBsAg negative blood donors. This study was aimed to characterize the OBI strains circulating among the blood donors and to estimate the risk associated with the prevailing viral variants/mutants. Blood samples from 2195 voluntary blood donors were included in the study. HBsAg, HBeAg, anti-HBc, and anti-HBs statuses of the samples were done by ELISA based detection. PCR amplification and sequencing were done to determine HBV genotypes, basal core promoter (BCP), and precore (Pre-C) mutations. Among the study samples, 268 were anti-HBc positive/HBsAg negative, among which 65 (24.25%) were HBV DNA positive. Phylogenetic analysis revealed the presence of HBV/D (87.23%), HBV/A (8.51%), and HBV/C (4.26%) (P < 0.0001). HBV/D3 (65.85%) was the significantly prevalent subgenotype over HBV/D2 (26.83%) and HBV/D1 (7.31%) (P = 0.0003). Considerable prevalence of differential BCP (1752C, 1753C, 1762T/1764A, 1753C+1762T/1764A, 1773C, and 1814C) and reverse transcriptase (rt) gene (rtI91L, rtL93P, rtS106C, rtR110G, rtN118T, rtS119T, rtY126H, rtG127W/R, rtC136R, and rtY158H) mutations was identified. Association of specific HBV subgenotypes with OBI was interesting and needs further study. Clinically relevant mutations were prevalent among the OBI strains which are of serious concern.
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42
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Loustaud-Ratti V, Wagner A, Carrier P, Marczuk V, Chemin I, Lunel F, Fouchard-Hubert I, Ahmed SS, Abergel A, Rousseau A, Lefebvre A, Debette-Gratien M, Denis F, Alain S. Distribution of total DNA and cccDNA in serum and PBMCs may reflect the HBV immune status in HBsAg+ and HBsAg- patients coinfected or not with HIV or HCV. Clin Res Hepatol Gastroenterol 2013; 37:373-383. [PMID: 23477988 DOI: 10.1016/j.clinre.2012.11.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 10/07/2012] [Accepted: 11/06/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND The potential reservoir role of serum and peripheral blood mononuclear cells (PBMCs) for total HBV DNA (tDNA) and cccDNA still remains unknown. MATERIAL AND METHODS We analyzed tDNA and cccDNA with a single sensitive and validated standardized real-time PCR method in serum and PBMCs in two populations of chronic HBV infection coinfected or not with HCV and/or HIV viruses: a retrospective cohort of 130 HBsAg-negative (HBsAg-) patients with "anti-HBc alone" or anti-HBc and anti-HBs antibodies (Ab) and a cohort of 70 HBsAg-positive patients, 16 of them being prospectively followed under treatment. RESULTS Among HBsAg- patients, HBV DNA was detected in serum or PBMCs in about half of the cases with various distributions of tDNA and cccDNA: in HIV-negative patients with an "antiHBc alone" profile, tDNA was mostly detected in PBMCs suggesting a possible active role of PBMCs; although cccDNA was not detected in PBMCs in HIV-positive patients, tDNA and cccDNA were mostly observed in serum, suggesting a specific pattern of more "persistent" than "occult" infection in this population. Patients with anti-HBc and anti-HBs Ab harbored tDNA in serum or in PBMCs, regardless of their HIV or HCV status, raising the question of a viral reactivation risk during immunosupression in these patients. Among HBsAg+ patients, tDNA was detected in serum and PBMCs of 88.5% of the cases and cccDNA in 22%. Levels of tDNA in both compartments were highly correlated during treatment, suggesting a passive reservoir role for PBMCs. CONCLUSION The respective distribution of tDNA and cccDNA in serum and PBMCs may reflect the different immune statuses of the host in HBsAg+ and HBsAg- patients. The frequency of HBV DNA in PBMCs from AgHBs- patients suggests a viral reactivation risk during immunodepression in those patients.
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Affiliation(s)
- V Loustaud-Ratti
- Inserm UMR 1092, Faculté de médecine, Université Limoges, 2, rue du Docteur-Marcland, 87025 Limoges cedex, France
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Shen G, Fu X, Zhou B, Yin J, Zhong C, Chen J, Hou J. Duck HBV DNA copy numbers in isolated hepatocyte nuclei vary dramatically and decline during entecavir therapy. Antivir Ther 2013; 18:987-996. [PMID: 23765241 DOI: 10.3851/imp2653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND We aimed to develop a quantitative assay to measure duck HBV (DHBV) DNA in single hepatocyte nuclei from DHBV-infected animals and to observe intranuclear DHBV DNA kinetics undergoing entecavir (ETV) therapy. METHODS DHBV DNA in isolated nuclei was amplified by quantitative real-time PCR. Liver tissues from chronically-infected ducks with or without ETV treatment were assessed. Cell cycle phases were defined with flow cytometry in single nuclei. RESULTS We successfully established a quantitative assay to measure intranuclear DHBV DNA in single nuclei with high specificity, sensitivity and acceptable interassay variations. The intranuclear viral DNA copy numbers varied dramatically (2-204 copies/nuclei) in 11 ducks with active viral replication. Average intranuclear DHBV DNA copies from individual animals (7.57-57.67 copies/nuclei) significantly correlated with total intranuclear (rs=0.955, P<0.001) and serum (rs=0.745, P=0.008) viral DNA levels. The median intranuclear DHBV DNA copies in virus-positive nuclei were greater in gap 0/1 than those in gap 2/mitosis and synthesis phases (P<0.001). Median intranuclear viral DNA copies in virus-positive nuclei decreased from 21 to 6 (P<0.001) under 14-19 weeks of ETV therapy. However, subsequently, further reductions were not achieved in four animals after extended 16 week treatment (6 versus 11, P=0.034). CONCLUSIONS Intranuclear DHBV DNA levels varied significantly, which could be partially attributed to effects of cell cycle phases, and could be decreased by ETV therapy.
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Affiliation(s)
- Guojun Shen
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
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44
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Biswas A, Panigrahi R, Pal M, Chakraborty S, Bhattacharya P, Chakrabarti S, Chakravarty R. Shift in the hepatitis B virus genotype distribution in the last decade among the HBV carriers from eastern India: Possible effects on the disease status and hbv epidemiology. J Med Virol 2013; 85:1340-7. [DOI: 10.1002/jmv.23628] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Avik Biswas
- ICMR Virus Unit; ID & BG Hospital Campus; Kolkata India
| | | | - Manisha Pal
- Department of Statistics; University of Calcutta; Kolkata India
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YE F, JIN Y, KONG Y, SHI JZ, QIU HT, ZHANG X, ZHANG SL, LIN SM. The presence of HBV mRNA in the fertilized in vitro embryo of HBV patients confirms vertical transmission of HBV via the ovum. Epidemiol Infect 2013; 141:926-30. [PMID: 22877604 PMCID: PMC9151867 DOI: 10.1017/s0950268812001690] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 07/11/2012] [Indexed: 12/12/2022] Open
Abstract
This study aimed to confirm that vertical transmission of hepatitis B virus (HBV) can occur via the infected ovum. Specimens studied were obtained from discarded test-tube embryos from mothers with chronic HBV infection who had received in vitro fertilization treatment. Single-cell reverse transcriptase-polymerase chain reaction was used to detect HBV mRNA in the embryos. HBV mRNA was detected in the cleavage embryos of patients with chronic HBV infection, with a detection rate of 13.2% (5/38). The level of serum HBV DNA was not related to the HBV mRNA positivity rates in embryos. In this study, HBV mRNA was detected in test-tube embryos from HBV-infected mothers who had received in vitro fertilization treatment. This confirms the theory of vertical transmission of HBV via the ovum, thereby providing an important theoretical basis for further study on the mechanism of HBV vertical transmission, influencing factors and blocking measures.
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Affiliation(s)
- F. YE
- Departments of Infectious Disease and Gynecology and Obstetrics, The First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Y. JIN
- Departments of Infectious Disease and Gynecology and Obstetrics, The First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Y. KONG
- Departments of Infectious Disease and Gynecology and Obstetrics, The First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - J. Z. SHI
- Reproductive Center, Shanxi Maternal and Child Care Hospital, Xi'an, China
| | - H. T. QIU
- Reproductive Center, Shanxi Maternal and Child Care Hospital, Xi'an, China
| | - X. ZHANG
- Departments of Infectious Disease and Gynecology and Obstetrics, The First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - S. L. ZHANG
- Departments of Infectious Disease and Gynecology and Obstetrics, The First Hospital of Xi'an Jiaotong University, Xi'an, China
| | - S. M. LIN
- Departments of Infectious Disease and Gynecology and Obstetrics, The First Hospital of Xi'an Jiaotong University, Xi'an, China
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Nagakawa O, Miyatomi Y, Shigeta Y, Inayama E, Murakami K, Sakai T, Kouno T, Masai M, Shirai K, Yoshida T. Occult Hepatitis B Virus Infection in Japanese Chronic Hemodialysis Patients. Ther Apher Dial 2013; 17:289-92. [DOI: 10.1111/1744-9987.12006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Quantification of pregenomic RNA and covalently closed circular DNA in hepatitis B virus-related hepatocellular carcinoma. Int J Hepatol 2013; 2013:849290. [PMID: 24455286 PMCID: PMC3880697 DOI: 10.1155/2013/849290] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 11/07/2013] [Accepted: 11/08/2013] [Indexed: 02/06/2023] Open
Abstract
Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P < 0.001). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development.
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Fabrizi F, Lunghi G, Alongi G, Aucella F, Barbisoni F, Bisegna S, Mangano S, Romei-Longhena G, Artoni A, Bettoni G, Messa P, Martin P. Kinetics of Hepatitis B Virus Load During Haemodialysis Sessions and a-Interferon: A Prospective Study. ACTA ACUST UNITED AC 2013; 37:286-94. [DOI: 10.1159/000350156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2013] [Indexed: 11/19/2022]
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Albuquerque ACCD, Coelho MRCD, Lemos MF, Moreira RC. Occult hepatitis B virus infection in hemodialysis patients in Recife, State of Pernambuco, Brazil. Rev Soc Bras Med Trop 2012; 45:558-62. [DOI: 10.1590/s0037-86822012000500004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 01/27/2012] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION: Persistence of the hepatitis B virus (HBV) genome in individuals negative for the HBV surface antigen (HBsAg) reflects occult infection. The aim of this study was to identify occult HBV infection among hemodialysis patients at 5 clinics in Recife, State of Pernambuco, Brazil, between August 2006 and August 2007. METHODS: Serum samples underwent enzyme-linked immunosorbent assay to investigate total antibodies against HBcAg (anti-HBc), HBsAg, and antibodies against HBsAg (anti-HBs). Samples that were HBsAg-negative were tested for total anti-HBc, and those that were positive for total anti-HBc were tested for anti-HBs. HBV DNA was investigated with an in-house PCR technique to identify samples positive for total anti-HBc. Subsequently, the samples positive for HBV DNA were sequenced to identify the genotype and mutations. RESULTS: The study population (n = 752) had a mean age of 50 15.1 years and included both sexes. All samples analyzed were negative for HBsAg. The seroprevalence of total anti-HBc was 26.7% (201/752), while that of anti-HBs was 67.2% (135/201). Total anti-HBc alone was detected in 5.7% of the patients. Occult infection was found in 1.5%, comprising genotypes A (33.3%, 1/3) and D (66.7%, 2/3). No mutations were found. CONCLUSIONS: The study detected occult hepatitis B virus infection in hemodialysis patients. Molecular studies on HBV are of fundamental importance because they identify patients that had been considered virus-negative but who, in reality, host the virus and have the ability to transmit it to other patients and staff.
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Anti-hepatitis B core positivity as a risk factor for hepatocellular carcinoma in alcoholic cirrhosis: a case-control study. Alcohol 2012; 46:537-41. [PMID: 22572059 DOI: 10.1016/j.alcohol.2012.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 10/09/2011] [Accepted: 03/29/2012] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) is occasionally developed in patients with alcoholic cirrhosis. Old age, male gender, lifetime quantity of alcohol, and presence of hepatitis C virus (HCV) infection are risk factors for HCC in alcoholic cirrhosis. In this study, we investigated whether anti-hepatitis B core (HBc) positivity or occult hepatitis B virus (HBV) infection is a risk factor for HCC in patients with alcoholic cirrhosis. Between January 2006 and August 2008, a total of 72 cirrhotic male patients with an initial diagnosis of HCC, hospitalized in three major hospitals in the Incheon area, were enrolled as cases. Another 72 cirrhotic male patients without HCC, who matched the cases by age (±3 years), were enrolled as controls. All cases and controls were negative for hepatitis B surface antigen and anti-HCV, but had history of chronic alcohol intake over 80 g per day. The clinical characteristics including presence of anti-HBc or serum HBV DNA (identified by nested polymerase chain reaction) were investigated. The mean age of both the cases and controls was 62 ± 10 years. The basal laboratory data, Child-Pugh scores, total lifetime alcohol intake (1459 ± 1364 versus 1641 ± 1045 kg), and detection rates of serum HBV DNA [31.7% (20/63) versus 29.9% (20/67)] of the cases and controls were not significantly different. However, the anti-HBc positivity rate was higher among the cases [86.1% (62/72)] than in the controls [66.7% (48/72); p=0.005] and was the only significant risk factor for HCC (odds ratio; 3.1, 95% confidence interval; 1.354-7.098, p=0.007). Anti-HBc positivity was identified as a risk factor for the development of HCC in patients with alcoholic cirrhosis.
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