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Guo H, Fang F, Lin L, Guo Z, Lai L, Shi Y, Chen T, Lai R, Ou Q, Fu Y. Novel prognostic scoring models for hepatitis B virus-related acute-on-chronic liver failure: A comparison with classical models. Virulence 2025; 16:2500490. [PMID: 40376958 PMCID: PMC12087482 DOI: 10.1080/21505594.2025.2500490] [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] [Received: 10/23/2024] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/18/2025] Open
Abstract
Early diagnosis and accurate prognostic evaluation are important for guiding clinical treatment and reducing mortality in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The present study established novel prognostic scoring models to guide the clinical treatment of patients with HBV-ACLF. We performed a retrospective analysis of clinical data from two cohorts of patients diagnosed with HBV-ACLF. By comparing differences in baseline characteristics and clinical indicators between the survival (n = 102) and dead (n = 64) groups in the derivation cohort(n = 166), four laboratory indicators (age, INR, TBIL, and HBeAg status) and three clinical signs (extrahepatic infection, ascites, and hepatic encephalopathy) were identified as independent risk factors. Logistic regression and nomogram models were used to construct three novel predictive models. By comparing the death and survival groups, we found that the three new models had higher predictions for AUROC (average of 0.856) than the three old models (average of 0.773). Model 1 had the strongest predictive power for the short-term survival rate of HBV-ACLF patients. Finally, we verified the predictive value of the new models for HBV-ACLF in a validation cohort (n = 42), and the Model 2 demonstrated good predictive accuracy for the 30-day survival rate of patients. The novel model based on seven predictors could accurately predict short-term mortality in patients with HBV-ACLF, which is promising for guiding clinical management and addressing the aetiological differences in Asian populations.
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Affiliation(s)
- Hongyan Guo
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- The School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Fengling Fang
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Lin Lin
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zhaopei Guo
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Lu Lai
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yue Shi
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Tianbin Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ruimin Lai
- Department of the Center of Liver Diseases, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ya Fu
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Gene Diagnosis Research Center, Fujian Medical University, Fuzhou, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Bucio-Ortiz L, Enriquez-Navarro K, Maldonado-Rodríguez A, Torres-Flores JM, Cevallos AM, Salcedo M, Lira R. Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO's Elimination Plan of Viral Hepatitis. Pathogens 2024; 13:662. [PMID: 39204261 PMCID: PMC11357063 DOI: 10.3390/pathogens13080662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 09/03/2024] Open
Abstract
Liver damage can progress through different stages, resulting in cirrhosis or hepatocellular carcinoma (HCC), conditions that are often associated with viral infections. Globally, 42% and 21% of cirrhosis cases correlate with HBV and HCV, respectively. In the Americas, the prevalence ranges from 1% to 44%. The WHO has the goal to eliminate viral hepatitis, but it is important to consider occult HBV infection (OBI), a clinical condition characterized by the presence of HBV genomes despite negative surface antigen tests. This review aims to provide an overview of recent data on OBI, focusing on its role in the development of hepatic diseases and its significance in the WHO Viral Hepatitis Elimination Plan. Specific HBV gene mutations have been linked to HCC and other liver diseases. Factors related to the interactions between OBI and mutated viral proteins, which induce endoplasmic reticulum stress and oxidative DNA damage, and the potential role of HBV integration sites (such as the TERT promoter) have been identified in HCC/OBI patients. Health initiatives for OBI research in Latin American countries are crucial to achieving the WHO's goal of eradicating viral hepatitis by 2030, given the difficulty in diagnosing OBI and its unclear association with hepatic diseases.
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Affiliation(s)
- Leticia Bucio-Ortiz
- Medicina y Carcinogénesis Experimental, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de Mexico 09340, Mexico; (L.B.-O.); (K.E.-N.)
| | - Karina Enriquez-Navarro
- Medicina y Carcinogénesis Experimental, Universidad Autónoma Metropolitana Iztapalapa, Ciudad de Mexico 09340, Mexico; (L.B.-O.); (K.E.-N.)
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico 06720, Mexico;
| | - Angélica Maldonado-Rodríguez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico 06720, Mexico;
| | - Jesús Miguel Torres-Flores
- Laboratorio Nacional de Vacunología y Virus Tropicales, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de Mexico 11350, Mexico;
| | - Ana María Cevallos
- Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico 04510, Mexico;
| | - Mauricio Salcedo
- Unidad de Investigación Biomédica Oncológica Genómica, Hospital de Gineco Pediatría 3-A, Instituto Mexicano del Seguro Social, Órgano de Operación Administrativa Desconcentrada (OOAD) Cd Mx Norte, Ciudad de Mexico 07760, Mexico;
| | - Rosalia Lira
- Unidad de Investigación Biomédica Oncológica Genómica, Hospital de Gineco Pediatría 3-A, Instituto Mexicano del Seguro Social, Órgano de Operación Administrativa Desconcentrada (OOAD) Cd Mx Norte, Ciudad de Mexico 07760, Mexico;
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Shoraka S, Hosseinian SM, Hasibi A, Ghaemi A, Mohebbi SR. The role of hepatitis B virus genome variations in HBV-related HCC: effects on host signaling pathways. Front Microbiol 2023; 14:1213145. [PMID: 37588887 PMCID: PMC10426804 DOI: 10.3389/fmicb.2023.1213145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/12/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, with a high prevalence in many regions. There are variations in the etiology of HCC in different regions, but most cases are due to long-term infection with viral hepatitis. Hepatitis B virus (HBV) is responsible for more than 50% of virus-related HCC, which highlights the importance of HBV in pathogenesis of the disease. The development and progression of HBV-related HCC is a complex multistep process that can involve host, viral, and environmental factors. Several studies have suggested that some HBV genome mutations as well as HBV proteins can dysregulate cell signaling pathways involved in the development of HCC. Furthermore, it seems that the pathogenicity, progression of liver diseases, response to treatment and also viral replication are different among HBV mutants. Understanding the relationship between HBV genome variations and host signaling pathway alteration will improve our understanding of the molecular pathogenesis of HBV-related HCC. Furthermore, investigating commonly dysregulated pathways in HBV-related HCC is necessary to discover more specific therapeutic targets and develop more effective strategies for HCC treatment. The objective of this review is to address the role of HBV in the HCC progression and primarily focus on the impacts of HBV genome variations on HCC-related signaling pathways.
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Affiliation(s)
- Shahrzad Shoraka
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Seyed Mahdi Hosseinian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ayda Hasibi
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ghaemi
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Belaiba Z, Ayouni K, Gdoura M, Kammoun Rebai W, Touzi H, Sadraoui A, Hammemi W, Yacoubi L, Abdelati S, Hamzaoui L, Msaddak Azzouz M, Chouikha A, Triki H. Whole genome analysis of hepatitis B virus before and during long-term therapy in chronic infected patients: Molecular characterization, impact on treatment and liver disease progression. Front Microbiol 2022; 13:1020147. [PMID: 36325017 PMCID: PMC9618822 DOI: 10.3389/fmicb.2022.1020147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/15/2022] [Indexed: 07/23/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains a serious public health concern worldwide despite the availability of an efficient vaccine and the major improvements in antiviral treatments. The aim of the present study is to analyze the mutational profile of the HBV whole genome in ETV non-responder chronic HBV patients, in order to investigate antiviral drug resistance, immune escape, and liver disease progression to Liver Cirrhosis (LC) or Hepatocellular Carcinoma (HCC). Blood samples were collected from five chronic hepatitis B patients. For each patient, two plasma samples were collected, before and during the treatment. Whole genome sequencing was performed using Sanger technology. Phylogenetic analysis comparing the studied sequences with reference ones was used for genotyping. The mutational profile was analyzed by comparison with the reference sequence M32138. Genotyping showed that the studied strains belong to subgenotypes D1, D7, and D8. The mutational analysis showed high genetic variability. In the RT region of the polymerase gene, 28 amino acid (aa) mutations were detected. The most significant mutations were the pattern rtL180M + rtS202G + rtM204V, which confer treatment resistance. In the S gene, 35 mutations were detected namely sP120T, sT126S, sG130R, sY134F, sS193L, sI195M, and sL216stop were previously described to lead to vaccine, immunotherapy, and/or diagnosis escape. In the C gene, 34 mutations were found. In particular, cG1764A, cC1766G/T, cT1768A, and cC1773T in the BCP; cG1896A and cG1899A in the precore region and cT12S, cE64D, cA80T, and cP130Q in the core region were associated with disease progression to LC and/or HCC. Other mutations were associated with viral replication increase including cT1753V, cG1764A/T, cC1766G/T, cT1768A, and cC1788G in the BCP as well as cG1896A and cG1899A in the precore region. In the X gene, 30 aa substitutions were detected, of which substitutions xT36D, xP46S, xA47T, xI88F, xA102V, xI127T, xK130M, xV131I, and xF132Y were previously described to lead to LC and/or HCC disease progression. In conclusion, our results show high genetic variability in the long-term treatment of chronic HBV patients causing several effects. This could contribute to guiding national efforts to optimize relevant HBV treatment management in order to achieve the global hepatitis elimination goal by 2030.
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Affiliation(s)
- Zeineb Belaiba
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Kaouther Ayouni
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Mariem Gdoura
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Wafa Kammoun Rebai
- Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Henda Touzi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Amel Sadraoui
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Walid Hammemi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Lamia Yacoubi
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Salwa Abdelati
- Department of Gastroenterology, Polyclinic of CNSS, Sousse, Tunisia
| | - Lamine Hamzaoui
- Department of Gastroenterology, Hospital of Tahar Maamouri, Nabeul, Tunisia
| | | | - Anissa Chouikha
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
| | - Henda Triki
- Laboratory of Clinical Virology, WHO Reference Laboratory for Poliomyelitis and Measles in the Eastern Mediterranean Region, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
- Research Laboratory “Virus, Vectors and Hosts: One Health Approach and Technological Innovation for a Better Health,” LR20IPT02, Pasteur Institute of Tunis, University Tunis El Manar (UTM), Tunis, Tunisia
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Jiang Y, Han Q, Zhao H, Zhang J. The Mechanisms of HBV-Induced Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:435-450. [PMID: 34046368 PMCID: PMC8147889 DOI: 10.2147/jhc.s307962] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy, and the hepatitis B virus (HBV) is its major pathogenic factor. Over the past decades, it has been confirmed that HBV infection could promote disease progression through a variety of mechanisms, ultimately leading to the malignant transformation of liver cells. Many factors have been identified in the pathogenesis of HBV-associated HCC (HBV-HCC), including HBV gene integration, genomic instability caused by mutation, and activation of cancer-promoting signaling pathways. As research in the progression of HBV-HCC progresses, the role of many new mechanisms, such as epigenetics, exosomes, autophagy, metabolic regulation, and immune suppression, is also being continuously explored. The occurrence of HBV-HCC is a complex process caused by interactions across multiple genes and multiple steps, where the synergistic effects of various cancer-promoting mechanisms accelerate the process of disease evolution from inflammation to tumorigenesis. In this review, we aim to provide a brief overview of the mechanisms involved in the occurrence and development of HBV-HCC, which may contribute to a better understanding of the role of HBV in the occurrence and development of HCC.
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Affiliation(s)
- Yu Jiang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China
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Wu JF, Chang KC, Ni YH, Hsu HY, Chang MH. Impacts of the Percentage of Basal Core Promoter Mutation on the Progression of Liver Fibrosis After Hepatitis B e Antigen Seroconversion. J Infect Dis 2020; 223:1381-1389. [PMID: 32860707 DOI: 10.1093/infdis/jiaa545] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 08/23/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND We investigated the relationships among the percentage of hepatitis B virus (HBV) mutations and liver fibrosis after hepatitis B e antigen (HBeAg) seroconversion. METHODS We quantified the percentage of HBV mutants by pyrosequencing using serum samples obtained at inflammatory phase and after HBeAg seroconversion in 160 initially HBeAg-positive chronic HBV-infected patients. The relationships between antiviral agents, percentages of HBV mutations, and liver stiffness measurements (LSMs) were analyzed. RESULTS We demonstrated that the percentages of A1762T/G1764A mutation are significantly higher in subjects with an LSM >7 kPa than in those with an LSM ≤7 kPa after HBeAg seroconversion. Hepatitis B e antigen seroconversion age is positively correlated with the percentages of A1762T/G1764A mutation at inflammatory phase before HBeAg seroconversion. Subjects who underwent interferon, entecavir, or tenofovir disoproxil fumarate therapy before HBeAg seroconversion possessed a lower percentage of A1762T/G1764A mutation after HBeAg seroconversion. The percentage of A1762T/G1764A ≥20% after HBeAg seroconversion was predictive of an LSM >7 kPa (hazard ratio = 6.37, P = .001). The presence of A1762T/G1764A led to downregulated messenger ribonucleic acid and protein levels of programmed-death ligand-1 (PD-L1) in hepatocytes. CONCLUSIONS The percentage of A1762T/G1764A mutations after HBeAg seroconversion was associated with liver fibrosis. The A1762T/G1764A mutation may evoke hepatic inflammation by suppressing PD-L1 in hepatocytes.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chi Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.,Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.,Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
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Ayana DA, Mulu A, Mihret A, Seyoum B, Aseffa A, Howe R. Hepatitis B virus seromarkers among HIV infected adults on ART: An unmet need for HBV screening in eastern Ethiopia. PLoS One 2019; 14:e0226922. [PMID: 31887187 PMCID: PMC6936828 DOI: 10.1371/journal.pone.0226922] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 12/07/2019] [Indexed: 02/08/2023] Open
Abstract
Progression of chronic HBV to cirrhosis, end-stage liver disease (ESLD), and hepatocellular carcinoma (HCC) is more rapid in HIV positive individuals than those with HBV alone; however, the distribution of HBV seromarkers in HIV infected individuals on antiretroviral therapy (ART) is not well described. To address this problem, we assessed the distribution of hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs) among HIV infected adults on ART in Eastern Ethiopia. A cross-sectional study was conducted from September 2017 to February 2018. Socio-demographic, behavioral and health related factors, and clinical data were collected using questionnaire and checklist. Plasma samples were tested for HBsAg, anti-HBc and anti-HBs seromarkers using ELISA. Data were double entered into EpiData 3.1, cleaned, exported to and analyzed using STATA 13. Descriptive and logistic regression analysis were conducted and statistical significance was decided at p≤0.05. A total of 901 participants were included and the prevalence of HBsAg was found to be 11.7% [95%CI (10, 14)]. Among the co-infected, 47.6% were also positive for anti-HBc, of which 58% were on an ART containing tenofovir (TDF). Among those screened for the three seromarkers, 38.1% were negative for all and 21% were positive only for anti-HBc (IAHBc). Being single, history of genital discharge and taking ART with TDF combination were significantly associated with HBV co-infection (p≤0.05). There is high burden HBV co-infection among individuals on ART. The unmet need of HBV screening prior to ART initiation leaves many co-infected individuals without appropriate management including therapy, close monitoring or vaccination when indicated, impacting disease prevention.
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Affiliation(s)
- Desalegn Admassu Ayana
- College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
- * E-mail:
| | - Andargachew Mulu
- College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Adane Mihret
- College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Berhanu Seyoum
- College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Abraham Aseffa
- College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Rawleigh Howe
- College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
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Chen HS, Wu JF, Su TH, Chen HL, Hsu HY, Xia NS, Chen PJ, Chang MH. Baseline Level of Hepatitis B Core Antibody Predicts Spontaneous Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Children With a Normal Alanine Aminotransferase Level. Hepatology 2019; 70:1903-1912. [PMID: 31121067 DOI: 10.1002/hep.30788] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/19/2019] [Indexed: 12/11/2022]
Abstract
It is not clear whether baseline hepatitis B core antibody (anti-HBc) level in hepatitis B e antigen (HBeAg)-positive children with a normal alanine aminotransferase (ALT) level is predictive of spontaneous HBeAg seroconversion. We investigated the correlation between anti-HBc level and the natural course of chronic hepatitis B (CHB) virus (HBV) infection in children, particularly the ability of baseline anti-HBc level to predict spontaneous HBeAg seroconversion during long-term follow-up. HBeAg-positive children with untreated CHB and a normal ALT level were followed longitudinally. Anti-HBc level was determined by double-sandwich immunoassay. Effects of anti-HBc levels and other parameters on spontaneous HBeAg seroconversion and the natural course of CHB were assessed. A total of 182 children (106 males) with a median age at enrollment of 10.6 years (interquartile range [IQR], 10.3-15.3) were followed for a median of 19.8 years (IQR, 11.9-21.9). Spontaneous HBeAg seroconversion occurred in 85 children (46.7%) during the follow-up. A baseline anti-HBc titer of >500 IU/mL (hazard ratio [HR] = 2.81), HBV genotype B and B + C (HR = 3.46), and a baseline hepatitis B surface antigen titer of ≤4.8 log10 IU/mL (HR = 3.09) were predictive of spontaneous HBeAg seroconversion, based on multivariable survival analysis (P < 0.001). In cases remaining HBeAg positive, their anti-HBc levels increased gradually during follow-up because of ongoing inflammation. Conclusion: Baseline anti-HBc level is predictive of spontaneous HBeAg seroconversion in HBeAg-positive children with a normal ALT level. Anti-HBc level reflects anti-HBV immune response in the HBeAg-positive normal ALT phase of CHB.
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Affiliation(s)
- Ho-Sheng Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Ning-Shao Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
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9
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Ségéral O, N'Diaye DS, Prak S, Nouhin J, Chhun S, Khamduang W, Chim K, Roque-Afonso AM, Piola P, Borand L, Ngo-Giang-Huong N, Rouet F. Usefulness of a serial algorithm of HBsAg and HBeAg rapid diagnosis tests to detect pregnant women at risk of HBV mother-to-child transmission in Cambodia, the ANRS 12328 pilot study. J Clin Virol 2018; 109:29-34. [PMID: 30388664 DOI: 10.1016/j.jcv.2018.10.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 10/15/2018] [Accepted: 10/18/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND In Cambodia, access to hepatitis B surface antigen (HBsAg) screening is low for pregnant women and Hepatitis B Virus (HBV) DNA quantification is poorly accessible. OBJECTIVES To evaluate the performance of a serial algorithm using two HBV rapid diagnostic tests (RDTs), in which samples positive for HBsAg were further tested for HBeAg as a surrogate marker for HBV DNA quantification. STUDY DESIGN In 2015, we prospectively collected plasma samples from 250 pregnant women consulting for antenatal care in one hospital in Phnom Penh including 128 with a known positive HBsAg status. All specimens were tested with the SD BIOLINE HBsAg RDT and HBsAg ELISA assay. In ELISA-positive samples, HBeAg status was determined using the SD BIOLINE HBeAg RDT and HBV DNA quantification was assessed. RESULTS Sensitivity and specificity of HBsAg RDT were 99.2% (97.7-99.9) and 100% (97.0-100), respectively. Among the 128 ELISA-positive samples, 29 (23%) tested HBeAg positive and 34 (26.5%) had HBV DNA > 5.3 Log10 IU/mL. Sensitivity and specificity of HBeAg RDT in identifying viremic samples were 76.5% (62.2.0-90.7) and 96.8% (93.3-100) for HBV DNA > 5.3 Log10 IU/mL and 89.3% (77.8-100) and 96.0% (92.2-99.8) for HBV DNA > 7.3 Log10IU/mL. Among the 99 negative HBeAg RDT women, 8 had HBV DNA > 5.3 Log10 IU/mL and 7 of them harbored BCP/PC HBV mutants. CONCLUSIONS A combination of HBsAg and HBeAg RDTs could be a low-cost strategy to identify HBV-infected pregnant women at risk of perinatal transmission in a country were HBV DNA quantification is not routinely available.
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Affiliation(s)
| | - Dieynaba S N'Diaye
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Sophearot Prak
- Virology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Janin Nouhin
- Virology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | | | - Wootichai Khamduang
- Faculty of Associated Medical Sciences, Institut de Recherche pour le Développement (IRD), UMI 174/Programs for HIV Prevention and Treatment (PHPT), Chiang Mai, Thailand
| | - Kenrena Chim
- Maternity Department, Hôpital Calmette, Phnom Penh, Cambodia
| | | | - Patrice Piola
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Laurence Borand
- Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
| | - Nicole Ngo-Giang-Huong
- Faculty of Associated Medical Sciences, Institut de Recherche pour le Développement (IRD), UMI 174/Programs for HIV Prevention and Treatment (PHPT), Chiang Mai, Thailand
| | - François Rouet
- Virology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia
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10
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Romani S, Hosseini SM, Mohebbi SR, Boonstra A, Sharifian A. Differential expression of innate immune response genes in clinical phases of chronic hepatitis B infection. J Viral Hepat 2017; 24:776-788. [PMID: 28218976 DOI: 10.1111/jvh.12699] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 02/01/2017] [Indexed: 12/16/2022]
Abstract
We investigated innate immune gene expression in clinical phases of chronic hepatitis B infection, including immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B e antigen (HBeAg)-negative phases, as well as healthy controls. Expression levels of interferon types I, II and III, their receptor subunits, IRFs, TLRs and other IFN-induced genes in peripheral blood mononuclear cells were compared. Forty HBsAg-positive treatment-naïve subjects without co-infection with HIV, HCV or HDV were enrolled. To complement the viral load, the expression levels of 37 innate immune genes were measured by qPCR. The highest response of the innate immune system was observed in the IT and HBeAg-negative phases, and the IC phase had the lowest response; 31 of the 37 studied genes reached their maximum mRNA expression levels in the IT and HBeAg-negative phases, and the minimum expression levels of 23 genes were found in the IC phase. The highest mRNA expression levels of IFNs, IFN receptor subunits, IRFs and TLRs genes in all clinical phases were IFN-λ2 and 3, IFN-γR2, IRF7 and TLR7, and the lowest levels of mRNA expression were observed for IFN-α, IFN-λR1, IRF8 and TLR2. We conclude that innate immune response genes are expressed differentially among chronic HBV phases, and this difference may help to develop new precise and noninvasive methods to determine the progression of disease in chronic HBV patients.
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Affiliation(s)
- S Romani
- Department of Microbiology, Faculty of Biological Sciences, Shahid Beheshti University, Tehran, Iran
| | - S M Hosseini
- Department of Microbiology, Faculty of Biological Sciences, Shahid Beheshti University, Tehran, Iran
| | - S R Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - A Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - A Sharifian
- Basic and Molecular Epidemiology of gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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11
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Wang J, Zhang H, Zhang Y, Jiang D, Li J, Goldmann S, Ren Q, Fei R, Wang X, Wei L. Influences on viral replication and sensitivity to GLS4, a HAP compound, of naturally occurring T109/V124 mutations in hepatitis B virus core protein. J Med Virol 2017; 89:1804-1810. [PMID: 28401569 DOI: 10.1002/jmv.24830] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 04/05/2017] [Indexed: 01/14/2023]
Abstract
Heteroaryldihydropyrimidine (HAP) compounds inhibit HBV replication by binding to a hydrophobic pocket at the interface between hepatitis B virus core protein (HBcAg) dimer, which interrupts capsid assembly by changing the kinetics and thermodynamics during this process. Structure biological studies have identified several amino acids in HBcAg crucial for compound binding. Here, we investigated the polymorphisms of T109 and V124 amino acids in HBV sequences submitted to GenBank database. Naturally occurring T109 and V124 and/or possible compensatory mutations in neighbored amino acids were introduced into HBV-expressing plasmids. Viral replication competence and sensitivity to GLS4, a HAP compound, were evaluated using transient transfection and in vitro infection cell models. All tested mutations in these amino acids led to decreasing viral DNA replication at different levels. Specially, T109N and all V124 mutants caused severe deficiencies in viral plus-strand DNA synthesis. T109I single mutation and all T109S/M/C/N mutations impaired HBeAg secretion. T109I showed modestly decreased sensitivities with IC50 3.3- to 6.8-folds higher than wild-type virus. In vitro infection assay showed T109N and all V124 mutants failed to synthesize cccDNA and following viral proteins. The other mutants, however, produced functional cccDNA pools as wild-type virus did. Taken together, we profiled the competences of viral replication and sensitivities to capsid inhibitor of naturally existing mutations in T109 and V124. This will help to understand the possible antiviral resistance issues in future clinical applications of capsid inhibitors.
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Affiliation(s)
- Jianghua Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing, China
| | - Haiying Zhang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing, China
| | - Yingjun Zhang
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd., Dong Guan, China
| | - Dong Jiang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jing Li
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd., Dong Guan, China
| | - Siegfried Goldmann
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd., Dong Guan, China
| | - Qingyun Ren
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd., Dong Guan, China
| | - Ran Fei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing, China
| | - Xueyan Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing, China
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12
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Hosseini SY, Baesi K, Azarpira N, Pakneiat A, Hosseini SA. The evaluation of fibrotic effects of the hepatitis B virus pre-core in hepatic stellate cells. Biomed Rep 2017; 6:671-674. [PMID: 28584639 DOI: 10.3892/br.2017.894] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 03/15/2017] [Indexed: 12/18/2022] Open
Abstract
The role of the hepatitis B virus (HBV) endogenous pre-core protein in liver fibrosis is controversial. Whether the expression of the pre-core induces the activation of human stellate cells (HSCs) has not yet been reported. Plasmids expressing HBx, or pre-core protein were transfected into LX-2 cells. Subsequently, total RNA extracted and reverse transcription-quantitative polymerase chain reaction was performed to measure the fold change of collagen type I, α1 chain, α-smooth muscle actin and TIMP metalloproteinase inhibitor-1. Moreover, transforming growth factor (TGF)-β in the supernatant of HSCs was evaluated by ELISA assay. In addition, a MTT assay was performed to test the cytotoxicity of the endogenous expression in LX-2 cells. None of the plasmids exhibited cytotoxic nor significant proliferative effects on LX-2 cells by MTT assessment. The gene expression analysis of fibrotic genes in LX-2 cells demonstrated that the pre-core protein presented no significant (P>0.05) fibrotic impact when compared to the empty control plasmid and HBx. The data from the TGF-β ELISA was consistent with the mRNA expression as detected with the control plasmid (P>0.05). The endogenous expression of the HBV pre-core exhibited no fibrotic impression in HSCs when compared to HBx.
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Affiliation(s)
- Seyed Younes Hosseini
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran.,Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran
| | - Kazem Baesi
- Hepatitis and AIDS Department, Pasteur institute of Iran, Tehran 13169-43551, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 14336-71348, Iran
| | - Ameneh Pakneiat
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran
| | - Seyedeh Akram Hosseini
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran
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13
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Soleimani F, Arabzadeh SAM, Mollaei H, Iranmanesh Z, Nikpour N, Motahar M. Evaluation of the frequency of precore/core mutation in patients with chronic hepatitis B, Kerman, Southeast of Iran. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(16)61093-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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14
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Kim H, Lee SA, Do SY, Kim BJ. Precore/core region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:4287-4296. [PMID: 27158197 PMCID: PMC4853686 DOI: 10.3748/wjg.v22.i17.4287] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients.
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15
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Wu JF, Chang MH. Natural history of chronic hepatitis B virus infection from infancy to adult life - the mechanism of inflammation triggering and long-term impacts. J Biomed Sci 2015; 22:92. [PMID: 26487087 PMCID: PMC4618235 DOI: 10.1186/s12929-015-0199-y] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward. The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course. Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.
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Affiliation(s)
- Jia-Feng Wu
- Departments of Pediatrics, National Taiwan University Children's Hospital, No. 8, Chung-Shan S. Rd., Taipei, Taiwan
| | - Mei-Hwei Chang
- Departments of Pediatrics, National Taiwan University Children's Hospital, No. 8, Chung-Shan S. Rd., Taipei, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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16
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Hou W, Fang C, Liu J, Yu H, Qi J, Zhang Z, Yuan R, Xiong D, Gao S, Adam Yuan Y, Li S, Gu Y, Xia N. Molecular insights into the inhibition of HIV-1 infection using a CD4 domain-1-specific monoclonal antibody. Antiviral Res 2015; 122:101-111. [PMID: 26259811 DOI: 10.1016/j.antiviral.2015.08.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 08/01/2015] [Accepted: 08/07/2015] [Indexed: 12/19/2022]
Abstract
An HIV-1 infection in a host cell occurs through an ordered process that involves HIV-1 attachment to the host's cellular CD4 receptor, co-receptor binding to CCR5 or CXCR4, and the subsequent fusion with the cellular membrane. The natural viral entry pathway into a host cell provides an opportunity to develop agents for the treatment of HIV-1 infections. Several engineered monoclonal antibodies specifically targeting CD4 have shown antiviral activities in clinical trials. Here, we report on an anti-CD4 mAb (15A7) that displays a unique binding specificity for domain 1 of CD4, whose epitope partially overlaps with the gp120 binding region. Moreover, 15A7 displays a much stronger binding affinity to CD4(+) cell lines after HIV infection. 15A7 is able to block and neutralize a broad range of primary HIV-1 isolates and T cell-line passage strains. Notably, the bivalent F(ab')2 form of 15A7 is more effective than the Fab form in blocking HIV-1 infection, which is further supported by molecular docking analyses. Together, these results suggest that this novel antibody may exert its antiviral activity by blocking gp120 targeting to the CD4 receptor or competing with gp120 for CD4 receptor binding and might present post-attachment neutralization activity. This antibody could provide a new candidate to efficiently block HIV-1 infection or provide new starting materials for HIV treatment, especially when HIV-1-resistant strains against the current CD4 mAb treatments have already been identified.
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Affiliation(s)
- Wangheng Hou
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | - Chu Fang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | - Jiayan Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | - Hai Yu
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China
| | - Jialong Qi
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China
| | - Zhiqing Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | - Ruixue Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | - Dan Xiong
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China
| | - Shuangquan Gao
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China
| | - Y Adam Yuan
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China; National University of Singapore (Suzhou) Research Institute, Suzhou 215123, China
| | - Shaowei Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China; National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China
| | - Ying Gu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China; National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China.
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen 361005, China; National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University, Xiamen 361005, China
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17
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Yousif M, Bell TG, Mudawi H, Glebe D, Kramvis A. Analysis of ultra-deep pyrosequencing and cloning based sequencing of the basic core promoter/precore/core region of hepatitis B virus using newly developed bioinformatics tools. PLoS One 2014; 9:e95377. [PMID: 24740330 PMCID: PMC3989311 DOI: 10.1371/journal.pone.0095377] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Accepted: 03/26/2014] [Indexed: 12/18/2022] Open
Abstract
Aims The aims of this study were to develop bioinformatics tools to explore ultra-deep pyrosequencing (UDPS) data, to test these tools, and to use them to determine the optimum error threshold, and to compare results from UDPS and cloning based sequencing (CBS). Methods Four serum samples, infected with either genotype D or E, from HBeAg-positive and HBeAg-negative patients were randomly selected. UDPS and CBS were used to sequence the basic core promoter/precore region of HBV. Two online bioinformatics tools, the “Deep Threshold Tool” and the “Rosetta Tool” (http://hvdr.bioinf.wits.ac.za/tools/), were built to test and analyze the generated data. Results A total of 10952 reads were generated by UDPS on the 454 GS Junior platform. In the four samples, substitutions, detected at 0.5% threshold or above, were identified at 39 unique positions, 25 of which were non-synonymous mutations. Sample #2 (HBeAg-negative, genotype D) had substitutions in 26 positions, followed by sample #1 (HBeAg-negative, genotype E) in 12 positions, sample #3 (HBeAg-positive, genotype D) in 7 positions and sample #4 (HBeAg-positive, genotype E) in only four positions. The ratio of nucleotide substitutions between isolates from HBeAg-negative and HBeAg-positive patients was 3.5∶1. Compared to genotype E isolates, genotype D isolates showed greater variation in the X, basic core promoter/precore and core regions. Only 18 of the 39 positions identified by UDPS were detected by CBS, which detected 14 of the 25 non-synonymous mutations detected by UDPS. Conclusion UDPS data should be approached with caution. Appropriate curation of read data is required prior to analysis, in order to clean the data and eliminate artefacts. CBS detected fewer than 50% of the substitutions detected by UDPS. Furthermore it is important that the appropriate consensus (reference) sequence is used in order to identify variants correctly.
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Affiliation(s)
- Mukhlid Yousif
- Hepatitis Virus Diversity Research Programme, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Trevor G. Bell
- Hepatitis Virus Diversity Research Programme, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Hatim Mudawi
- Department of Medicine, Faculty of Medicine, University of Khartoum, Khartoum, Khartoum State, Sudan
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre of Hepatitis B and D, Justus, Liebig-University of Giessen, Giessen, Hesse, Germany
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Programme, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
- * E-mail:
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