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Qiu Y, Tang Q, Liu XQ, Xue YL, Zeng Y, Hu P. Hepatitis B core-related antigen as a promising serological marker for monitoring hepatitis B virus cure. World J Hepatol 2025; 17:98658. [PMID: 39871916 PMCID: PMC11736480 DOI: 10.4254/wjh.v17.i1.98658] [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: 07/02/2024] [Revised: 11/25/2024] [Accepted: 12/13/2024] [Indexed: 01/06/2025] Open
Abstract
Hepatitis B virus (HBV) infection is a global health concern. The current sequential endpoints for the treatment of HBV infection include viral suppression, hepatitis B e antigen (HBeAg) seroconversion, functional cure, and covalently closed circular DNA (cccDNA) clearance. Serum hepatitis B core-related antigen (HBcrAg) is an emerging HBV marker comprising three components: HBeAg, hepatitis B core antigen, and p22cr. It responds well to the transcriptional activity of cccDNA in the patient's liver and is a promising alternative marker for serological testing. There is a strong correlation, and a decrease in its level corresponds to sustained viral suppression. In patients with chronic hepatitis B (CHB), serum HBcrAg levels are good predictors of HBeAg seroconversion (both spontaneous and after antiviral therapy), particularly in HBeAg-positive patients. Both low baseline HBcrAg levels and decreasing levels early in antiviral therapy favored HBsAg seroconversion, which may serve as a good surrogate option for treatment endpoints. In this review, we summarize the role of serum HBcrAg in the treatment of CHB. Therefore, long-term continuous monitoring of serum HBcrAg levels contributes to the clinical management of patients with CHB and optimizes the choice of treatment regimen, making it a promising marker for monitoring HBV cure.
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Affiliation(s)
- Yue Qiu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Qiao Tang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Xiao-Qing Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Yun-Ling Xue
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Yi Zeng
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Peng Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
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Causse X, Potier P, Valéry A, Labadie H, Macaigne G, Cadranel J, Fontanges T, Mouna L, Roque‐Afonso A. Predictive Factors for HBsAg Loss in Chronic HBeAg-Negative Hepatitis B Virus Infection: Insights From a 5-Year French Cohort. J Viral Hepat 2025; 32:e14041. [PMID: 39673688 PMCID: PMC11646079 DOI: 10.1111/jvh.14041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/20/2024] [Accepted: 11/23/2024] [Indexed: 12/16/2024]
Abstract
Prognostic factors for the long-term evolution of chronic hepatitis B e antigen (HBeAg)-negative hepatitis B virus (HBV) infection may vary depending on local epidemiology. We aimed to identify these factors in France, where the epidemiology is influenced by diverse immigration. Hepatitis B surface antigen (HBsAg)-positive, HBeAg-negative adults with normal transaminase levels and viral loads < 20,000 IU/mL for 1 year, without viral co-infection or advanced liver disease, were enrolled for a 5-year follow-up. A total of 564 patients were recruited from 23 centres (54.4% women, mean age 42.3 ± 12 years, 47.7% from sub-Saharan Africa). HBV DNA was detectable but < 2000 IU/mL for most (71.3%). Genotypes E (27.8%) and A (20.0%) were predominant. The mean HBsAg titre was 3.8 ± 3.4 log IU/mL, > 1000 IU/mL in 60% of cases, and higher in genotype E (p < 0.0001). During follow-up, 18 patients received antiviral treatment, 9 for viral reactivation (0.3% per year) and 9 preemptively. HBsAg loss occurred in 39 patients (1.4% per year). These patients were older (p < 0.0001), more frequently treated for dyslipidemia, hypertension or diabetes (p < 0.05), and had lower baseline HBV DNA (p = 0.0112) and HBsAg (p < 0.0001), but similar levels of HBcrAg compared to those who did not clear HBsAg. Baseline HBsAg was the only independent predictor of HBsAg loss (p = 0.009). In this cohort, HBsAg < 153 IU/mL predicted clearance with 87% sensitivity and specificity. In conclusion, baseline HBsAg accurately predicted seroclearance at 5 years in patients with chronic HBeAg-negative infection, regardless of genotype, sex, or geographical origin, indicating that this marker is widely applicable for reducing the frequency of patient monitoring.
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Affiliation(s)
- Xavier Causse
- Service d'Hépato‐Gastroentérologie et d'Oncologie DigestiveCentre Hospitalier Universitaire d'OrléansOrléansFrance
| | - Pascal Potier
- Service d'Hépato‐Gastroentérologie et d'Oncologie DigestiveCentre Hospitalier Universitaire d'OrléansOrléansFrance
- Département d'Information MédicaleCentre Hospitalier Universitaire d'OrléansOrléansFrance
| | - Antoine Valéry
- Département d'Information MédicaleCentre Hospitalier Universitaire d'OrléansOrléansFrance
| | - Hélène Labadie
- Service d'Hépato‐GastroentérologieCentre Hospitalier de Saint DenisSaint DenisFrance
| | - Gilles Macaigne
- Groupe Hospitalier Intercommunal Le Raincy‐MontfermeilService d'Hépato‐GastroentérologieLe Raincy MontfermeilFrance
| | | | | | - Lina Mouna
- Inserm U1193, Assistance Publique‐Hôpitaux de Paris, Hôpital Paul Brousse, Service de VirologieUniversité Paris‐SaclayVillejuifFrance
| | - Anne‐Marie Roque‐Afonso
- Inserm U1193, Assistance Publique‐Hôpitaux de Paris, Hôpital Paul Brousse, Service de VirologieUniversité Paris‐SaclayVillejuifFrance
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Sandmann L, Bremer B, Ohlendorf V, Jaroszewicz J, Wedemeyer H, Cornberg M, Maasoumy B. Kinetics and Value of Hepatitis B Core-Related Antigen in Patients with Chronic Hepatitis B Virus Infection during Antiviral Treatment. Viruses 2024; 16:255. [PMID: 38400031 PMCID: PMC10891644 DOI: 10.3390/v16020255] [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: 12/11/2023] [Revised: 02/02/2024] [Accepted: 02/03/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND The hepatitis B core-related antigen (HBcrAg) correlates with HBV DNA in patients with chronic HBV infection without antiviral treatment. Its utility in monitoring patients during and after the cessation of nucleos(t)ide analog (NA) treatment is unknown. METHODS The levels of HBcrAg were longitudinally determined in two cohorts of chronic HBV-infected patients with (A) newly started NA treatment or (B) after NA cessation during a median follow up (FU) of 60 months or 48 weeks, respectively. The correlation of HBcrAg and HBV DNA and the predictive value for HBeAg seroconversion and HBsAg loss were evaluated. RESULTS Fifty-six patients with newly-started NA treatment and 22 patients with NA cessation were identified. HBcrAg and HBV DNA strongly correlated before NA treatment (r = 0.77, p < 0.0001) and at virological relapse (0.66, p = 0.0063). At the individual level, the discrepant kinetics of HBcrAg and HBV DNA became evident. During NA treatment, 33% (6/18) and 9% (5/56) of patients showed HBeAg seroconversion or HBsAg loss/HBsAg < 100 IU/mL, respectively. Low levels of HBcrAg were associated with these endpoints. CONCLUSION HBcrAg levels before antiviral treatment help to identify patients with chances of HBsAg loss or HBeAg seroconversion. However, its utility in replacing quantitative HBV DNA to evaluate treatment efficacy or virological relapse off-treatment is limited.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, 30625 Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
| | - Valerie Ohlendorf
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University in Katowice, 40635 Katowice, Poland
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 30625 Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 30625 Hannover, Germany
- Centre for Individualised Infection Medicine, Helmholtz Centre for Infection Research/Hannover Medical School, 30625 Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 30625 Hannover, Germany
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Ghany MG, King WC, Hinerman AS, Lok ASF, Lisker-Melman M, Chung RT, Terrault N, Janssen HL, Khalili M, Lee WM, Lau DT, Cloherty GA, Sterling RK. Use of HBV RNA and to predict change in serological status and disease activity in CHB. Hepatology 2023; 78:1542-1557. [PMID: 37074026 PMCID: PMC11165989 DOI: 10.1097/hep.0000000000000413] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 03/28/2023] [Indexed: 04/20/2023]
Abstract
BACKGROUND AND AIMS Predicting changes in disease activity and serological endpoints is necessary for the management of patients with chronic hepatitis B (CHB). We examined whether HBV RNA and hepatitis B core-related antigen (HBcrAg), two specialized virological markers proposed to reflect the activity of covalently closed circular DNA, may improve the ability to predict not sustained inactive carrier phase, spontaneous alanine aminotransferase (ALT) flare, HBeAg loss, and HBsAg loss. APPROACH AND RESULTS Among eligible participants enrolled in the North American Hepatitis B Research Network Adult Cohort Study, we evaluated demographic, clinical, and virologic characteristics, including HBV RNA and HBcrAg, to predict not sustained inactive carrier phase, ALT flare, HBeAg loss, and HBsAg loss through a series of Cox proportional hazard or logistic regression models, controlling for antiviral therapy use. Among the study population, 54/103 participants experienced not sustained inactive carrier phase, 41/1006 had a spontaneous ALT flare, 83/250 lost HBeAg, and 54/1127 lost HBsAg. HBV RNA or HBcrAg were predictive of all 4 events. However, their addition to models of the readily available host (age, sex, race/ethnicity), clinical (ALT, use of antiviral therapy), and viral factors (HBV DNA), which had acceptable-excellent accuracy (e.g., AUC = 0.72 for ALT flare, 0.92 for HBeAg loss, and 0.91 for HBsAg loss), provided only small improvements in predictive ability. CONCLUSION Given the high predictive ability of readily available markers, HBcrAg and HBV RNA have a limited role in improving the prediction of key serologic and clinical events in patients with CHB.
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Affiliation(s)
- Marc G. Ghany
- Liver Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
| | - Wendy C. King
- Graduate School of Public Health University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Amanda S. Hinerman
- Department of Epidemiology, Graduate School of Public Health University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anna SF. Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Mauricio Lisker-Melman
- Washington University School of Medicine and John Cochran VA Medical Center, St. Louis, Missouri, USA
| | | | - Norah Terrault
- Division of Gastrointestinal and Liver Diseases, Keck Medicine of University of Southern California, Los Angeles, California, USA
| | - Harry L.A. Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Mandana Khalili
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - William M. Lee
- Meredith Mosle Chair in Liver Disease, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daryl T.Y. Lau
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Gavin A. Cloherty
- Head of Infectious Disease Research, Abbott Diagnostics, Abbott Park, Illinois, USA
| | - Richard K. Sterling
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
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Roade L, Riveiro-Barciela M, Pfefferkorn M, Sopena S, Palom A, Bes M, Rando-Segura A, Casillas R, Tabernero D, Rodríguez-Frías F, Berg T, Esteban R, van Bömmel F, Buti M. HBsAg protein composition and clinical outcomes in chronic hepatitis D and variations across HBeAg-negative chronic HBsAg carriers. JHEP Rep 2023; 5:100842. [PMID: 37745192 PMCID: PMC10514556 DOI: 10.1016/j.jhepr.2023.100842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/25/2023] [Accepted: 06/24/2023] [Indexed: 09/26/2023] Open
Abstract
BACKGROUND & AIMS HBsAg proteins are useful to identify HBV inactive carriers (ICs), but data on chronic hepatitis D (CHD) are scarce. This study aimed to describe HBsAg composition in CHD, its changes during the evolution, and the potential association with clinical outcomes. In addition, we assess the composition of HBsAg across different HBV genotypes and validate previous results on HBsAg proteins in an independent HBV cohort. METHODS Quantitative HBsAg, medium HBsAg proteins (MHBs), and large HBsAg proteins (LHBs) were measured in two cohorts. The first cohort consisted of patients with CHD. A cross-sectional study of samples from two European institutions (N = 46) was conducted. Outcomes were assessed in a retrospective-prospective study of those patients with a follow-up of >1 year (n = 36), and the longitudinal evolution of HBsAg proteins in those with samples >5 years apart (n = 12) was analysed. The second cohort consisted of patients with HBeAg-negative HBV, and a cross-sectional study was performed (N = 141). RESULTS Forty-one (89%) patients with CHD had detectable HDV-RNA, and the presence of HDV-RNA was associated with higher LHBs proportion (p = 0.010). Baseline MHBs (p = 0.051) and MHBs proportion (p = 0.086) tended to be higher in those developing clinical outcomes (9/36, 25%) after a median follow-up of 5.9 years. Patients in which HDV-RNA became spontaneously undetectable during follow-up (5/31, 16.1%) tended to present lower MHBs proportion (p = 0.085). In the longitudinal study, changes in LHBs proportion were observed (p = 0.041), whereas MHBs proportion remained stable (p = 0.209). Regarding HBV, ICs showed lower LHBs proportion (p = 0.027). LHBs and MHBs differed significantly according to HBV genotype, regardless of the HBV phase. CONCLUSIONS Patients with CHD with detectable HDV-RNA presented higher LHBs proportion than those with undetectable HDV-RNA. A trend toward having higher baseline MHBs proportion was observed in patients who developed clinical outcomes or remained with detectable HDV-RNA. This study validates the different HBsAg composition in HBV ICs and reveals the HBV-genotype influence in HBsAg composition. IMPACT AND IMPLICATIONS The composition of HBsAg in chronic hepatitis D differs in patients with detectable and undetectable HDV viral load and may help predict the likelihood of achieving undetectable HDV viraemia and the development of clinical events such as decompensation. The composition of the surface antigen is also useful to distinguish inactive carriers of HBV, and it varies according to HBV genotype.
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Affiliation(s)
- Luisa Roade
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Mar Riveiro-Barciela
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Pfefferkorn
- Division of Hepatology, Department of Medicine, Leipzig University Medical Center, Leipzig, Germany
| | - Sara Sopena
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Adriana Palom
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Bes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - Ariadna Rando-Segura
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Rosario Casillas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - David Tabernero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
- Liver Diseases-Viral Hepatitis, Liver Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
- Liver Diseases-Viral Hepatitis, Liver Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Thomas Berg
- Division of Hepatology, Department of Medicine, Leipzig University Medical Center, Leipzig, Germany
| | - Rafael Esteban
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine, Leipzig University Medical Center, Leipzig, Germany
| | - María Buti
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Sant'Anna TB, Araujo NM. Hepatitis B Virus Genotype D: An Overview of Molecular Epidemiology, Evolutionary History, and Clinical Characteristics. Microorganisms 2023; 11:1101. [PMID: 37317074 PMCID: PMC10221421 DOI: 10.3390/microorganisms11051101] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 06/16/2023] Open
Abstract
The hepatitis B virus (HBV) genotype D (HBV/D) is the most extensively distributed genotype worldwide with distinct molecular and epidemiological features. This report provides an up-to-date review on the history of HBV/D subgenotyping and misclassifications, along with large-scale analysis of over 1000 HBV/D complete genome sequences, with the aim of gaining a thorough understanding of the global prevalence and geographic distribution of HBV/D subgenotypes. We have additionally explored recent paleogenomic findings, which facilitated the detection of HBV/D genomes dating back to the late Iron Age and provided new perspectives on the origins of modern HBV/D strains. Finally, reports on distinct disease outcomes and responses to antiviral therapy among HBV/D subgenotypes are discussed, further highlighting the complexity of this genotype and the importance of HBV subgenotyping in the management and treatment of hepatitis B.
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Affiliation(s)
- Thaís B Sant'Anna
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21041-250, RJ, Brazil
| | - Natalia M Araujo
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21041-250, RJ, Brazil
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Adraneda C, Tan YC, Yeo EJ, Kew GS, Khakpoor A, Lim SG. A critique and systematic review of the clinical utility of hepatitis B core-related antigen. J Hepatol 2023; 78:731-741. [PMID: 36586590 DOI: 10.1016/j.jhep.2022.12.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 12/03/2022] [Accepted: 12/14/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Hepatitis B core-related antigen (HBcrAg) is a new biomarker for chronic hepatitis B (CHB) whose performance has not been critically or systematically appraised. Herein, we performed a systematic review to determine its clinical utility. METHODS We evaluated the biological pathway of HBcrAg and performed a systematic review of PubMed for clinical trials, cohort studies, and case-control studies that evaluated the clinical utility of HBcrAg. The effectiveness of HBcrAg in predicting HBV-specific clinical events (e.g. HBeAg seroconversion, phases of CHB, HBsAg loss, treatment response, and relapse after stopping therapy) was examined using receiver-operating characteristic curves. The correlation coefficients of HBcrAg with HBV DNA, quantitative HBsAg (qHBsAg), HBV RNA, and cccDNA were summarised from published studies. Median values were used as estimates. RESULTS HBcrAg consists of three precore/core protein products: HBcAg, HBeAg, and a 22 kDa precore protein. HBcrAg assays have been associated with false-positive rates of 9.3% and false-negative rates of between 12-35% for CHB. The new iTACT-HBcrAg is more sensitive but does not reduce the false-positive rate. A PubMed search found 248 papers on HBcrAg, of which 59 were suitable for analysis. The clinical performance of HBcrAg was evaluated using AUROC analyses, with median AUROCs of 0.860 for HBeAg seroconversion, 0.867 for predicting HBeAg(-) hepatitis, 0.645 for HBsAg loss, 0.757 for treatment response, and 0.688 for relapse after stopping therapy. The median correlation coefficient (r) was 0.630 with HBV DNA, 0.414 with qHBsAg, 0.619 with HBV RNA and 0.550 with cccDNA. Correlation decreased during antiviral therapy, but combined biomarkers improved performance. CONCLUSIONS HBcrAg has a mixed performance and has a poor correlation with HBsAg loss and antiviral therapy, hence HBcrAg results should be interpreted with caution. IMPACT AND IMPLICATIONS Hepatitis B core-related antigen (HBcrAg) has been used to assess management of patients with chronic hepatitis B (CHB) without a systematic and critical Sreview of its performance. Our finding that HBcrAg had a false-positive rate of 9% and a false-negative rate of 12-35% raises concerns, although larger studies are needed for validation. A systematic review showed that the performance of HBcrAg was variable depending on the CHB endpoint; it was excellent at predicting HBeAg seroconversion and HBeAg-negative chronic hepatitis (vs. chronic infection), which should be its main use, but it was poor for relapse after stopping antiviral therapy and for HBsAg loss. HBcrAg results should be interpreted with considerable caution, particularly by physicians, researchers, guideline committees and agencies that approve diagnostic tests.
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Affiliation(s)
| | - Yong Chuan Tan
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ee Jin Yeo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Guan Sen Kew
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Atefeh Khakpoor
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore.
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8
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Inoue T, Tanaka Y. Noninvasive assessments of liver disease severity based on biomarkers. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:31-60. [DOI: 10.1016/b978-0-323-98368-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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9
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Roade L, Riveiro-Barciela M, Palom A, Rodríguez-Frías F, Bes M, Rando A, Salcedo MT, Casillas R, Vargas-Accarino E, Tabernero D, Sauleda S, Esteban R, Buti M. ACE Score Identifies HBeAg-negative Inactive Carriers at a Single-point Evaluation, Regardless of HBV Genotype. J Clin Transl Hepatol 2022; 10:1068-1076. [PMID: 36381089 PMCID: PMC9634781 DOI: 10.14218/jcth.2022.00068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) biomarkers have been used for a better categorization of patients, even though the lack of simple algorithms and the impact of genotypes limit their application. Our aim was to assess the usefulness of noninvasive markers for the identification of HBV inactive carriers (ICs) in a single-point evaluation and to design a predictive model for their identification. METHODS This retrospective-prospective study included 343 consecutive HBeAg-negative individuals. Clinical, analytical, and virological data were collected, and a liver biopsy was performed if needed. Subjects were classified at the end of follow-up as ICs, chronic hepatitis B and gray zone.A predictive model was constructed, and validated by 1000-bootstrap samples. RESULTS After 39 months of follow-up, 298 subjects were ICs, 36 were chronic hepatitis B CHB, and nine were gray zone. Eighty-nine (25.9%) individuals required a liver biopsy. Baseline HBV DNA hazard ratio (HR) 6.0, p<0.001), HBV core-related antigen (HBcrAg) (HR 6.5, p<0.001), and elastography (HR 4.6, p<0.001) were independently associated with the IC stage. The ACE score (HBV DNA, HBcrAg, elastography), obtained by bootstrapping, yielded an area under the receiver operating characteristics (AUROC) of 0.925 (95% CI: 0.880-0.970, p<0.001) for identification of ICs. The AUROC for genotype D was 0.95, 0.96 for A, 0.90 for E, and 0.88 for H/F. An ACE score of <1 had a positive predictive value of 99.5%, and a score ≤12 points had a diagnostic accuracy of 93.8%. CONCLUSIONS Low baseline HBV DNA, HBcrAg, and liver stiffness were independently associated with the IC phase. A score including those variables identified ICs at a single-point evaluation, and might be applied to implement less intensive follow-up strategies.
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Affiliation(s)
- Luisa Roade
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
| | - Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
| | - Adriana Palom
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Rodríguez-Frías
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Marta Bes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institut de Recerca (VHIR), Liver Diseases Group, Barcelona, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - Ariadna Rando
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - María Teresa Salcedo
- Department of Pathology, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rosario Casillas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Elena Vargas-Accarino
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
- Vall d’Hebron Institut de Recerca (VHIR), Liver Diseases Group, Barcelona, Spain
| | - David Tabernero
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Lab, Biochemistry and Microbiology Departments (Clinical Laboratories), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Silvia Sauleda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Vall d’Hebron Institut de Recerca (VHIR), Liver Diseases Group, Barcelona, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - Rafael Esteban
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
| | - María Buti
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Medicine, Barcelona, Spain
- Universitat Autònoma de Barcelona (UAB), Department of Biochemistry and Molecular Biology, Barcelona, Spain
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10
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Kramvis A, Chang KM, Dandri M, Farci P, Glebe D, Hu J, Janssen HLA, Lau DTY, Penicaud C, Pollicino T, Testoni B, Van Bömmel F, Andrisani O, Beumont-Mauviel M, Block TM, Chan HLY, Cloherty GA, Delaney WE, Geretti AM, Gehring A, Jackson K, Lenz O, Maini MK, Miller V, Protzer U, Yang JC, Yuen MF, Zoulim F, Revill PA. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022; 19:727-745. [PMID: 35859026 PMCID: PMC9298709 DOI: 10.1038/s41575-022-00649-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/13/2022]
Abstract
Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Hamburg, Germany
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Philadelphia, PA, USA
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Daryl T Y Lau
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Capucine Penicaud
- Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Teresa Pollicino
- Laboratory of Molecular Hepatology, Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Florian Van Bömmel
- Department of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Ourania Andrisani
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | | | | | - Henry L Y Chan
- Chinese University of Hong Kong, Shatin, Hong Kong
- Union Hospital, Shatin, Hong Kong
| | | | | | - Anna Maria Geretti
- Roche Pharma Research & Early Development, Basel, Switzerland
- Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Adam Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | | | - Mala K Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | | | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
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11
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Surrogate Markers for Hepatitis B Virus Covalently Closed Circular DNA. Semin Liver Dis 2022; 42:327-340. [PMID: 35445388 DOI: 10.1055/a-1830-2741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral transcripts, covalently closed circular deoxyribonucleic acid (cccDNA). Detecting changes in cccDNA transcriptional activity is key to understanding fundamental virology, determining the efficacy of new therapies, and deciding the optimal clinical management of HBV patients. In this review, we summarize surrogate circulating biomarkers that have been used to infer cccDNA levels and activity in people with chronic hepatitis B. Moreover, we outline the current shortcomings of the current biomarkers and highlight the clinical importance in improving them and expanding their use.
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12
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Cortese MF, Riveiro-Barciela M, Tabernero D, Rodriguez-Algarra F, Palom A, Sopena S, Rando-Segura A, Roade L, Kuchta A, Ferrer-Costa R, Quer J, Pacin B, Vila M, Casillas R, Garcia-Garcia S, Esteban R, Pumarola T, Buti M, Rodriguez-Frias F. Standardized Hepatitis B Virus RNA Quantification in Untreated and Treated Chronic Patients: a Promising Marker of Infection Follow-Up. Microbiol Spectr 2022; 10:e0214921. [PMID: 35377229 PMCID: PMC9045303 DOI: 10.1128/spectrum.02149-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/11/2022] [Indexed: 02/07/2023] Open
Abstract
The measurement and interpretation of HBV DNA and RNA levels in HBV infected patients treated with antiviral therapy supports the objective of HBV disease management. Here, we quantified circulating HBV RNA through a standardized and sensitive assay in follow-up samples from both naive and treated patients as a marker of infection evolution. HBV DNA (HBV DNA for use in Cobas 6800/8800 Automated Roche Molecular Systems), RNA (Roche HBV RNA Investigational Assay for use in the Cobas 6800/8800; Roche), HBeAg and HBsAg (Elycsys HBsAg chemiluminescence immunoassay by Cobas 8000; Roche), and core-related antigen (Lumipulse G chemiluminescence assay; Fujirebio) levels were measured in cohorts of untreated or nucleos(t)ide treated, HBV-infected subjects in an outpatient hospital setting. HBV DNA levels in untreated people were 3.6 log10 higher than corresponding RNA levels and were stable over 5 years of observation. While only five of 52 treated patients had DNA levels below the lower limit of quantification (10 IU/mL) at the end of follow-up, 13 had HBV RNA levels persistently above this limit, including eight with undetectable DNA. In samples with undetectable core-related antigen we observed a median HBsAg titer 2.7-fold higher than in samples with undetectable RNA (adjusted P = 0.012). Detectable HBV RNA with undetectable HBV DNA was a negative predictor of HBsAg decrease to a level ≤100 IU/mL (P = 0.03). In naive patients the difference between HBV DNA and RNA was higher than previously reported. HBV RNA rapidly decreased during treatment. However, in some cases, it was detectable even after years of effective therapy, being a negative predictor of HBsAg decrease. The investigational RNA assay for use on the Cobas 6800/8800 instruments is a sensitive and standardized method that could be applied in general management of HBV infection. IMPORTANCE This study focused on the quantification of circulating HBV RNA by using a standardized and sensitive assay. Thanks to this system we observed a higher difference between circulating HBV DNA and RNA than previously reported. In treated patients, HBV RNA decreased together with DNA, although some patients presented detectable levels even after years of successful antiviral treatment, suggesting a persistent viral transcription. Of note, the detection of viral RNA when HBV DNA is undetectable was a negative predictor of HBsAg decrease to a level ≤100 IU/mL. This assay could be extremely helpful in HBV patients management to study viral transcription and to identify those treated patients that may achieve sustained viral suppression.
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Affiliation(s)
- Maria Francesca Cortese
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Mar Riveiro-Barciela
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - David Tabernero
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Francisco Rodriguez-Algarra
- The Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Adriana Palom
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Sara Sopena
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ariadna Rando-Segura
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Virology Unit, Microbiology Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Luisa Roade
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alison Kuchta
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Roser Ferrer-Costa
- Department of Biochemistry, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Josep Quer
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Digestive and Liver Disease, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Beatriz Pacin
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Marta Vila
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rosario Casillas
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Selene Garcia-Garcia
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
| | - Rafael Esteban
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Tomás Pumarola
- Virology Unit, Microbiology Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Maria Buti
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
- Liver Unit, Internal Medicine Department, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francisco Rodriguez-Frias
- Clinical Biochemestry, Vall D'hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biochemistry and Microbiology, Liver Pathology Unit, Vall D'hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro De Investigación Biomédica En Red, Enfermedades Hepáticas y Digestvas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain
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13
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Fainboim H, Di Benedetto N, Paz S, Mendizabal M, Campuzano S, Elizalde M, Tadey L, Deluchi G, Bouzas MB, Mammana L, Flichman D. Quantitative HBsAg an unreliable marker for diagnosis and disease progression in genotype F chronic HBeAg-negative infections. J Viral Hepat 2022; 29:298-301. [PMID: 35152530 DOI: 10.1111/jvh.13657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/01/2022] [Indexed: 12/09/2022]
Affiliation(s)
- Hugo Fainboim
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | | | - Silvia Paz
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | | | - Soledad Campuzano
- Unidad de Hepatopatías Infecciosas, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina
| | - Mercedes Elizalde
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS), Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Gabriel Deluchi
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - María Belén Bouzas
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Lilia Mammana
- Unidad de Virología, Hospital de Infecciosas "Francisco J. Muñiz", Buenos Aires, Argentina
| | - Diego Flichman
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS), Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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14
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Armandi A, Rosso C, Ribaldone DG, Caviglia GP. Moving towards core antigen for the management of patients with overt and occult HBV infection. Panminerva Med 2021; 63:499-507. [PMID: 33073556 DOI: 10.23736/s0031-0808.20.04163-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic Hepatitis B virus (HBV) infection encompasses a wide virologic and clinical spectrum with heterogeneous outcomes. The natural history of chronic HBV infection ranges from an inactive carrier state (hepatitis B e antigen-negative chronic infection) to progressive chronic hepatitis that may evolve in end-stage liver disease and hepatocellular carcinoma. The issue becomes even more complicated when we consider the unique biology of the virus; the HBV covalently-closed-circular DNA, that acts as virus transcription template, is the key factor responsible of the persistence of the infection even after hepatitis B surface antigen loss. In the last decade, novel serological and immunological biomarkers associated to the core protein of HBV have been approached in different clinical conditions. Remarkable results have been obtained both in the setting of overt and occult HBV infection. Here, we reviewed the meaning and the potential clinical applications of the measurement of core antigen and antibodies.
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Affiliation(s)
- Angelo Armandi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Davide G Ribaldone
- Department of Medical Sciences, University of Turin, Turin, Italy
- Division of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
| | - Gian P Caviglia
- Department of Medical Sciences, University of Turin, Turin, Italy -
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15
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Lee JH, Kim HS. Current laboratory tests for diagnosis of hepatitis B virus infection. Int J Clin Pract 2021; 75:e14812. [PMID: 34487586 DOI: 10.1111/ijcp.14812] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/03/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) has a long history in human infectious diseases. HBV infection can progress chronically, leading to cancer. After introduction of a vaccine, the overall incidence rate of HBV infection has decreased, although it remains a health problem in many countries. PURPOSE The aim of this review was to summarise current diagnostic efforts for HBV infection and future HBV diagnosis perspectives. METHODS We reviewed and summarised current laboratory diagnosis related with HBV infection in clinical practice. RESULTS There have been various serologic- and molecular-based methods to diagnose acute or chronic HBV infection. Since intrahepatic covalently closed circular DNAs (cccDNAs) function as robust HBV replication templates, cure of chronic HBV infection is limited. Recently, new biomarkers such as hepatitis B virus core-related antigen (HBcrAg) and HBV RNA have emerged that appear to reflect intrahepatic cccDNA status. These new biomarkers should be validated before clinical usage. CONCLUSION An effective diagnostic approach and current updated knowledge of treatment response monitoring are important for HBV infection management. Brand new ultrasensitive and accurate immunologic methods may pave the way to manage HBV infection in parallel with immunotherapy era.
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Affiliation(s)
- Jong-Han Lee
- Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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16
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Riveiro-Barciela M, Pericàs JM, Buti M. How to interpret viral markers in the management of chronic hepatitis B infection. Clin Microbiol Infect 2021; 28:355-361. [PMID: 34768018 DOI: 10.1016/j.cmi.2021.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a global public health issue with several unsolved clinical challenges. As multiple new drugs are under development, HBV markers are gaining importance for both diagnostic and prognostic purposes. OBJECTIVES This review summarizes the most important data on the usefulness of HBV markers in the natural history of this infection, and in predicting clinical and treatment outcomes. SOURCES Selected peer-reviewed publications on HBV markers published between January 2009 and July 2021. CONTENT In addition to the classical markers (e.g. HBV-DNA), newer ones, such as quantitative HBsAg, HBcrAg, HBV-RNA and quantitative anti-HBc, have proven useful for predicting events within the natural history of HBV infection, the development of complications (e.g. hepatocellular carcinoma) and the response to antiviral therapy. Most data regarding the response to treatment have been related to nucleos(t)ide analogues, whereas evidence on new therapeutic agents, such as capsid assembly modulators or small interference RNAs, is promising, but still scarce. IMPLICATIONS Knowledge on the use of viral markers is a key factor for optimizing the clinical appraisal of HBV infection. The new markers have an enhanced ability to predict clinical outcomes. Further studies should expand the current evidence on the use of markers in relation to antiviral agents currently under evaluation. Wide availability of these markers in regions with a high incidence of HBV infection is of paramount importance.
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Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Juan M Pericàs
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Buti
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
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17
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Elizalde MM, Tadey L, Mammana L, Quarleri JF, Campos RH, Flichman DM. Biological Characterization of Hepatitis B virus Genotypes: Their Role in Viral Replication and Antigen Expression. Front Microbiol 2021; 12:758613. [PMID: 34803982 PMCID: PMC8600256 DOI: 10.3389/fmicb.2021.758613] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/13/2021] [Indexed: 01/12/2023] Open
Abstract
Hepatitis B virus (HBV) inter-host evolution has resulted in genomic diversification reflected in the existence of nine genotypes (A-I) and numerous subgenotypes. There is growing evidence that genotypes influence HBV natural history, clinical outcomes, and treatment response. However, the biological characteristics underlying these differences have not yet been established. By transfecting HuH-7 cells with unit-length constructs of genotypes A2, B2, C1, D1, and F1b, we identified major differences in HBV replicative capacity and antigen expression across genotypes. Genotypes B2 and F1b showed a 2-fold increase in cccDNA levels compared to the other genotypes (p<0.005). Genotype A2 expressed the lowest pgRNA levels, with a 70-fold decrease in relation to the other genotypes (p<0.0001), while genotype B2 showed the lowest Precore RNA levels, with a 100-fold reduction compared to genotype A2 (p<0.0001). The highest intracellular HBV DNA levels were observed for genotype B2 and the lowest for genotypes A2 and C1 (p<0.0001). Regarding antigen expression, genotype F1b secreted the highest HBsAg levels and genotype D1 the lowest (p<0.0001), while genotypes A2 and B2 showed the highest intracellular HBsAg levels (p<0.0001). Interestingly, genotype C1 secreted the highest HBeAg levels, while genotype A2 showed the highest intracellular levels (p<0.0001). Finally, the analysis of the intra/extracellular antigen ratios revealed that most genotypes retained intracellularly 5-20% of the antigens, except the genotype A2 that retained 50% of the total expressed antigens. In conclusion, this study provides new insights into the biological characteristics of HBV genotypes, being the first study to comparatively analyze European (A and D) and Asian (B and C) genotypes with the Latin American (F) genotype. The differences in HBV replication and antigen expression might contribute to understand the differential role of genotypes in pathogenesis.
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Affiliation(s)
- María Mercedes Elizalde
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital de Infecciosas “Francisco J. Muñiz”, Buenos Aires, Argentina
| | - Lilia Mammana
- Unidad de Virología, Hospital de Infecciosas “Francisco J. Muñiz”, Buenos Aires, Argentina
| | - Jorge Fabián Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Rodolfo Héctor Campos
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Martín Flichman
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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18
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Ghany MG, King WC, Lisker‐Melman M, Lok AS, Terrault N, Janssen HL, Khalili M, Chung RT, Lee WM, Lau DT, Cloherty GA, Sterling RK. Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America. Hepatology 2021; 74:2395-2409. [PMID: 34133774 PMCID: PMC8895675 DOI: 10.1002/hep.32018] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/30/2021] [Accepted: 05/09/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear. APPROACH AND RESULTS Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log10 IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg+ and 58% of HBeAg- participants; HBcrAg was quantifiable in 20% of HBeAg+ (above linear range in the other 80%) and 51% of HBeAg- participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg+ and HBeAg- immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg+ and HBeAg- phases (HBV RNA: e+ ρ = 0.84; e- ρ = 0.78; HBcrAg: e+ ρ = 0.66; e- ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg+ phases only (HBV RNA: e+ ρ = 0.71; P < 0.001; e- ρ = 0.18; P = 0.56; HBcrAg: e+ ρ = 0.51; P < 0.001; e- ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg- , but not HBeAg+ , phases. CONCLUSIONS Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.
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Affiliation(s)
| | - Wendy C. King
- Graduate School of Public Health University of PittsburghPittsburghPA
| | | | - Anna S.F. Lok
- Division of Gastroenterology and HepatologyUniversity of MichiganAnn ArborMI
| | - Norah Terrault
- Division of Gastrointestinal and Liver DiseasesKeck Medicine of University of Southern CaliforniaLos AngelesCA
| | | | - Mandana Khalili
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of California San FranciscoSan FranciscoCA
| | - Raymond T. Chung
- Hepatology and Liver CenterMassachusetts General HospitalBostonMA
| | - William M. Lee
- Meredith Mosle Chair in Liver DiseaseUT Southwestern Medical CenterDallasTX
| | - Daryl T.Y. Lau
- Division of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMA
| | | | - Richard K. Sterling
- Division of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth UniversityRichmondVA
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19
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Watanabe T, Inoue T, Tanaka Y. Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B. Microorganisms 2021; 9:2083. [PMID: 34683404 PMCID: PMC8537336 DOI: 10.3390/microorganisms9102083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B core-related antigen (HBcrAg) is an unprecedented novel HBV biomarker that plays an essential role in reflecting covalently closed circular DNA (cccDNA) in chronic hepatitis B (CHB) because its levels correlate with intrahepatic cccDNA and serum HBV DNA. In this review, we describe the clinical application of serum HBcrAg in CHB patients, with a particular focus on new therapies targeting intrahepatic HBV replication. (1) HBcrAg can be detected in clinical cases where serum HBV DNA is undetectable during anti-HBV therapy. (2) A highly sensitive HBcrAg assay (iTACT-HBcrAg) may be useful for monitoring HBV reactivation, as an alternative to HBV DNA. (3) Decreased HBcrAg levels have been significantly associated with promising outcomes in CHB patients, reducing the risk of progression or recurrence of hepatocellular carcinoma. Additionally, we focus on and discuss several drugs in development that target HBV replication, and monitoring HBcrAg may be useful for determining the therapeutic efficacies of such novel drugs. In conclusion, HBcrAg, especially when measured by the recently developed iTACT-HBcrAg assay, may be the most appropriate surrogate marker, over other HBV biomarkers, to predict disease progression and treatment response in CHB patients.
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Affiliation(s)
- Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
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20
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Vachon A, Osiowy C. Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management. Viruses 2021; 13:951. [PMID: 34064049 PMCID: PMC8224022 DOI: 10.3390/v13060951] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of HBV-related liver disease. There is currently a lack of predictive markers to guide clinical management and to allow treatment cessation with reduced risk of viral reactivation. Novel HBV biomarkers are in development in an effort to improve the management of people living with CHB, to predict disease outcomes of CHB, and further understand the natural history of HBV. This review focuses on novel HBV biomarkers and their use in the clinical setting, including the description of and methodology for quantification of serum HBV RNA, hepatitis B core-related antigen (HBcrAg), quantitative hepatitis B surface antigen (qHBsAg), including ultrasensitive HBsAg detection, quantitative anti-hepatitis B core antigen (qAHBc), and detection of HBV nucleic acid-related antigen (HBV-NRAg). The utility of these biomarkers in treatment-naïve and treated CHB patients in several clinical situations is further discussed. Novel HBV biomarkers have been observed to provide critical clinical information and show promise for improving patient management and our understanding of the natural history of HBV.
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Affiliation(s)
- Alicia Vachon
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| | - Carla Osiowy
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
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21
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Lee HW, Ahn SH, Chan HLY. Hepatitis B Core-Related Antigen: From Virology to Clinical Application. Semin Liver Dis 2021; 41:182-190. [PMID: 33957693 DOI: 10.1055/s-0041-1723088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a marker of intrahepatic viral activity, which may influence the risk of hepatocellular carcinoma. In this article, we review the virology and role of HBcrAg in defining phases of chronic hepatitis B. Furthermore, the function of HBcrAg in predicting treatment outcomes and its role in monitoring response to novel antiviral agents will be discussed.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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22
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Brunetto MR, Carey I, Maasoumy B, Marcos-Fosch C, Boonstra A, Caviglia GP, Loglio A, Cavallone D, Scholtes C, Ricco G, Smedile A, Riveiro-Barciela M, van Bömmel F, van der Eijk A, Zoulim F, Berg T, Cornberg M, Lampertico P, Agarwal K, Buti M. Incremental value of HBcrAg to classify 1582 HBeAg-negative individuals in chronic infection without liver disease or hepatitis. Aliment Pharmacol Ther 2021; 53:733-744. [PMID: 33465257 DOI: 10.1111/apt.16258] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/24/2020] [Accepted: 12/24/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND An accurate, single-point differential diagnosis between HBeAg-negative infection (ENI) and chronic hepatitis B (CHB) is an unmet need. AIMS To assess the diagnostic value of the new hepatitis B core-related antigen (HBcrAg) assay. METHODS A retrospective anonymised data analysis was performed in a multicentre European (nine centres and six countries) cohort of 1582 consecutive HBsAg-positive/HBeAg-negative subjects classified according to EASL guidelines as: 550-CHB, 710-ENI and 322-GZ (grey-zone, HBV-DNA <20 000 IU/mL). RESULTS Mean age was 44 (±13.2 y), 59% were men; HBV genotypes were 15% A, 2% B, 2% C, 45% D, 9% E, 1% F and 26% unknown. Median HBV-DNA serum levels were 2.2 (1.5-2.7), 3.5 (3.2-3.8) and 5.6 (4.8-6.6) logIU/mL in ENI, GZ and CHB, P < 0.0001. HBsAg serum levels (HBsAgsl) were comparable in CHB and GZ, but lower in ENI (2.9 [2.1-3.6] logIU/mL), P < 0.0001. HBcrAg serum levels (HBcrAgsl) were <3 logU/mL in 90.7% (644/710) ENI, 75.2% (242/322) GZ and 4.7% (26/550) CHB (P < 0.0001). Median HBcrAgsl were 4.8 (3.9-5.7), 2.5 (2.0-2.9) and 2.0 (2.0-2.5) logU/mL in CHB, GZ and ENI, (P < 0.0001). ROC-AUCs for HBcrAg and HBsAg were 0.968 (95% CI, 0.958-0.977) and 0.732 (95% CI, 0.704-0.760) respectively. The optimal HBcrAgsl cut-off to distinguish CHB from ENI was 3.14 logU/mL (95% CI, 3.02-3.25, 91% SE, 93% SP and 92.4% DA). HBcrAgsl were associated with HBV genotypes (P < 0.001, one-way ANOVA) but using genotype-specific cut-offs, HBcrAg DA remained unchanged with overlapping 95% CI. CONCLUSION The HBcrAg assay showed high diagnostic performance in the accurate single-point identification of patients with HBeAg-negative CHB, independently of HBV genotype. This should prompt future prospective studies to confirm its diagnostic role in clinical practice.
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23
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Caviglia GP, Armandi A, Rosso C, Ribaldone DG, Pellicano R, Fagoonee S. Hepatitis B Core-Related Antigen as Surrogate Biomarker of Intrahepatic Hepatitis B Virus Covalently-Closed-Circular DNA in Patients with Chronic Hepatitis B: A Meta-Analysis. Diagnostics (Basel) 2021; 11:187. [PMID: 33525443 PMCID: PMC7910971 DOI: 10.3390/diagnostics11020187] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) covalently-closed-circular (ccc)DNA is the key molecule responsible for viral persistence within infected hepatocytes. The evaluation of HBV cccDNA is crucial for the management of patients with chronic HBV infection and for the personalization of treatment. However, the need for liver biopsy is the principal obstacle for the assessment of intrahepatic HBV cccDNA. In the last decade, several studies have investigated the performance of hepatitis B core-related antigen (HBcrAg) as a surrogate of HBV cccDNA amount in the liver. In this meta-analysis, we collected 14 studies (1271 patients) investigating the correlation between serum HBcrAg and intrahepatic HBV cccDNA. Serum HBcrAg showed a high correlation with intrahepatic HBV cccDNA (r = 0.641, 95% confidence interval (CI) 0.510-0.743, p < 0.001). In a head-to-head comparison, we observed that the performance of HBcrAg was significantly superior to that of hepatitis B surface antigen (r = 0.665 vs. r = 0.475, respectively, p < 0.001). Subgroup analysis showed that the correlation between HBcrAg and intrahepatic HBV cccDNA was high, both in hepatitis B e antigen-positive and -negative patients (r = 0.678, 95% CI 0.403-0.840, p < 0.001, and r = 0.578, 95% CI 0.344-0.744, p < 0.001, respectively). In conclusion, the measurement of serum HBcrAg qualifies as a reliable non-invasive surrogate for the assessment of an intrahepatic HBV cccDNA reservoir.
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Affiliation(s)
- Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (A.A.); (C.R.); (D.G.R.)
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (A.A.); (C.R.); (D.G.R.)
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (A.A.); (C.R.); (D.G.R.)
| | | | - Rinaldo Pellicano
- Unit of Gastroenterology, Città della Salute e della Scienza di Torino-Molinette Hospital, 10126 Turin, Italy;
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center, 10126 Turin, Italy
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24
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Lim SG, Phyo WW, Ling JZJ, Cloherty G, Butler EK, Kuhns MC, McNamara AL, Holzmayer V, Gersch J, Yang WL, Ngu JH, Chang J, Tan J, Ahmed T, Dan YY, Lee YM, Lee GH, Tan PS, Huang DQ, Khine HTW, Lee C, Tay A, Chan E. Comparative biomarkers for HBsAg loss with antiviral therapy shows dominant influence of quantitative HBsAg (qHBsAg). Aliment Pharmacol Ther 2021; 53:172-182. [PMID: 33159496 DOI: 10.1111/apt.16149] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/14/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Biomarkers such as quantitative HBsAg (qHBsAg), quantitative hepatitis B virus (HBV) core-related antigen (qHBcrAg) and HBV RNA may be useful in predicting HBsAg loss in patients with chronic hepatitis B (CHB) undergoing antiviral therapy. AIM(S) Our study evaluated qHBsAg, HBV RNA and qHBcrAg as a posthoc analysis of a randomized clinical trial of peginterferon±NA to determine their utility in predicting HBsAg loss. METHODS CHB patients who completed therapy with 48weeks peginterferon alpha2b ± nucleoside analogue therapy (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBsAg loss. The predictive ability of qHBsAg, qHBcrAg, HBV RNA and other variables were investigated by univariate and multivariate logistic models for HBeAg-negative patients by odds ratios, area under the curve (AUC), sensitivity, specificity, and positive and negative likelihood ratios (LR). RESULTS HBsAg loss occurred in 15/114(13%) HBeAg-negative CHB patients who completed 48 weeks of peginterferon. At baseline, qHBsAg was superior to HBcrAg and HBV RNA with AUC 0.916, 0.649 and 0.542, respectively. Using multivariate analysis, the model comprising treatmentarm, age, gender, baseline qHBsAg, HBcrAg and HBV RNA, weeks 4 & 8 qHBsAg had the highest AUC(0.98), but the univariate model with week 8 qHBsAg <70 IU/mL had AUC 0.96. Hence, the contributions of variables other than qHBsAg were marginal. HBV RNA and qHBcrAg were weak predictors of HBsAg loss. Kinetics of the novel markers showed only qHBsAg had a good relationship with HBsAg loss while HBV RNA had a marginal relationship and HBcrAg did not change at all, and none had a good relationship with viral rebound. CONCLUSIONS On-treatment biomarker predictors were better than baseline ones, and the best predictor of HBsAg loss at 72 weeks was week 8 qHBsAg <70 IU/mL.
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Affiliation(s)
- Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | | | | | | | | | | | | | | | | | | | | | | | | | - Yock Young Dan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Guan Huei Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Daniel Q Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Htet Toe Wai Khine
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Chris Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Amy Tay
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Edwin Chan
- Singapore Clinical Research Institute, Singapore
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25
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Yang HC, Su TH. Viral and Host Factors Affecting Disease Progression of Hepatitis B Virus Infection. HEPATITIS B VIRUS AND LIVER DISEASE 2021:205-230. [DOI: 10.1007/978-981-16-3615-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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26
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Yoshida K, Desbiolles A, Feldman SF, Ahn SH, Alidjinou EK, Atsukawa M, Bocket L, Brunetto MR, Buti M, Carey I, Caviglia GP, Chen EQ, Cornberg M, Enomoto M, Honda M, Zu Siederdissen CH, Ishigami M, Janssen HLA, Maasoumy B, Matsui T, Matsumoto A, Nishiguchi S, Riveiro-Barciela M, Takaki A, Tangkijvanich P, Toyoda H, van Campenhout MJH, Wang B, Wei L, Yang HI, Yano Y, Yatsuhashi H, Yuen MF, Tanaka E, Lemoine M, Tanaka Y, Shimakawa Y. Hepatitis B Core-Related Antigen to Indicate High Viral Load: Systematic Review and Meta-Analysis of 10,397 Individual Participants. Clin Gastroenterol Hepatol 2021; 19:46-60.e8. [PMID: 32360825 DOI: 10.1016/j.cgh.2020.04.045] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS To eliminate hepatitis B virus (HBV) infection, scale-up of testing and treatment in resource-limited countries is crucial. However, access to nucleic acid testing to quantify HBV DNA, an essential test to examine treatment eligibility, remains severely limited. We assessed the performance of a novel immunoassay, HBV core-related antigen (HBcrAg), as a low-cost (less than US $15/assay) alternative to nucleic acid testing to indicate clinically important high viremia in chronic HBV patients infected with different genotypes. METHODS We searched Medline, Embase, Scopus, and Web of Science databases through June 27, 2018. Three reviewers independently selected studies measuring HBV DNA and HBcrAg in the same blood samples. We contacted authors to provide individual participant data (IPD). We randomly allocated each IPD to a derivation or validation cohort. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity/specificity. RESULTS Of 74 eligible studies, IPD were obtained successfully for 60 studies (81%). Meta-analysis included 5591 IPD without antiviral therapy and 4806 treated with antivirals. In untreated patients, the pooled area under the receiver operating characteristic curve and optimal cut-off values were as follows: 0.88 (95% CI, 0.83-0.94) and 3.6 log U/mL to diagnose HBV DNA level of 2000 IU/mL or greater; and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/mL for 200,000 IU/mL or greater, respectively. In the validation set, the sensitivity and specificity were 85.2% and 84.7% to diagnose HBV DNA level of 2000 IU/mL or greater, and 91.8% and 90.5% for 200,000 IU/mL or greater, respectively. The performance did not vary by HBV genotypes. In patients treated with anti-HBV therapy the correlation between HBcrAg and HBV DNA was poor. CONCLUSIONS HBcrAg might be a useful serologic marker to indicate clinically important high viremia in treatment-naïve, HBV-infected patients.
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Affiliation(s)
- Kyoko Yoshida
- Department of Surgery and Cancer, Liver Unit, Imperial College London, Paddington, London, United Kingdom
| | - Alice Desbiolles
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Sarah F Feldman
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Enagnon K Alidjinou
- Laboratoire de Virologie, Centre de Biologie Pathologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
| | - Laurence Bocket
- Laboratoire de Virologie, Centre de Biologie Pathologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Maurizia R Brunetto
- Hepatology Unit, Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, University Hospital of Pisa, Pisa PI, Italy
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | | | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, Osaka, Japan
| | - Masao Honda
- Department of Gastroenterology, Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Ishikawa, Japan
| | | | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Takeshi Matsui
- Center for Gastroenterology, Teine-Keijinkai Hospital, Hokkaido, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Mar Riveiro-Barciela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, GD Rotterdam, The Netherlands
| | - Bo Wang
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Lai Wei
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing, China
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Yoshihiko Yano
- Center for Infectious Diseases, Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization, Nagasaki Medical Center, Nagasaki, Japan
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Eiji Tanaka
- Department for the Promotion of Regional Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Maud Lemoine
- Department of Surgery and Cancer, Liver Unit, Imperial College London, Paddington, London, United Kingdom
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Shimakawa
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France.
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27
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Salpini R, Battisti A, Piermatteo L, Carioti L, Anastasiou OE, Gill US, Di Carlo D, Colagrossi L, Duca L, Bertoli A, La Rosa KY, Fabeni L, Iuvara A, Malagnino V, Cerva C, Lichtner M, Mastroianni CM, De Sanctis GM, Paoloni M, Marignani M, Pasquazzi C, Iapadre N, Parruti G, Vecchiet J, Sarmati L, Andreoni M, Angelico M, Grelli S, T Kennedy P, Verheyen J, Aquaro S, Silberstein FC, Perno CF, Svicher V. Key mutations in the C-terminus of the HBV surface glycoprotein correlate with lower HBsAg levels in vivo, hinder HBsAg secretion in vitro and reduce HBsAg structural stability in the setting of HBeAg-negative chronic HBV genotype-D infection. Emerg Microbes Infect 2020; 9:928-939. [PMID: 32312174 PMCID: PMC7269061 DOI: 10.1080/22221751.2020.1757998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico. HBsAg-levels were investigated in 323 drug-naïve HBeAg-negative patients chronically infected with HBV genotype-D(N = 228), -A(N = 65) and -E(N = 30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7–3.8]IU/ml; 3.8[3.5–4.2]IU/ml and 3.9[3.7–4.2]IU/ml, P < 0.001). Results confirmed by multivariable analysis correcting for patients’demographics, HBV-DNA, ALT and infection-status. In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAg<1000IU/ml(P-value from <0.001 to 0.04). These mutations lie in divergent pathways involving other HBsAg C-terminus mutations: V190A + F220L (Phi = 0.41, P = 0.003), S204N + L205P (Phi = 0.36, P = 0.005), Y206F + S210R (Phi = 0.47, P < 0.001) and S210N + F220L (Phi = 0.40, P = 0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them(P-value from 0.003 to 0.02). In-vitro, the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt(P-value from <0.001 to 0.02). Structurally, these mutational pairs reduced HBsAg C-terminus stability and determined a rearrangement of this domain. In conclusion, HBsAg-levels in genotype-D are significantly lower than in genotype-A and -E in HBeAg-negative patients. In genotype-D, specific mutational clusters in HBsAg C-terminus correlate with lower HBsAg-levels in-vivo, hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression.
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Affiliation(s)
- Romina Salpini
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Arianna Battisti
- Barts Liver Centre, Blizard Institute, Barts and The London SMD, QMUL, London, UK
| | - Lorenzo Piermatteo
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Luca Carioti
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Olympia E Anastasiou
- Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany
| | - Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London SMD, QMUL, London, UK
| | - Domenico Di Carlo
- Paediatric Clinical Research Center "Romeo and Enrica Invernizzi", University of Milan, Milan, Italy
| | - Luna Colagrossi
- Microbiology and Virology Unit, University of Milan, Milan, Italy
| | - Leonardo Duca
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Ada Bertoli
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Katia Yu La Rosa
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Lavinia Fabeni
- Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" -IRCCS, Rome, Italy
| | - Alessandra Iuvara
- Microbiology and Virology Unit, Tor Vergata University Hospital, Rome, Italy
| | | | - Carlotta Cerva
- Infectious Diseases Unit, Tor Vergata University Hospital, Rome, Italy
| | - Miriam Lichtner
- Public Health and Infectious Disease Department, "Sapienza" University, Rome, Italy
| | | | | | - Maurizio Paoloni
- Infectious Disease Unit, "S.S. Filippo e Nicola" Hospital, Avezzano, Italy
| | | | | | | | - Giustino Parruti
- Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
| | - Jacopo Vecchiet
- Department of Medicine and Science of Aging, Clinic of Infectious Diseases, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy
| | - Loredana Sarmati
- Infectious Diseases Unit, Tor Vergata University Hospital, Rome, Italy
| | - Massimo Andreoni
- Infectious Diseases Unit, Tor Vergata University Hospital, Rome, Italy
| | - Mario Angelico
- Hepatology Unit, Tor Vergata University Hospital, Rome, Italy
| | - Sandro Grelli
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.,Microbiology and Virology Unit, Tor Vergata University Hospital, Rome, Italy
| | - Patrick T Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London SMD, QMUL, London, UK
| | - Jens Verheyen
- Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany
| | - Stefano Aquaro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | | | | | - Valentina Svicher
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
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28
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Chemiluminescent Optical Fiber Immunosensor Combining Surface Modification and Signal Amplification for Ultrasensitive Determination of Hepatitis B Antigen. SENSORS 2020; 20:s20174912. [PMID: 32878030 PMCID: PMC7506923 DOI: 10.3390/s20174912] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 08/25/2020] [Accepted: 08/28/2020] [Indexed: 12/20/2022]
Abstract
Optical fiber based immunosensors are very attractive for biomarker detection. In order to improve the sensor response, we propose a promising strategy which combines porous-layer modification of the fiber surface and streptavidin-biotin-peroxidase nano-complex signal amplification in chemiluminescent detection. Two hepatitis B antigens, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), are used as the targets for analysis using the proposed sensor. Comparing to immunoassays using normal optical fiber sensors, the response of the present sensor is enhanced by a factor of 4.8 and 6.7 for detection of HBsAg and HBeAg, respectively. The limit-of-quantitation of the proposed method is as low as 0.3 fg/mL (0.01 fg/mL) with a wide linear response range of 3 fg/mL–150 ng/mL (0.1 fg/mL–160 ng/mL) for sensing HBsAg (HBeAg). Quantitative determination of HBsAg and HBeAg in human serum samples is performed, showing the applicability of the proposed method for biomarker detection.
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29
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Rodríguez M, Buti M, Esteban R, Lens S, Prieto M, Suárez E, García-Samaniego J. Consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B virus infection (2020). GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:559-587. [PMID: 32778356 DOI: 10.1016/j.gastrohep.2020.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.
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Affiliation(s)
- Manuel Rodríguez
- Sección de Hepatología, Servicio de Digestivo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España.
| | - María Buti
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Rafael Esteban
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Sabela Lens
- Servicio de Hepatología, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Universidad de Barcelona, Barcelona, España
| | - Martín Prieto
- Sección de Hepatología, Servicio de Medicina Digestiva, Hospital Universitari ì Politècnic La Fe, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Valencia, España
| | - Emilio Suárez
- Unidad de Enfermedades Digestivas, Hospital Universitario Virgen de Valme, Sevilla, España
| | - Javier García-Samaniego
- Unidad de Hepatología, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, España.
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30
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Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020; 26:261-279. [PMID: 32536045 PMCID: PMC7364351 DOI: 10.3350/cmh.2020.0032] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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31
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Yll M, Cortese MF, Guerrero-Murillo M, Orriols G, Gregori J, Casillas R, González C, Sopena S, Godoy C, Vila M, Tabernero D, Quer J, Rando A, Lopez-Martinez R, Esteban R, Riveiro-Barciela M, Buti M, Rodríguez-Frías F. Conservation and variability of hepatitis B core at different chronic hepatitis stages. World J Gastroenterol 2020; 26:2584-2598. [PMID: 32523313 PMCID: PMC7265140 DOI: 10.3748/wjg.v26.i20.2584] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/08/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Since it is currently not possible to eradicate hepatitis B virus (HBV) infection with existing treatments, research continues to uncover new therapeutic strategies. HBV core protein, encoded by the HBV core gene (HBC), intervenes in both structural and functional processes, and is a key protein in the HBV life cycle. For this reason, both the protein and the gene could be valuable targets for new therapeutic and diagnostic strategies. Moreover, alterations in the protein sequence could serve as potential markers of disease progression. AIM To detect, by next-generation sequencing, HBC hyper-conserved regions that could potentially be prognostic factors and targets for new therapies. METHODS Thirty-eight of 45 patients with chronic HBV initially selected were included and grouped according to liver disease stage [chronic hepatitis B infection without liver damage (CHB, n = 16), liver cirrhosis (LC, n = 5), and hepatocellular carcinoma (HCC, n = 17)]. HBV DNA was extracted from patients' plasma. A region between nucleotide (nt) 1863 and 2483, which includes HBC, was amplified and analyzed by next-generation sequencing (Illumina MiSeq platform). Sequences were genotyped by distance-based discriminant analysis. General and intergroup nt and amino acid (aa) conservation was determined by sliding window analysis. The presence of nt insertion and deletions and/or aa substitutions in the different groups was determined by aligning the sequences with genotype-specific consensus sequences. RESULTS Three nt (nt 1900-1929, 2249-2284, 2364-2398) and 2 aa (aa 117-120, 159-167) hyper-conserved regions were shared by all the clinical groups. All groups showed a similar pattern of conservation, except for five nt regions (nt 1946-1992, 2060-2095, 2145-2175, 2230-2250, 2270-2293) and one aa region (aa 140-160), where CHB and LC, respectively, were less conserved (P < 0.05). Some group-specific conserved regions were also observed at both nt (2306-2334 in CHB and 1935-1976 and 2402-2435 in LC) and aa (between aa 98-103 in CHB and 28-30 and 51-54 in LC) levels. No differences in insertion and deletions frequencies were observed. An aa substitution (P79Q) was observed in the HCC group with a median (interquartile range) frequency of 15.82 (0-78.88) vs 0 (0-0) in the other groups (P < 0.05 vs CHB group). CONCLUSION The differentially conserved HBC and HBV core protein regions and the P79Q substitution could be involved in disease progression. The hyper-conserved regions detected could be targets for future therapeutic and diagnostic strategies.
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MESH Headings
- Adult
- Aged
- Base Sequence/genetics
- Biomarkers
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Conserved Sequence/genetics
- DNA, Viral/blood
- DNA, Viral/genetics
- DNA, Viral/isolation & purification
- Disease Progression
- Female
- Genes, Viral/genetics
- Hepatitis B virus/genetics
- Hepatitis B virus/isolation & purification
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/therapy
- Hepatitis B, Chronic/virology
- Humans
- Liver Cirrhosis/blood
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/blood
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Middle Aged
- Prognosis
- Sequence Analysis, DNA
- Viral Core Proteins/genetics
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Affiliation(s)
- Marçal Yll
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Maria Francesca Cortese
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Mercedes Guerrero-Murillo
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Department of Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Gerard Orriols
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Josep Gregori
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Rosario Casillas
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Carolina González
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Sara Sopena
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Cristina Godoy
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Marta Vila
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - David Tabernero
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Josep Quer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Ariadna Rando
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Rosa Lopez-Martinez
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Rafael Esteban
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain
| | - Maria Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain
| | - Francisco Rodríguez-Frías
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
- Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
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32
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Buti M, Riveiro‐Barciela M, Esteban R. Rethinking the inactive carrier state: management of patients with low‐replicative HBeAg‐negative chronic hepatitis B and normal liver enzymes. CLINICAL DILEMMAS IN VIRAL LIVER DISEASE 2020:150-155. [DOI: 10.1002/9781119533481.ch26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Shimakawa Y, Ndow G, Njie R, Njai HF, Takahashi K, Akbar SMF, Cohen D, Nayagam S, Jeng A, Ceesay A, Sanneh B, Baldeh I, Imaizumi M, Moriyama K, Aoyagi K, D'Alessandro U, Mishiro S, Chemin I, Mendy M, Thursz MR, Lemoine M. Hepatitis B Core-related Antigen: An Alternative to Hepatitis B Virus DNA to Assess Treatment Eligibility in Africa. Clin Infect Dis 2020; 70:1442-1452. [PMID: 31102406 DOI: 10.1093/cid/ciz412] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/16/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND To eliminate hepatitis B virus (HBV) infection, it is essential to scale up testing and treatment. However, conventional tools to assess treatment eligibility, particularly nucleic acid testing (NAT) to quantify HBV DNA, are hardly available and affordable in resource-limited countries. We therefore assessed the performance of a novel immunoassay, hepatitis B core-related antigen (HBcrAg), as an inexpensive (US$ <15/assay) alternative to NAT to diagnose clinically important HBV DNA thresholds (≥2000, ≥20 000, and ≥200 000 IU/mL) and to select patients for antiviral therapy in Africa. METHODS Using a well-characterized cohort of treatment-naive patients with chronic HBV infection in The Gambia, we evaluated the accuracy of serum HBcrAg to diagnose HBV DNA levels and to indicate treatment eligibility determined by the American Association for the Study of Liver Diseases, based on reference tests (HBV DNA, hepatitis B e antigen, alanine aminotransferase, liver histopathology, and/or FibroScan). RESULTS A total of 284 treatment-naive patients were included in the analysis. The area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum HBcrAg were 0.88 (95% confidence interval [CI], .82-.93), 83.3%, and 83.9%, respectively, to diagnose HBV DNA ≥2000 IU/mL; and 0.94 (95% CI, .88-.99), 91.4%, and 93.2% for ≥200 000 IU/mL. A simplified treatment algorithm using HBcrAg without HBV DNA showed high AUROC (0.91 [95% CI, .88-.95]) with a sensitivity of 96.6% and specificity of 85.8%. CONCLUSIONS HBcrAg might be an accurate alternative to HBV DNA quantification as a simple and inexpensive tool to identify HBV-infected patients in need of antiviral therapy in low- and middle-income countries.
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Affiliation(s)
- Yusuke Shimakawa
- Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Gibril Ndow
- Medical Research Council (MRC) Unit, London School of Hygiene and Tropical Medicine, Fajara, The Gambia
- Liver Unit, Department of Surgery and Cancer, Imperial College London, United Kingdom
| | - Ramou Njie
- The Gambia Hepatitis Intervention Study, International Agency for Research on Cancer (IARC), MRC Unit, Fajara, The Gambia
| | - Harr Freeya Njai
- Medical Research Council (MRC) Unit, London School of Hygiene and Tropical Medicine, Fajara, The Gambia
| | | | | | - Damien Cohen
- Institut national de la santé et de la recherche médicale U1052, Centre national de la recherche scientifique UMR5286, Centre de Recherche en Cancérologie, Université Claude Bernard, Lyon, France
| | - Shevanthi Nayagam
- Liver Unit, Department of Surgery and Cancer, Imperial College London, United Kingdom
| | - Adam Jeng
- Medical Research Council (MRC) Unit, London School of Hygiene and Tropical Medicine, Fajara, The Gambia
| | - Amie Ceesay
- Medical Research Council (MRC) Unit, London School of Hygiene and Tropical Medicine, Fajara, The Gambia
| | - Bakary Sanneh
- National Public Health Laboratory, Banjul, The Gambia
| | | | | | | | - Katsumi Aoyagi
- Research and Development Division, Fujirebio Inc, Tokyo, Japan
| | - Umberto D'Alessandro
- Medical Research Council (MRC) Unit, London School of Hygiene and Tropical Medicine, Fajara, The Gambia
| | - Shunji Mishiro
- Department of Medical Sciences, Toshiba General Hospital, Tokyo
| | - Isabelle Chemin
- Department of Pathology, Ehime University Graduate School of Medicine, Japan
| | - Maimuna Mendy
- International Agency for Research on Cancer, Lyon, France
| | - Mark R Thursz
- Liver Unit, Department of Surgery and Cancer, Imperial College London, United Kingdom
| | - Maud Lemoine
- Liver Unit, Department of Surgery and Cancer, Imperial College London, United Kingdom
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Papatheodoridi M, Papatheodoridis G. Emerging Diagnostic Tools to Decide When to Discontinue Nucleos(t)ide Analogues in Chronic Hepatitis B. Cells 2020; 9:cells9020493. [PMID: 32093411 PMCID: PMC7072769 DOI: 10.3390/cells9020493] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 12/27/2022] Open
Abstract
The aim of this review is to outline emerging biomarkers that can serve as diagnostic tools to identify non-cirrhotic chronic hepatitis B (CHB) patients who could safely discontinue nucleos(t)ide analogues (NAs) before HBsAg loss. Regarding possible predictors of post-NAs outcomes, a number of studies have evaluated numerous factors, which can be categorised in markers of hepatitis B virus (HBV) activity, markers of host immune response and markers of other patient characteristics. In clinical practice, the most important question for patients who discontinue NAs is to differentiate those who will benefit by achieving HBsAg loss or at least by remaining in remission and those who will relapse requiring retreatment. Most of the discontinuation studies so far came from Asian and only few from European populations and examined the rates and predictors of post-NA virological and/or combined relapses or HBsAg loss. To date, there is still controversy about predictors of post-NA relapses, while only HBsAg serum levels at NA discontinuation seem to be the most robust predictive marker of the probability of subsequent off-treatment HBsAg seroclearance. Newer viral markers such as HBV RNA and hepatitis B core-related antigen seem promising, but further research is required.
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Affiliation(s)
- Margarita Papatheodoridi
- Institute of Liver and Digestive Health, Royal Free Hospital, University College of London, London NW3 2QG, UK;
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, 11527 Athens, Greece
- Correspondence: ; Tel.: +30-2132061115
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35
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Baudi I, Inoue T, Tanaka Y. Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi. Int J Mol Sci 2020; 21:949. [PMID: 32023902 PMCID: PMC7037346 DOI: 10.3390/ijms21030949] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/19/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022] Open
Abstract
The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.
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Affiliation(s)
- Ian Baudi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan;
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
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36
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Novel Biomarkers of Hepatitis B and Hepatocellular Carcinoma: Clinical Significance of HBcrAg and M2BPGi. Int J Mol Sci 2020. [DOI: 10.3390/ijms21030949
expr 921756688 + 899694353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
The hepatitis B virus (HBV) cannot be removed completely from infected hepatocytes, owing to the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), predicting HCC development in high-risk patients with high viral replicative activity or advanced fibrosis is important. Novel serological biomarkers reflect intrahepatic viral replicative activity or the progression of liver fibrosis, indicating non-invasive alternatives to liver biopsy: (1) Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients, a decrease in HBcrAg is associated with favorable outcomes. HBcrAg can predict HCC occurrence or recurrence. (2) Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. An increase in M2BPGi in CHB patients is related to the progression of liver fibrosis and high potential (risk) of HCC development. Here, we describe the clinical applications of HBcrAg and M2BPGi in CHB patients. Additionally, because new potential therapeutic agents that eliminate intrahepatic cccDNA are being developed, monitoring of HBcrAg or M2BPGi might be suitable for evaluating therapeutic effects and the clinical outcomes. In conclusion, these would be appropriate surrogate markers for predicting disease progression.
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37
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Gill US, Battisti A, Kennedy PTF. Emerging tools in the changing landscape of chronic hepatitis B management. Expert Rev Anti Infect Ther 2019; 17:943-955. [PMID: 31738607 DOI: 10.1080/14787210.2019.1694906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: The availability of a preventative vaccine, interferon, and nucleos(t)ide analogs have provided progress in the control of chronic hepatitis B (CHB). Despite this, it remains a major contributor to global morbidity and mortality. Developments in our understanding of the pathogenesis of CHB and the emergence of new therapies are paving the way, as we move toward HBV cure.Areas covered: We performed bibliographical searches of online databases to review the literature regarding conventional disease phases of CHB. We provide the latest evidence challenging the perception of the natural history of CHB, noting that previously considered quiescent disease phases may not represent benign disease states devoid of progression. We explore the use of potential novel immunological and viral tools which should enhance disease stratification and management decisions in the coming years. Finally, we discuss the timing of treatment and how this could be initiated earlier to improve treatment outcomes, preventing sequelae of chronic infection.Expert opinion: The treatment paradigm in CHB is set to change with multiple novel agents in early phase clinical trials with the aim of a functional cure. An improved understanding of disease pathogenesis and the timing of treatment will be critical to the success of new therapies.
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Affiliation(s)
- Upkar S Gill
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Arianna Battisti
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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38
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Peiffer KH, Kuhnhenn L, Jiang B, Mondorf A, Vermehren J, Knop V, Susser S, Walter D, Dietz J, Carra G, Finkelmeier F, Zeuzem S, Sarrazin C, Hildt E. Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients. J Infect Dis 2019. [PMID: 29528436 DOI: 10.1093/infdis/jiy119] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal. Methods We analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells. Results We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients. Conclusion Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.
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Affiliation(s)
- Kai-Henrik Peiffer
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany.,Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Lisa Kuhnhenn
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany.,Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Bingfu Jiang
- Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Antonia Mondorf
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Johannes Vermehren
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Viola Knop
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Simone Susser
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Dirk Walter
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Julia Dietz
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Gert Carra
- Paul Ehrlich Institute, Division of Virology, Langen, Germany
| | - Fabian Finkelmeier
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Stefan Zeuzem
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany
| | - Christoph Sarrazin
- University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany.,St. Josefs Hospital, Department of Gastroenterology, Wiesbaden, Germany
| | - Eberhard Hildt
- Paul Ehrlich Institute, Division of Virology, Langen, Germany.,German Center for Infection Research, Germany
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39
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Loggi E, Vukotic R, Conti F, Grandini E, Gitto S, Cursaro C, Galli S, Furlini G, Re MC, Andreone P. Serum hepatitis B core-related antigen is an effective tool to categorize patients with HBeAg-negative chronic hepatitis B. J Viral Hepat 2019; 26:568-575. [PMID: 30576048 DOI: 10.1111/jvh.13054] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 10/29/2018] [Indexed: 12/14/2022]
Abstract
The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a "grey" zone. Hepatitis B core-related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg-negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment-naive HBeAg-negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV-DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow-up of at least 1 year. In the overall population of 160 HBeAg-negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV-DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut-off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long-term clinical evaluation, a single measurement of HBcrAg at the established cut-off was optimally consistent with clinical outcome. Conversely, the HBsAg cut-off performed well in the true quiescent phase and less in more difficult-to-categorize patients. In conclusion, single-point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification.
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Affiliation(s)
- Elisabetta Loggi
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Ranka Vukotic
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Fabio Conti
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Elena Grandini
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Stefano Gitto
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Carmela Cursaro
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
| | - Silvia Galli
- Dipartimento di Medicina Specialistica, Diagnostica e SSprimentale-UO di Microbiologia, Università degli Studi di Bologna Bologna, Bologna, Italy
| | - Giuliano Furlini
- Dipartimento di Medicina Specialistica, Diagnostica e SSprimentale-UO di Microbiologia, Università degli Studi di Bologna Bologna, Bologna, Italy
| | - Maria Carla Re
- Dipartimento di Medicina Specialistica, Diagnostica e SSprimentale-UO di Microbiologia, Università degli Studi di Bologna Bologna, Bologna, Italy
| | - Pietro Andreone
- Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca per lo Studio delle Epatiti, Università degli Studi di Bologna, Bologna, Italy
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40
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. New viral biomarkers for Hepatitis B: Are we able to change practice? J Viral Hepat 2018; 25:1226-1235. [PMID: 30187603 DOI: 10.1111/jvh.12993] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV-infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver-related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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41
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Viral Biomarkers in Chronic HBeAg Negative HBV Infection. Genes (Basel) 2018; 9:genes9100469. [PMID: 30262738 PMCID: PMC6210948 DOI: 10.3390/genes9100469] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 02/07/2023] Open
Abstract
Viral biomarkers are important tools for monitoring chronic hepatitis B virus (HBV) hepatitis B early antigen (HBeAg) negative infection, both in its natural course as well as during and after treatment. The biomarkers consist of antibodies against viral epitopes, viral proteins, and molecular surrogate markers of the quantity and transcriptional activity of the stable episomal HBV covalently closed circular DNA (cccDNA) which is located in the nuclei of the infected hepatocytes. HBV deoxyribonucleic acid (DNA) or else viral load measurement in plasma or serum is a marker of HBV replication of major clinical importance. HBV DNA is used for staging and treatment monitoring as described in international scientific guidelines. Quantification of HBV antigens, mainly hepatitis B surface antigen (HBsAg) as well as Hepatitis B core related antigen (HBcrAg), play an important yet secondary role, especially in cases of low or undetectable HBV DNA and has been evaluated for the classification of the inactive carrier state, as a predictor of subsequent HBsAg clearance, treatment outcome, and development of hepatocellular carcinoma (HCC). The measurement of the replicative intermediate HBV RNA in serum is currently evaluated and may also prove to be a significant biomarker particularly in patients treated with nucleot(s)ide analogs. This review focuses on the viral biomarkers mentioned above and their role in HBV, HBeAg negative, infection.
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42
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Alexopoulou A, Karayiannis P. Editorial: HBsAg serum levels in HBeAg-negative chronic HBV infection-is it a matter of genotype? Aliment Pharmacol Ther 2018; 48:102-103. [PMID: 29882982 DOI: 10.1111/apt.14681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- A Alexopoulou
- 2nd Department of Medicine, Medical School, National & Kapodisrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - P Karayiannis
- University of Nicosia Medical School, Engomi, Nicosia, Cyprus
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43
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Kuhnhenn L, Jiang B, Kubesch A, Zeuzem S, Sarrazin C, Hildt E, Peiffer KH. Editorial: HBsAg serum levels in HBeAg-negative chronic HBV infection-is it a matter of genotype? Authors' reply. Aliment Pharmacol Ther 2018; 48:103-104. [PMID: 29882986 DOI: 10.1111/apt.14793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- L Kuhnhenn
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - B Jiang
- Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - A Kubesch
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - S Zeuzem
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - C Sarrazin
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Department of Gastroenterology, St. Josefs Hospital, Wiesbaden, Germany
| | - E Hildt
- Division of Virology, Paul Ehrlich Institute, Langen, Germany.,German Center for Infection Research (DZIF), Gießen-Marburg-Langen, Germany
| | - K-H Peiffer
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Division of Virology, Paul Ehrlich Institute, Langen, Germany
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44
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Abstract
Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic infection in humans through immune anergy. Currently, 3.5% of the global population is chronically infected with HBV, although the incidence of HBV infections is decreasing owing to vaccination and, to a lesser extent, the use of antiviral therapy to reduce the viral load of chronically infected individuals. The course of chronic HBV infection typically comprises different clinical phases, each of which potentially lasts for decades. Well-defined and verified serum and liver biopsy diagnostic markers enable the assessment of disease severity, viral replication status, patient risk stratification and treatment decisions. Current therapy includes antiviral agents that directly act on viral replication and immunomodulators, such as interferon therapy. Antiviral agents for HBV include reverse transcriptase inhibitors, which are nucleoside or nucleotide analogues that can profoundly suppress HBV replication but require long-term maintenance therapy. Novel compounds are being actively investigated to achieve the goal of HBV surface antigen seroclearance (functional cure), a serological state that is associated with a higher remission rate (thus, no viral rebound) after treatment cessation and a lower rate of cirrhosis and hepatocellular carcinoma. This Primer addresses several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis, prevention and management.
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45
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Kuhnhenn L, Jiang B, Kubesch A, Vermehren J, Knop V, Susser S, Dietz J, Carra G, Finkelmeier F, Grammatikos G, Zeuzem S, Sarrazin C, Hildt E, Peiffer KH. Impact of HBV genotype and mutations on HBV DNA and qHBsAg levels in patients with HBeAg-negative chronic HBV infection. Aliment Pharmacol Ther 2018; 47:1523-1535. [PMID: 29637585 DOI: 10.1111/apt.14636] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/02/2018] [Accepted: 03/06/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND HBV DNA and quantitative (q)HBsAg levels as prognostic markers for HBV-related disease are mostly validated in Asia and their significance in Western populations is uncertain. AIM To analyse the impact of the HBV genotype and frequent mutations in precore (PC), basal core promoter (BCP) and preS on HBV DNA and qHBsAg levels. METHODS HBV DNA and qHBsAg serum levels of 465 patients with HBeAg-negative chronic HBV infection were correlated with the HBV genotype and mutations in PC, BCP and preS. For a detailed analysis of the molecular virology, genotype A2 genomes harbouring these mutations were analysed for replication efficacy and HBsAg release in cell culture. RESULTS While no impact of the HBV genotype on HBV DNA levels was observed, qHBsAg levels differed up to 1.4 log among the genotypes (P < 0.001), reflected by large differences regarding the 1000 IU/mL HBsAg cut-off. While PC mutations were associated with higher (P < 0.001), BCP mutations were associated with lower HBV DNA levels (P < 0.001). Higher qHBsAg levels were associated with preS and lower levels with PC mutations (P < 0.001 and P = 0.001, respectively). The cell culture experiments revealed a higher HBsAg release and shorter filaments in case of a HBV genome harbouring a preS deletion. In contrast, a perinuclear HBsAg accumulation was detected for the PC and BCP-variants, reflecting an impaired HBsAg release. CONCLUSIONS qHBsAg serum levels depend on the HBV genotype and together with HBV DNA levels on frequent mutations in PC, BCP and preS in HBeAg-negative patients. qHBsAg cut-offs when used as prognostic markers require genotype-dependent validation.
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Affiliation(s)
- L Kuhnhenn
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - B Jiang
- Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - A Kubesch
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - J Vermehren
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - V Knop
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - S Susser
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - J Dietz
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - G Carra
- Division of Virology, Paul Ehrlich Institute, Langen, Germany
| | - F Finkelmeier
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - G Grammatikos
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - S Zeuzem
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany
| | - C Sarrazin
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Department of Gastroenterology, St. Josefs Hospital, Wiesbaden, Germany
| | - E Hildt
- Division of Virology, Paul Ehrlich Institute, Langen, Germany.,German Center for Infection Research (DZIF), Gießen-Marburg-Langen, Germany
| | - K-H Peiffer
- Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany.,Division of Virology, Paul Ehrlich Institute, Langen, Germany
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Bonacci M, Lens S, Mariño Z, Londoño MC, Rodríguez-Tajes S, Mas A, García-López M, Pérez-Del-Pulgar S, Sánchez-Tapias JM, Forns X. Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the Grey Zone. Aliment Pharmacol Ther 2018; 47:1397-1408. [PMID: 29577350 DOI: 10.1111/apt.14613] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/21/2017] [Accepted: 02/24/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Grey Zone (GZ) is an ill-defined situation including patients falling between inactive carrier (IC) state and HBeAg-negative chronic hepatitis B (HBeAg-negative CHB). AIMS To assess the long-term outcomes of GZ patients compared to IC in the absence of treatment. METHODS Retrospective analysis of 287 IC and GZ HBeAg-negative patients. Patients were classified into 4 groups at baseline: HBV-DNA <2000 IU/mL and ALT <40 U/L (IC), HBV-DNA <2000 IU/mL and ALT 40-80 U/L (GZ-1), HBV-DNA 2000-20 000 IU/mL and ALT <40 U/L (GZ-2) or ALT 40-80 U/L (GZ-3). Data were also analysed using AASLD ALT criteria. RESULTS After a median follow-up of 8.2 (5-19) years, HBsAg loss occurred in about 15% ICs or GZ patients. Transition into IC state occurred in 40% of GZ patients. DNA fluctuations >2000 IU/mL correlated inversely with transition into IC and HBsAg loss. HBsAg levels were significantly lower in ICs than in GZ patients (338 IU/mL [20-3269] vs 5763 IU/mL [2172-17 754]; P < 0.05). Among the latter group, there was an increasing gradient of HBsAg levels from GZ-1 to GZ-3 patients (P < 0.05). HBeAg-negative CHB occurred in only 18 (6.3%) GZ patients. No patient developed cirrhosis nor advanced fibrosis. ALT/HBV-DNA fluctuations and HBeAg-negative CHB development were more frequent in genotype B/C patients, whereas HBsAg loss occurred only in genotype A/D patients. CONCLUSIONS Most Caucasian GZ patients present excellent long-term outcomes in the absence of treatment, with a high rate of HBsAg loss and low rate of progression to HBeAg-negative CHB. HBV-genotyping and HBsAg levels could help to predict outcomes and better classify GZ patients.
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Affiliation(s)
- M Bonacci
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - S Lens
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Z Mariño
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - M-C Londoño
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - S Rodríguez-Tajes
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - A Mas
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - M García-López
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - S Pérez-Del-Pulgar
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - J M Sánchez-Tapias
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - X Forns
- Liver Unit, Hospital Clínic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain
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47
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Zhang S, Wang F, Zhang Z. Current advances in the elimination of hepatitis B in China by 2030. Front Med 2017; 11:490-501. [PMID: 29170919 DOI: 10.1007/s11684-017-0598-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 10/11/2017] [Indexed: 12/11/2022]
Abstract
With its 78 million chronic carriers, hepatitis B virus (HBV) infection is still one of the leading public health challenges in China. Over the last two decades, China has made great progress on the prevention of HBV transmission through national vaccination programs. Zero transmission from mother to infant has been proposed as the current goal. Available anti-HBV therapy is efficacious in suppressing HBV replication; however, it fails to completely cure patients with chronic hepatitis B and even requires lifelong treatment. To reduce the costs and improve the efficacy, several trials have been recently conducted in China to optimize the current anti-HBV managements. Novel biomarkers were identified to predict treatment outcomes, and new promising treatment strategies were developed. Reports also indicate that coinfections of HBV with other hepatotropic viruses and human immunodeficiency virus are common in China and cause severe liver diseases, which should be recognized early and treated properly. Work is still needed to eliminate hepatitis B in China by 2030.
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Affiliation(s)
- Shuye Zhang
- Shanghai Public Health Clinical Center and Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Fusheng Wang
- Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | - Zheng Zhang
- Research Center for Clinical & Translational Medicine, Beijiing 302 Hospital, Beijing, 100039, China.
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48
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Höner Zu Siederdissen C, Maasoumy B, Cornberg M. What is new on HBsAg and other diagnostic markers in HBV infection? Best Pract Res Clin Gastroenterol 2017; 31:281-289. [PMID: 28774410 DOI: 10.1016/j.bpg.2017.04.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Challenges in the management of chronic hepatitis B virus (HBV) infection involve the prediction of the natural course to identify patients who require antiviral therapy and the prediction of functional cure as ultimate goal of antiviral therapy. HBV DNA as marker for viral replication is important but not sufficient for an adequate management of patients with chronic HBV infection. Data on the quantification of additional HBV marker such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here we review the current evidence how to use these markers and discuss open issues that require additional research.
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Affiliation(s)
- Christoph Höner Zu Siederdissen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.
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