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Yang SS, Fu F, Xuan QK, Zhang ZX, Li ZJ, Li GB, Yu XY. Hepatitis B surface antigen-negative but hepatitis B envelope antigen-positive false occult hepatitis B virus infection: A case report. World J Hepatol 2024; 16:1199-1207. [PMID: 39474578 PMCID: PMC11514620 DOI: 10.4254/wjh.v16.i10.1199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 08/13/2024] [Accepted: 09/14/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum (usually HBV DNA < 200 IU/mL) or the liver but negativity for hepatitis B surface antigen (HBsAg). The diagnosis of OBI relies on the sensitivity of assays used in the detection of HBV DNA and HBsAg. HBsAg assays with inadequate sensitivity or inability to detect HBV S variants may lead to misdiagnosis of OBI in people with overt HBV infection.
CASE SUMMARY We report a HBsAg-negative but hepatitis B envelope antigen-positive patient who had a significant HBV DNA level. The patient was initially diagnosed as having OBI. However, sequence analysis revealed a unique insertion of amino acid residues at positions 120-124 in the S protein, which affects the formation of a disulfide bond that is associated with the formation of a loop. It is well known that there is an overlap between the S protein and Pol protein. We found that this new insertion site occurred in polymerase/reverse transcriptase domain, indicating that this insertion might be involved in HBV pathogenicity. The patient was finally diagnosed with a false OBI.
CONCLUSION An insertion of amino acid residues at positions 120-124 of the S protein affects the formation of immunodominant epitopes and results in negative HBsAg levels.
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Affiliation(s)
- Shu-Sheng Yang
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Fei Fu
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Qian-Kun Xuan
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Zhou-Xiang Zhang
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Zhi-Jun Li
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Guang-Bo Li
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Xiao-Yu Yu
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
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Yang SS, Fu F, Xuan QK, Zhang ZX, Li ZJ, Li GB, Yu XY. Hepatitis B surface antigen-negative but hepatitis B envelope antigen-positive false occult hepatitis B virus infection: A case report. World J Hepatol 2024; 16:1379-1387. [DOI: 10.4254/wjh.v16.i10.1379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 08/13/2024] [Accepted: 09/14/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum (usually HBV DNA < 200 IU/mL) or the liver but negativity for hepatitis B surface antigen (HBsAg). The diagnosis of OBI relies on the sensitivity of assays used in the detection of HBV DNA and HBsAg. HBsAg assays with inadequate sensitivity or inability to detect HBV S variants may lead to misdiagnosis of OBI in people with overt HBV infection.
CASE SUMMARY We report a HBsAg-negative but hepatitis B envelope antigen-positive patient who had a significant HBV DNA level. The patient was initially diagnosed as having OBI. However, sequence analysis revealed a unique insertion of amino acid residues at positions 120-124 in the S protein, which affects the formation of a disulfide bond that is associated with the formation of a loop. It is well known that there is an overlap between the S protein and Pol protein. We found that this new insertion site occurred in polymerase/reverse transcriptase domain, indicating that this insertion might be involved in HBV pathogenicity. The patient was finally diagnosed with a false OBI.
CONCLUSION An insertion of amino acid residues at positions 120-124 of the S protein affects the formation of immunodominant epitopes and results in negative HBsAg levels.
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Affiliation(s)
- Shu-Sheng Yang
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Fei Fu
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Qian-Kun Xuan
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Zhou-Xiang Zhang
- Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Zhi-Jun Li
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Guang-Bo Li
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Xiao-Yu Yu
- Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
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Gridneva GI, Belov BS, Aronova ES. [Chronic hepatitis B in rheumatic diseases: issues of screening and reactivation of infection: A review]. TERAPEVT ARKH 2024; 96:523-530. [PMID: 38829815 DOI: 10.26442/00403660.2024.05.202707] [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: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/05/2024]
Abstract
Patients with rheumatic diseases infected with hepatitis B virus (HBV) are difficult to manage not only due to the presence of risk factors for the development and rapid progression of liver cirrhosis, but also due to the likelihood of reactivation of this infection. Despite the successes achieved in the fight against HBV, the virus cannot be completely defeated due to the presence of hidden forms of the disease, escaping the field of vision of a rheumatologist and an infectionist. Based on the results of the analysis of current publications, the paper presents the rationale for a complete immunological screening of patients with rheumatic diseases when prescribing antirheumatic therapy. The issues of the role of COVID-19 in the exacerbation of chronic viral hepatitis B, antiviral prevention and monitoring are discussed, the classification of antirheumatic drugs according to the risk of HBV reactivation is presented.
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Affiliation(s)
| | - B S Belov
- Nasonova Research Institute of Rheumatology
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Ma H, Yan QZ, Ma JR, Li DF, Yang JL. Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies. World J Gastroenterol 2024; 30:1295-1312. [PMID: 38596493 PMCID: PMC11000084 DOI: 10.3748/wjg.v30.i10.1295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/25/2023] [Accepted: 01/24/2024] [Indexed: 03/14/2024] Open
Abstract
Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.
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Affiliation(s)
- Hui Ma
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Qing-Zhu Yan
- Department of Ultrasound Medicine, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Jing-Ru Ma
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Dong-Fu Li
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Jun-Ling Yang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
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Hu J, Zhao J, Wang C, Jia M, Su M, Li S. Epstein-Barr virus reactivation correlates with worse outcomes for patients exposed to hepatitis B virus after haploidentical hematopoietic stem cell transplantation. Ann Hematol 2023; 102:3593-3601. [PMID: 37831153 DOI: 10.1007/s00277-023-05492-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/03/2023] [Indexed: 10/14/2023]
Abstract
Hepatitis B virus (HBV)has a high, chronic infection rate in Asian populations, but only few studies have analyzed the effect of Epstein-Barr virus (EBV) or Cytomegalovirus (CMV) reactivation in patients exposed to HBV after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study aimed to assess the clinical outcomes of these patients. We conducted a retrospective research including 61 patients exposed to HBV after undergoing haplo-HSCT. The patients were classified into two groups: the CMV reactivation group and no CMV reactivation group. The results were compared between the two groups using the K-W test for continuous variables, Pearson's chi-square test for categorical variables, Kaplan-Meier curves to estimate overall survival (OS) and leukemia-free survival (LFS), and a Cox proportional hazards model to analyze multivariable influences. The 3-year cumulative HBV reactivation rate was 8.2%. The median duration of HBV reactivation was 16 months (16-22 months) after haplo-HSCT. The CMV reactivation group had a higher cumulative incidence of HBV reactivation than the group without CMV reactivation. The EBV reactivation was substantially higher in the CMV reactivation group compared to that in the no CMV reactivation group (37.0% vs.5.9% respectively; P = 0.002). Furthermore, EBV reactivation was a risk factor for 1-year LFS and 1-year OS. Based on our data, EBV reactivation was related to worse outcomes in patients exposed to HBV after haplo-HSCT, whereas CMV reactivation was not.
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Affiliation(s)
- Jiajia Hu
- Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China
| | - Jie Zhao
- Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China
| | - Chunyan Wang
- Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China
| | - Mei Jia
- Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China
| | - Ming Su
- Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China.
| | - Shanshan Li
- Department of Clinical Laboratory, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People's Republic of China.
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Bhat SA, Hasan SK, Parray ZA, Siddiqui ZI, Ansari S, Anwer A, Khan S, Amir F, Mehmankhah M, Islam A, Minuchehr Z, Kazim SN. Potential antiviral activities of chrysin against hepatitis B virus. Gut Pathog 2023; 15:11. [PMID: 36895013 PMCID: PMC9995728 DOI: 10.1186/s13099-023-00531-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 01/26/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Interferon and nucleos(t)ide analogues are current therapeutic treatments for chronic Hepatitis B virus (HBV) infection with the limitations of a functional cure. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid, known for its antiviral and hepatoprotective activities. However, its anti-HBV activity is unexplored. METHODS In the present study, the anti-hepatitis B activity of chrysin was investigated using the in vitro experimental cell culture model, HepG2 cells. In silico studies were performed where chrysin and lamivudine (used here as a positive control) were docked with high mobility group box 1 protein (HMGB1). For the in vitro studies, wild type HBV genome construct (pHBV 1.3X) was transiently transfected in HepG2. In culture supernatant samples, HBV surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) were measured by enzyme-linked immunosorbent assay (ELISA). Secreted HBV DNA and intracellular covalently closed circular DNA (cccDNA) were measured by SYBR green real-time PCR. The 3D crystal structure of HMGB1 (1AAB) protein was developed and docked with the chrysin and lamivudine. In silico drug-likeness, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of finest ligands were performed by using SwissADME and admetSAR web servers. RESULTS Data showed that chrysin significantly decreases HBeAg, HBsAg secretion, supernatant HBV DNA and cccDNA, in a dose dependent manner. The docking studies demonstrated HMGB1 as an important target for chrysin as compared to lamivudine. Chrysin revealed high binding affinity and formed a firm kissing complex with HMGB1 (∆G = - 5.7 kcal/mol), as compared to lamivudine (∆G = - 4.3 kcal/mol), which might be responsible for its antiviral activity. CONCLUSIONS The outcome of our study establishes chrysin as a new antiviral against HBV infection. However, using chrysin to treat chronic HBV disease needs further endorsement and optimization by in vivo studies in animal models.
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Affiliation(s)
- Sajad Ahmad Bhat
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Syed Kazim Hasan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Zahoor Ahmad Parray
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Zaheenul Islam Siddiqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Shabnam Ansari
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Ayesha Anwer
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Saniya Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Fatima Amir
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
- Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Mahboubeh Mehmankhah
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Zarrin Minuchehr
- National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Syed Naqui Kazim
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
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Peng J, Yao X, Yuan C, Liu X, Xia R, He J, Li R, Yao Y. The Investigation of Hepatitis B Vaccine Immune Responses in Occult Hepatitis B Virus-Infected Patients. Front Immunol 2022; 13:903685. [PMID: 35747142 PMCID: PMC9211749 DOI: 10.3389/fimmu.2022.903685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/03/2022] [Indexed: 11/13/2022] Open
Abstract
Objectives There is no effective treatment for occult hepatitis B virus infection (OBI) patients, and immunotherapy may be one of the most promising options. We aim to investigate the underlying mechanism and therapeutic potential of hepatitis B vaccine immunotherapy for OBI patients. Methods Outpatient OBI patients were screened and randomly divided into treatment (Group A) and control (Group B) groups. At weeks 0, 4, and 24, patients in Group A received a subcutaneous/intramuscular injection of hepatitis B vaccine (Engerix-B, 20 μg/time) according to the standard vaccination schedule; patients in Group B served as blank control. The patients were followed for 36 weeks, with clinical, biochemical, virological, immunological, and imaging data collected and analyzed at weeks 0, 12, 24, and 36, respectively, and the relation between the virology and immunology results was analyzed. Results Of the 228 OBI patients, 28 were excluded, and 200 were enrolled for observation. In the end, 44 patients were included in Group A and 39 in Group B after excluding lost cases. At week 0 (baseline), some patients in two groups had liver disease symptoms, HBV-related liver function damage, and liver fibrosis. 86.36% (38/44) and 82.05% (32/39) patients were positive for serum hepatitis B surface antibodies (anti-HBs) in Group A and Group B, respectively, with the median (quartile) of 42.47 (16.85, 109.1) and 39.27 (16.06, 117.4) mIU/ml, respectively. Reduced peripheral blood CD4+T, CD8+T, and B lymphocytes were found in some patients in two groups. These results were not statistically different between Group A and Group B (P>0.05). At week 36, all patients were serum anti-HBs (+) in Group A, with a median (quartile) of 1000 (483.9, 1000) mIU/ml, which was significantly higher than that at week 0 (P<0.05) and that in Group B (P<0.05). Compared to week 0, the number of CD8+ T and B lymphocytes increased significantly and were significantly higher than Group B at the same point. Two patients in Group B were found to have hepatitis B virus reactivation from week 12 to week 36. Correlation Analysis Anti-HBs in Group A patients were positively correlated with B lymphocytes (r=0.3431, 0.3087, and 0.3041, respectively) and positively correlated with CD8+ T lymphocytes (r=0.4954, 0.3054, and 0.3455, respectively) at weeks 12, 24, and 36. Conclusion Virological reactivation is a risk for OBI patients. Serum hepatitis B surface antibodies were significantly increased after hepatitis B vaccine treatment, the same as the numbers of peripheral blood B and CD8+ T lymphocytes; changes in hepatitis B surface antibody levels were positively correlated with the changes in peripheral blood B and CD8+ T lymphocytes.
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Affiliation(s)
- Jing Peng
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xueying Yao
- The Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chunyan Yuan
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoli Liu
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Renxiang Xia
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian He
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Li
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunqing Yao
- The Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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