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Pfefferkorn M, Brehm J, Brehm M, Honshoven F, Deichsel D, Vernoux L, Pavlovic V, Wat C, Berg T, van Bömmel F. Overrange dilution for improvement of hepatitis B core related antigen as a biomarker: protocol validation and examples for application. Virology 2025; 609:110576. [PMID: 40393306 DOI: 10.1016/j.virol.2025.110576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 04/14/2025] [Accepted: 05/14/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Hepatitis B core related antigen (HBcrAg) measurement predicts treatment outcomes and reflects intrahepatic HBV replication. The commercially available automated assay for HBcrAg has a linear range of 3.0 - 7.0 logU/mL, with higher levels requiring dilution. However, using different diluents across studies may impact comparability and cross-reactivity, which has not been thoroughly investigated. This study aims to validate a dilution method for specimens above the upper limit of quantification (7.0 logU/mL) to improve comparability. METHODS The dilution procedure was two-site tested with three matrices for practicability, accuracy and repeatability using samples from HBV-infected patients with high HBcrAg levels. Samples were tested undiluted or diluted when overrange using Fujirebio's specific dilution reagent (SD1) with reflex testing of pre-treated samples, or manually diluted with fetal calf serum (FCS) or human serum (HS) of samples before restarting pre-treatment. Overrange dilution was further validated in three patient cohorts: untreated HBV-infected patients (n = 157) and patients treated with nucleos(t)ide analogues (NA, n = 19), or pegylated interferon-2alpha (PEG-IFN, n = 80) RESULTS: On-board dilution with SD1 showed higher background signals compared to HS or FCS. The dilution process was reproducible across sites, but SD1 underestimated HBcrAg levels. Dilution with FCS showed an early decrease in HBcrAg levels in patients with HBeAg SC during NA treatment (after 3 months, p = 0.022) and PEG-IFN treatment, whereas no change in HBcrAg levels was found without overrange dilution. CONCLUSION Validation showed high background and underestimating levels of HBcrAg with SD1, while FCS-based overrange dilution resulted in significant early HBcrAg decreases and better correlation with treatment response.
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Affiliation(s)
- Maria Pfefferkorn
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
| | | | | | | | - Danilo Deichsel
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | | | | | | | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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Liang LB, Zhang HJ, Liu F, Su QL. Hepatitis B core-related antigen as a predictive biomarker for recurrence in primary hepatocellular carcinoma: A meta-analysis. World J Gastrointest Oncol 2025; 17:105148. [DOI: 10.4251/wjgo.v17.i5.105148] [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: 01/12/2025] [Revised: 02/24/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies, with high recurrence rates after treatment. Identifying reliable biomarkers for predicting recurrence is essential for improving patient outcomes. Hepatitis B core-related antigen (HBcrAg) has shown potential as a predictive marker for HCC recurrence.
AIM To evaluate the association between HBcrAg levels and the risk of HCC recurrence.
METHODS A systematic review was conducted following PRISMA guidelines. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched without restrictions on date or language. Observational studies reporting hazard ratios (HRs) for HBcrAg as a predictor of HCC recurrence were included. Data extraction and quality assessment were performed independently by two reviewers. Statistical analyses used a random-effects model to account for heterogeneity (I² ≥ 50%), and sensitivity analysis was performed to ensure the robustness of the results.
RESULTS A total of 1339 articles were initially identified, and 17 studies were included in the final meta-analysis after screening. The pooled analysis showed a significant association between elevated HBcrAg levels and HCC recurrence (HR = 4.42, 95% confidence interval: 3.43-5.41) with substantial heterogeneity (I² = 92.6%). Subgroup analysis revealed higher pooled HRs in studies with ≥ 500 participants (HR = 4.18) and HBcrAg cut-offs ≥ 4.0 LogU/mL (HR = 5.29). Studies with ≥ 10 years of follow-up showed a lower HR (2.89) compared to those with < 10 years (3.27). Patients treated with nucleos(t)ide analogs had a pooled HR of 1.98, while those without nucleos(t)ide analog had a higher HR of 3.87. Sensitivity analysis confirmed the robustness of the results, with no significant publication bias detected.
CONCLUSION This meta-analysis provides strong evidence that elevated HBcrAg levels are associated with an increased risk of HCC recurrence. HBcrAg may serve as a valuable biomarker for predicting recurrence, aiding personalized management and surveillance strategies for HCC patients.
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Affiliation(s)
- Ling-Bo Liang
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hai-Jun Zhang
- General Practice Ward/International Medical Center Ward, West China Healthcare Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Feng Liu
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Qiao-Li Su
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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3
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Okumura T, Umemura T. Growing evidence on the highly sensitive iTACT assay of hepatitis B core-related antigen for predicting hepatitis B virus reactivation. J Gastroenterol 2025; 60:129-130. [PMID: 39611969 DOI: 10.1007/s00535-024-02187-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 11/17/2024] [Indexed: 11/30/2024]
Affiliation(s)
- Taiki Okumura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano , 390-8621, Japan.
| | - Takeji Umemura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano , 390-8621, Japan
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Huang SW, Long H, Huang JQ. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens 2024; 14:8. [PMID: 39860969 PMCID: PMC11768139 DOI: 10.3390/pathogens14010008] [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: 11/05/2024] [Revised: 12/25/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up.
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Affiliation(s)
- Shuai-Wen Huang
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Hong Long
- Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
| | - Jia-Quan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China;
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Pawlotsky JM. Virological markers for clinical trials in chronic viral hepatitis. JHEP Rep 2024; 6:101214. [PMID: 39524203 PMCID: PMC11550202 DOI: 10.1016/j.jhepr.2024.101214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 11/16/2024] Open
Abstract
Chronic hepatitis virus infections remain a major public health problem, despite significant therapeutic advances over the past two decades. Considerable progress has been made in the treatment of chronic viral hepatitis, but continued efforts are needed to develop and bring to market new drugs to fill the gaps in the current therapeutic armamentarium. Thus, clinical trials to assess the safety and efficacy of these new therapeutic approaches, including the selection of reliable and objective treatment endpoints, are still needed. Virological biomarkers play an important role in the diagnosis, monitoring, and evaluation of antiviral treatment efficacy. They are often used as primary or secondary endpoints in the evaluation of new treatments for chronic viral hepatitis. However, these markers are not all equally informative. The aim of this review article is to provide a comprehensive overview of the available virological tests for chronic viral hepatitis due to hepatitis B, D, C and E viruses, the information they provide and lack, the specific challenges associated with each, and their use in clinical trials of new treatments.
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Affiliation(s)
- Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- Team “Viruses, Hepatology, Cancer”, Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France
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6
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Cao QH, Liu H, Yan LJ, Wang HC, Ding ZN, Mao XC, Li RZ, Pan GQ, Zhang X, Tian BW, Han CL, Dong ZR, Tan SY, Wang DX, Yan YC, Li T. Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis. J Gastroenterol Hepatol 2024; 39:1464-1475. [PMID: 38686439 DOI: 10.1111/jgh.16558] [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: 10/26/2023] [Revised: 03/08/2024] [Accepted: 03/25/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIM The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.
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Affiliation(s)
- Qi-Hang Cao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Han-Chao Wang
- Institute for Financial Studies, Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xin-Cheng Mao
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Rui-Zhe Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Okumura T, Joshita S, Kitamura Y, Sagi H, Umemura T. Detection Rates of Hepatitis B Surface and Core-related Antigens Using Novel Highly Sensitive Assays in Chronic Hepatitis B Patients With Hepatitis B Surface Antigen Seroclearance. GASTRO HEP ADVANCES 2024; 3:885-887. [PMID: 39286623 PMCID: PMC11402281 DOI: 10.1016/j.gastha.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 06/27/2024] [Indexed: 09/19/2024]
Affiliation(s)
- Taiki Okumura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Health Promotion Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Internal Medicine, NHI Yodakubo Hospital, Nagawa, Japan
| | | | - Haruka Sagi
- Research and Development Division, Fujirebio Inc., Hachioji, Japan
| | - Takeji Umemura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Health Promotion Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Advanced Therapeutic Endoscopy, Shinshu University School of Medicine, Matsumoto, Japan
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto, Japan
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8
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Shen L, Zhang Y, Shi M, Shao L, Feng S, Li W, Fang Z, Yin J, Li T. Performance evaluation of the MAGLUMI Hepatitis B virus surface antigen chemiluminescence immunoassay. J Med Virol 2024; 96:e29817. [PMID: 39034740 DOI: 10.1002/jmv.29817] [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: 04/18/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/23/2024]
Abstract
A highly sensitive and reliable Hepatitis B virus surface antigen (HBsAg) measurement is essential to universal screening, timely diagnosis, and management of Hepatitis B virus (HBV) infection. This study aimed to evaluate the performance of MAGLUMI HBsAg chemiluminescence immunoassay (CLIA). MAGLUMI HBsAg (CLIA) was compared against ARCHITECT HBsAg. 411 HBsAg positive samples, including different stages of infection, genotypes, subtypes, mutants, and 30 seroconversion panels were tested to evaluate diagnostic sensitivity. Diagnostic specificity was evaluated by testing 205 hospitalized samples and 5101 blood donor samples. Precision, limit of blank (LoB), limit of detection (LoD), and linearity were also verified. The diagnostic sensitivity of the MAGLUMI HBsAg (CLIA) was 100% with better seroconversion sensitivity than ARCHITECT HBsAg. The MAGLUMI HBsAg (CLIA) has optimal detection efficacy for HBV subgenotypes samples. The analytical sensitivity is 0.039 IU/mL. The initial diagnostic specificity is 99.63% on blood donors and 96.59% on hospitalized samples. The verification data demonstrated high repeatability, a LoB of 0.02 IU/mL, LoD of 0.05 IU/mL and an excellent linearity of 0.050-250 IU/mL (R2 = 0.9946). The MAGLUMI HBsAg (CLIA) is proved a highly sensitive and reliable assay with optimal subgenotype detection efficacy.
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Affiliation(s)
- Lihong Shen
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Yun Zhang
- Research & Development Department, Shenzhen New Industries Biomedical Engineering Co. Ltd., Shenzhen, China
| | - Min Shi
- Research & Development Department, Shenzhen New Industries Biomedical Engineering Co. Ltd., Shenzhen, China
| | - Lijia Shao
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shengchun Feng
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Weiting Li
- Research & Development Department, Shenzhen New Industries Biomedical Engineering Co. Ltd., Shenzhen, China
| | - Zhonggang Fang
- Research & Development Department, Shenzhen New Industries Biomedical Engineering Co. Ltd., Shenzhen, China
| | - Jun Yin
- Research & Development Department, Shenzhen New Industries Biomedical Engineering Co. Ltd., Shenzhen, China
| | - Tinghua Li
- Research & Development Department, Shenzhen New Industries Biomedical Engineering Co. Ltd., Shenzhen, China
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9
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Inoue T, Yagi S, Tanaka Y. Two Concepts of Hepatitis B Core-Related Antigen Assay: A Highly Sensitive and Rapid Assay or an Effective Tool for Widespread Screening. Viruses 2024; 16:848. [PMID: 38932141 PMCID: PMC11209401 DOI: 10.3390/v16060848] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/20/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis B core-related antigen (HBcrAg) reflects the activity of intrahepatic covalently closed circular DNA. HBcrAg can be detected even in chronic hepatitis B patients in whom serum HBV DNA or hepatitis B surface antigen is undetectable. The HBcrAg measurement system was developed based on two concepts. One is a fully-automated and highly-sensitive HBcrAg assay (iTACT-HBcrAg) and the other is a point-of-care testing (POCT) that can be used in in resource-limited areas. iTACT-HBcrAg is an alternative to HBV DNA for monitoring HBV reactivation and predicting the development of hepatocellular carcinoma. This validated biomarker is available in routine clinical practice in Japan. Currently, international guidelines for the prevention of mother-to-child transmission recommend anti-HBV prophylaxis for pregnant women with high viral loads. However, over 95% of HBV-infected individuals live in countries where HBV DNA quantification is widely unavailable. Given this situation, a rapid and simple HBcrAg assay for POCT would be highly effective. Long-term anti-HBV therapy may have potential side effects and appropriate treatment should be provided to eligible patients. Therefore, a simple method of determining the indication for anti-HBV treatment would be ideal. This review provides up-to-date information regarding the clinical value of HBcrAg in HBV management, based on iTACT-HBcrAg or POCT.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Shintaro Yagi
- Research and Development Department, Advanced Life Science Institute, Inc., Hachioji 192-0031, Japan;
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Leowattana W, Leowattana P, Leowattana T. Quantitative hepatitis B core antibody and quantitative hepatitis B surface antigen: Novel viral biomarkers for chronic hepatitis B management. World J Hepatol 2024; 16:550-565. [PMID: 38689745 PMCID: PMC11056893 DOI: 10.4254/wjh.v16.i4.550] [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: 12/12/2023] [Revised: 02/03/2024] [Accepted: 03/12/2024] [Indexed: 04/24/2024] Open
Abstract
The management of hepatitis B virus (HBV) infection now involves regular and appropriate monitoring of viral activity, disease progression, and treatment response. Traditional HBV infection biomarkers are limited in their ability to predict clinical outcomes or therapeutic effectiveness. Quantitation of HBV core antibodies (qAnti-HBc) is a novel non-invasive biomarker that may help with a variety of diagnostic issues. It was shown to correlate strongly with infection stages, hepatic inflammation and fibrosis, chronic infection exacerbations, and the presence of occult infection. Furthermore, qAnti-HBc levels were shown to be predictive of spontaneous or treatment-induced HBeAg and HBsAg seroclearance, relapse after medication termination, re-infection following liver transplantation, and viral reactivation in the presence of immunosuppression. qAnti-HBc, on the other hand, cannot be relied on as a single diagnostic test to address all problems, and its diagnostic and prognostic potential may be greatly increased when paired with qHBsAg. Commercial qAnti-HBc diagnostic kits are currently not widely available. Because many methodologies are only semi-quantitative, comparing data from various studies and defining universal cut-off values remains difficult. This review focuses on the clinical utility of qAnti-HBc and qHBsAg in chronic hepatitis B management.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand.
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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11
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Watanabe T, Nagaoka K. An RNA-degrading enzyme emerges as a biomarker in a study of human hepatitis virus B. Hepatol Res 2024; 54:220-221. [PMID: 38146795 DOI: 10.1111/hepr.14005] [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] [Indexed: 12/27/2023]
Affiliation(s)
- Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Katsuya Nagaoka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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12
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Suzuki F, Hosaka T, Suzuki Y, Sezaki H, Akuta N, Fujiyama S, Kawamura Y, Saitoh S, Arase Y, Kobayashi M, Kumada H. Clinical outcome after cessation of nucleos(t)ide analog treatment in chronic hepatitis B patients who achieved HBsAg seroclearance. J Gastroenterol 2024; 59:34-44. [PMID: 37837569 DOI: 10.1007/s00535-023-02046-y] [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: 07/26/2023] [Accepted: 09/20/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND We determined the long-term clinical outcome and the durability of treatment cessation after HBsAg seroclearance following nucleos(t)ide analog (NA) therapy in patients with chronic hepatitis B (CHB). METHODS We analyzed virological relapse (VR), HBsAg reversion, clinical relapse, and changes in HBsAg and HBcrAg levels by iTACT assay after treatment cessation of 90 CHB patients who achieved HBsAg seroclearance by NA treatment. RESULTS Median age of patients at treatment cessation was 57 years. Median duration of NA treatment and follow-up from cessation of NA were 9.25 and 5.2 years, respectively. Although VR occurred in 19 of 90 (21.1%) patients, HBV DNA levels of 18 patients had temporal elevations and sustained levels under the detection level thereafter. HBsAg reversion using Architect HBsAg QT assay occurred in six patients (6.7%) after cessation of NA. Five patients had temporal HBsAg level elevations and sustained levels under the detection level thereafter. One patient had virological and clinical relapse at 6 months after cessation of NA, and received NA re-treatment. HBsAg levels by iTACT assay from end of treatment (EOT) gradually decreased and in 18 of 28 (64%) patients reached an undetectable level at 5 years after EOT. In contrast, HBcrAg levels by iTACT assay slowly decreased, and in 8 of 29 patients (28%) reached an undetectable level at 5 years after EOT. CONCLUSIONS Patients receiving NA treatment who achieved HBsAg seroclearance as determined by HBsAg QT assay rarely experienced virological or clinical relapse after the cessation of treatment.
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Affiliation(s)
- Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan.
- Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
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13
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Kim SR, Kim SK. Hepatocellular Carcinoma and Hepatitis: Advanced Diagnosis and Management with a Focus on the Prevention of Hepatitis B-Related Hepatocellular Carcinoma. Diagnostics (Basel) 2023; 13:3212. [PMID: 37892033 PMCID: PMC10605503 DOI: 10.3390/diagnostics13203212] [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: 08/29/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Though the world-wide hepatitis B virus (HBV) vaccination program has been well completed for almost thirty years in many nations, almost HBV-related hepatocellular carcinoma (HCC) occurs in unvaccinated middle-aged and elderly adults. Apparently, treating 80% of qualified subjects could decrease HBV-related mortality by 65% in a short period. Nevertheless, globally, only 2.2% of CHB patients undergo antiviral therapy. The HBV markers related to HCC occurrence and prevention are as follows: the HCC risk is the highest at a baseline of HBV DNA of 6-7 log copies/mL, and it is the lowest at a baseline of an HBV DNA level of >8 log copies/mL and ≤4 log copies/mL (parabolic, and not linear pattern). The titer of an HBV core-related antigen (HBcrAg) reflecting the amount of HBV covalently closed circular DNA (ccc DNA) in the liver is related to HCC occurrence. The seroclearance of HBs antigen (HBsAg) is more crucial than HBV DNA negativity for the prevention of HCC. In terms of the secondary prevention of hepatitis B-related HCC involving antiviral therapies with nucleos(t)ide analogues (NAs), unsolved issues include the definition of the immune-tolerant phase; the optimal time for starting antiviral therapies with NAs; the limits of increased aminotransferase (ALT) levels as criteria for therapy in CHB patients; the normalization of ALT levels with NAs and the relation to the risk of HCC; and the relation between serum HBV levels and the risk of HCC. Moreover, the first-line therapy with NAs including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) remains to be clarified. Discussed here, therefore, are the recent findings of HBV markers related to HCC occurrence and prevention, unsolved issues, and the current secondary antiviral therapy for the prevention of HBV-related HCC.
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Affiliation(s)
| | - Soo Ki Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 653-0801, Japan;
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14
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Inoue T, Watanabe T, Tanaka Y. Hepatitis B core-related antigen: A novel and promising surrogate biomarker to guide anti-hepatitis B virus therapy. Clin Mol Hepatol 2023; 29:851-868. [PMID: 36891607 PMCID: PMC10577333 DOI: 10.3350/cmh.2022.0434] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/19/2023] [Accepted: 03/07/2023] [Indexed: 03/10/2023] Open
Abstract
The current requirement for biomarkers to detect hepatitis B virus (HBV) infection is polarized. One is a fully-automated and highly sensitive measurement system; the other is a simple system for point-of-care testing (POCT) in resource-limited areas. Hepatitis B core-related antigen (HBcrAg) reflects intrahepatic covalently closed circular DNA and serum HBV DNA. Even in patients with undetectable serum HBV DNA or HBsAg loss, HBcrAg may remain detectable. Decreased HBcrAg levels are associated with reduction of the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B. Recently, a fully-automated, novel high-sensitivity HBcrAg assay (iTACT-HBcrAg, cut-off value: 2.1 logIU/mL) has been developed. This attractive assay has been released in Japan very recently. iTACT-HBcrAg can be useful for monitoring HBV reactivation and prediction of HCC occurrence, as an alternative to HBV DNA. Moreover, monitoring HBcrAg may be suitable for determining the therapeutic effectiveness of approved drugs and novel drugs under development. Presently, international guidelines recommend anti-HBV prophylaxis for pregnant women with high viral loads to prevent mother-to-child transmission of HBV. However, >95% of HBV-infected individuals live in countries where HBV DNA quantification is not available. Worldwide elimination of HBV needs the scaling-up of examination and medication services in resource-limited areas. Based on this situation, a rapid and easy HBcrAg assay as a POCT is valuable. This review provides the latest information regarding the clinical use of a new surrogate marker, HBcrAg, in HBV management, based on iTACT-HBcrAg or POCT, and introduces novel agents targeting HBV RNA/protein.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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15
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Suzuki T, Matsuura K, Watanabe T, Matsui T, Ogawa S, Kawamura H, Kuno K, Fujiwara K, Nojiri S, Kataoka H, Tanaka Y. Kinetics of HBcrAg and HBsAg using highly sensitive iTACT assays in chronic hepatitis B patients with HBsAg seroclearance. J Med Virol 2023; 95:e29109. [PMID: 37721406 DOI: 10.1002/jmv.29109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/13/2023] [Accepted: 09/07/2023] [Indexed: 09/19/2023]
Abstract
Two novel assays have been developed, iTACT-hepatitis B core-related antigen (iTACT-HBcrAg) and iTACT-hepatitis B surface antigen (iTACT-HBsAg) assays. We investigated the longitudinal profiles of iTACT-HBcrAg- and -HBsAg in patients with HBsAg seroclearance (SC) (<0.05 IU/mL). This study comprises 60 HBV-infected patients with HBsAg SC, 27 in chronic hepatitis/liver cirrhosis (CH/LC) group and 33 in inactive carrier (IC) group. Longitudinal profiles of iTACT-HBcrAg and -HBsAg were examined using stored serum samples. The median period from HBsAg SC to iTACT-HBcrAg loss or to the last observation was longer in the CH/LC group than the IC group (39 vs. -3 months, p = 0.004), but this tendency was not observed in that by iTACT-HBsAg. Comparing the times of iTACT-HBcrAg and -HBsAg loss, the rate of patients who lost HBcrAg first was significantly higher in the IC group (p = 0.008). The cumulative incidence rate of iTACT-HBcrAg loss after HBsAg SC was higher in the IC group that the CH/LC group (p = 0.002). Patients in the CH/LC group had higher rates of detectable iTACT-HBcrAg than those in the IC group after HBsAg SC, suggesting that the presence of HBcrAg possibly contribute to the progression of chronic hepatitis B.
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Affiliation(s)
- Takanori Suzuki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Hokkaido, Japan
| | - Shintaro Ogawa
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
| | - Hayato Kawamura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kayoko Kuno
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kei Fujiwara
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shunsuke Nojiri
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
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16
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Wang ZL, Zheng JR, Yang RF, Huang LX, Chen HS, Feng B. An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss. J Clin Transl Hepatol 2023; 11:197-206. [PMID: 36406318 PMCID: PMC9647097 DOI: 10.14218/jcth.2022.00289] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/12/2022] [Accepted: 08/02/2022] [Indexed: 12/04/2022] Open
Abstract
In the era of antiviral therapy, the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus (HBV) replication to the pursuit of serological clearance of HBs surface antigen (HBsAg). Based on the life cycle of HBV, HBsAg originates from covalently closed circular DNA (cccDNA) and integrated HBV DNA, thus reflecting their transcriptional activity. Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA. HBsAg loss improves the recovery of abnormal immune function, which in turn, may further promote the clearance of residual viruses. Combined with functional cure and the great improvement of clinical outcomes, the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B (CHB). For many other risk factors besides HBV itself, patients with HBsAg loss still need regular monitoring. In this review, we summarized the evolution of CHB treatment, the origin of serum HBsAg, the pattern of HBsAg seroclearance, and the effect of HBsAg loss on immune function and disease outcomes. In addition, we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.
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Affiliation(s)
| | | | - Rui-Feng Yang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Lin-Xiang Huang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Hong-Song Chen
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Bo Feng
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
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17
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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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18
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Afifi AM, Elgenidy A, Hashim M, Awad AK, Jalal PK. Hepatitis B virus core-related antigen (HBcrAg) as a prognostic marker for the development of hepatocellular carcinoma: A mini systematic review of the literature. Rev Med Virol 2022; 32:e2353. [PMID: 35441759 DOI: 10.1002/rmv.2353] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/17/2022] [Accepted: 03/25/2022] [Indexed: 11/07/2022]
Abstract
Chronic hepatitis B (CHB) infection is a risk factor for hepatocellular carcinoma (HCC). Previous studies showed that elevated levels of Hepatitis B Virus (HBV) DNA and HBsAg are associated with increased HCC risk in patients with chronic HBV infection. Multiple studies showed that high levels of HBV DNA and Hepatitis B Surface Antigen (HBsAg) are associated with higher HCC risk in CHB patients. Patients treated with antiviral therapy may have undetectable or low levels of HBV DNA and HBsAg loss. However, HCC may develop in some patients with low-level HBV DNA and HBsAg seroconversion. In this study, we evaluated the role of HBcrAg in predicting HBV related HCC development. We searched PubMed, Scopus, and Web of Science databases using keywords (hepatitis B core-related antigen, hepatocellular carcinoma, liver neoplasm, hepatocellular and hepatic cancer, to identify studies assessing serum level of HBcrAg in patients with CHB and HCC. The search resulted in 184 studies. Seven studies were included: Four of which were retrospective cohort studies, and the rest were prospective cohort, case controls. Six of them reported a higher HBcrAg positivity rate in the HCC group when compared with the HBV DNA assay, yet with similar hazard ratio (HR) in predicting the incidence of HCC. However, four studies found that HBcrAg positivity was an independent risk factor for HCC development with a HR ranging from 3.27 to 7.05. HBV-related HCC has many proposed biomarkers in its prediction, yet our findings revealed HBcrAg to may have superiority over other biomarkers. High quality studies with bigger sample size research is needed to understand the potential role of HBcrAg in CHB induced HCC.
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Affiliation(s)
- Ahmed M Afifi
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | | | - Mahmoud Hashim
- Gastrointestinal Medical Oncology Department, MD Anderson Cancer Center, Houston, Texas, USA
| | - Ahmed K Awad
- Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| | - Prasun K Jalal
- Baylor College of Medicine Departments of Medicine and Surgery Physician (non-surgery), Houston, Texas, USA
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19
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Ceesay A, Bouherrou K, Tan BK, Lemoine M, Ndow G, Testoni B, Chemin I. Viral Diagnosis of Hepatitis B and Delta: What We Know and What Is Still Required? Specific Focus on Low- and Middle-Income Countries. Microorganisms 2022; 10:2096. [PMID: 36363693 PMCID: PMC9694472 DOI: 10.3390/microorganisms10112096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/11/2022] [Accepted: 10/18/2022] [Indexed: 01/25/2023] Open
Abstract
To achieve the World Health Organization's (WHO) goals of eradicating viral hepatitis globally by 2030, the regional prevalence and epidemiology of hepatitis B virus (HBV) and hepatitis delta virus (HDV) coinfection must be known in order to implement preventiveon and treatment strategies. HBV/HDV coinfection is considered the most severe form of vira l hepatitis due to it's rapid progression towards cirrhosis, hepatocellular carcinoma, and liver-related death. The role of simplified diagnosticsis tools for screening and monitoring HBV/HDV-coinfected patients is crucial. Many sophisticated tools for diagnoses have been developed for detection of HBV alone as well as HBV/HDV coinfection. However, these advanced techniques are not widely available in low-income countries and there is no standardization for HDV detection assays, which are used for monitoring the response to antiviral therapy. More accessible and affordable alternative methods, such as rapid diagnostic tests (RDTs), are being developed and validated for equipment-free and specific detection of HBV and HDV. This review will provide some insight into both existing and diagnosis tools under development, their applicability in developing countries and how they could increase screening, patient monitoring and treatment eligibility.
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Affiliation(s)
- Amie Ceesay
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
- Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara P.O. Box 273, Banjul, The Gambia
- School of Arts and Sciences, University of The Gambia, Serrekunda P.O. Box 3530, Banjul, The Gambia
| | - Khaled Bouherrou
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
| | - Boun Kim Tan
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
- Department of Intensive Care Unit, Hôpital Lyon Sud, Hospices Civils de Lyon, 165, Chemin du Grand Revoyet, 69310 Pierre-Bénite, France
| | - Maud Lemoine
- Division of Digestive Diseases, Section of Hepatology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W2 1NY, UK
| | - Gibril Ndow
- Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Atlantic Boulevard, Fajara P.O. Box 273, Banjul, The Gambia
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
| | - Isabelle Chemin
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France
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20
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Joshita S. Toward the accumulation of evidence for a novel high-sensitivity hepatitis B core-related antigen assay in patients with hepatitis B virus infection. Hepatol Res 2022; 52:743-744. [PMID: 36047630 DOI: 10.1111/hepr.13815] [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] [Indexed: 02/08/2023]
Affiliation(s)
- Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.,Department of Health Promotion Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
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21
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Hagiwara S, Kusumoto S, Inoue T, Ogawa S, Narita T, Ito A, Ri M, Komatsu H, Suzuki T, Matsuura K, Yagi S, Kaneko A, Aoyagi K, Iida S, Tanaka Y. Management of hepatitis B virus (HBV) reactivation in patients with resolved HBV infection based on a highly sensitive HB core-related antigen assay. Hepatol Res 2022; 52:745-753. [PMID: 35199427 DOI: 10.1111/hepr.13761] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/13/2022] [Accepted: 02/18/2022] [Indexed: 12/23/2022]
Abstract
AIMS To prevent hepatitis B virus (HBV) reactivation-related hepatitis, we examined the clinical usefulness of a highly sensitive HB core-related antigen (iTACT-HBcrAg) assay in patients with resolved HBV infection after nucleos(t)ide analog (NA) treatment for HBV reactivation. METHODS We retrospectively analyzed 27 patients with resolved HBV infection who experienced HBV reactivation (defined as HBV DNA levels of 1.3 log IU/ml or more), and who received systemic chemotherapies for hematological malignancies between 2008 and 2020. iTACT-HBcrAg, HBsAg-HQ, and antibodies against hepatitis B surface antigen (anti-HBs) were measured using samples stored after HBV reactivation. The lower limit of quantification for iTACT-HBcrAg was 2.0 log U/ml. RESULTS HBV reactivation was diagnosed at a median HBV DNA level of 1.8 log IU/ml, and then all patients received NA treatment. No patient had HBV-related hepatitis with a median maximum HBV DNA level of 2.0 log IU/ml. The positivities of iTACT-HBcrAg and HBsAg-HQ were 96% and 52% after HBV reactivation, respectively. Of 25 patients with detectable iTACT-HBcrAg at the initiation of NA treatment, 17 (68%) achieved iTACT-HBcrAg loss. Median durations from NA treatment to HBV DNA loss and iTACT-HBcrAg loss or the last follow-up were 35 and 175 days, respectively. Recurrence of HBV reactivation after NA cessation was not observed in seven of eight patients who achieved iTACT-HBcrAg loss or seropositive for anti-HBs during follow-up, except for one without anti-HBs after allogeneic transplantation. CONCLUSIONS iTACT-HBcrAg could be a potential surrogate marker for diagnosing early-stage HBV reactivation as well as safe cessation of NA treatment in patients with resolved HBV infection after HBV reactivation.
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Affiliation(s)
- Shinya Hagiwara
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shigeru Kusumoto
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Shintaro Ogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomoko Narita
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Asahi Ito
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masaki Ri
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirokazu Komatsu
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takanori Suzuki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shintaro Yagi
- Department of Research and Development, Advanced Life Science Institute, Inc., Hachioji, Japan
| | - Atsushi Kaneko
- Research and Development Division, Fujirebio Inc., Hachioji, Japan
| | - Katsumi Aoyagi
- Department of Research and Development, Advanced Life Science Institute, Inc., Hachioji, Japan
- Research and Development Division, Fujirebio Inc., Hachioji, Japan
| | - Shinsuke Iida
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan
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22
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Watanabe T, Hayashi S, Tanaka Y. Drug Discovery Study Aimed at a Functional Cure for HBV. Viruses 2022; 14:1393. [PMID: 35891374 PMCID: PMC9321005 DOI: 10.3390/v14071393] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/19/2022] [Accepted: 06/23/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) causes acute and, most importantly, chronic hepatitis B worldwide. Antiviral treatments have been developed to reduce viral loads but few patients with chronic hepatitis B (CHB) achieve a functional cure. The development of new therapeutic agents is desirable. Recently, many novel agents have been developed, including drugs targeting HBV-DNA and HBV-RNA. This review provides an overview of the developmental status of these drugs, especially direct acting antiviral agents (DAAs). Serological biomarkers of HBV infection are essential for predicting the clinical course of CHB. It is also important to determine the amount and activity of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. Hepatitis B core-associated antigen (HBcrAg) is a new HBV marker that has an important role in reflecting cccDNA in CHB, because it is associated with hepatic cccDNA, as well as serum HBV DNA. The highly sensitive HBcrAg (iTACT-HBcrAg) assay could be a very sensitive HBV activation marker and an alternative to HBV DNA testing for monitoring reactivation. Many of the drugs currently in clinical trials have shown efficacy in reducing hepatitis B surface antigen (HBsAg) levels. Combination therapies with DAAs and boost immune response are also under development; finding the best combinations will be important for therapeutic development.
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Affiliation(s)
| | | | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.W.); (S.H.)
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23
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Non-Achievement of Alanine Aminotransferase Normalization Associated with the Risk of Hepatocellular Carcinoma during Nucleos(t)ide Analogue Therapies: A Multicenter Retrospective Study. J Clin Med 2022; 11:jcm11092354. [PMID: 35566481 PMCID: PMC9101732 DOI: 10.3390/jcm11092354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with a chronic hepatitis B virus (HBV) infection who are treated with nucleos(t)ide analogues (NAs) are still at risk for hepatocellular carcinoma (HCC), and it has been clinically questioned whether patients with a high risk of HCC can be identified efficiently. We aimed to clarify the risk factors associated with the development of HCC during NA therapies. A total of 611 chronically HBV-infected patients without a history of HCC, who were treated with NAs for more than 6 months (median 72 months), from 2000 to 2021, were included from 16 hospitals in the Tohoku district in Japan. Incidences of HCC occurrence were analyzed with clinical factors, including on-treatment responses. Alanine aminotransferase (ALT) normalization, based on the criteria of three guidelines, was analyzed with other parameters, including the age−male−ALBI−platelets (aMAP) risk score. During the observation period, 48 patients developed HCC, and the cumulative HCC incidence was 10.6% at 10 years. Non-achievement of ALT normalization at 1 year of therapy was mostly associated with HCC development when ALT ≤ 30 U/L was used as the cut-off (cumulative incidence, 19.9% vs. 5.3% at 10 years, p < 0.001). The effectiveness of the aMAP risk score at the start of treatment was validated in this cohort. A combination of an aMAP risk score ≥ 50 and non-achievement of ALT normalization could stratify the risk of HCC significantly, and notably, there was no HCC development in 103 patients without these 2 factors. In conclusion, non-achievement of ALT normalization (≤30 U/L) at 1 year might be useful in predicting HCC during NA therapies and, in combination with the aMAP risk score, could stratify the risk more precisely.
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24
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Enomoto M, Umemura T, Suzuki F. I shall be released (from infinite HBV nucleos(t)ide analog therapy): Japanese experience. J Hepatol 2021; 75:1496-1497. [PMID: 34245805 DOI: 10.1016/j.jhep.2021.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/24/2021] [Accepted: 07/01/2021] [Indexed: 01/22/2023]
Affiliation(s)
- Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
| | - Takeji Umemura
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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25
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Tsuge M. The association between hepatocarcinogenesis and intracellular alterations due to hepatitis B virus infection. Liver Int 2021; 41:2836-2848. [PMID: 34559952 DOI: 10.1111/liv.15065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/13/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem leading to severe liver dysfunction, including liver cirrhosis and hepatocellular carcinoma. Although current antiviral therapies for chronic HBV infection have been improved and can lead to a strong suppression of viral replication, it is difficult to completely eliminate the virus with these therapies once chronic HBV infection is established in the host. Furthermore, chronic HBV infection alters intracellular metabolism and signalling pathways, resulting in the activation of carcinogenesis in the liver. HBV produces four viral proteins: hepatitis B surface-, hepatitis B core-, hepatitis B x protein, and polymerase; each plays an important role in HBV replication and the intracellular signalling pathways associated with hepatocarcinogenesis. In vitro and in vivo experimental models for analyzing HBV infection and replication have been established, and gene expression analyses using microarrays or next-generation sequencing have also been developed. Thus, it is possible to clarify the molecular mechanisms for intracellular alterations, such as endoplasmic reticulum stress, oxidative stress, and epigenetic modifications. In this review, the impact of HBV viral proteins and intracellular alterations in HBV-associated hepatocarcinogenesis are discussed.
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Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
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26
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Kawanaka M, Nishino K, Kawamoto H, Haruma K. Hepatitis B: Who should be treated?-managing patients with chronic hepatitis B during the immune-tolerant and immunoactive phases. World J Gastroenterol 2021; 27:7497-7508. [PMID: 34887645 PMCID: PMC8613739 DOI: 10.3748/wjg.v27.i43.7497] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/31/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
New hepatitis B virus (HBV) infections are decreasing owing to improved antiviral therapy and increased HBV vaccination worldwide; however, the number of HBV infections remains a major cause of liver carcinogenesis. HBV triggers cytotoxic immunity to eliminate HBV-infected cells. Therefore, the HBV pathophysiology changes in persistently infected individuals depending on host immune responses and HBV DNA proliferation state. To prevent liver cirrhosis and carcinogenesis caused by HBV, it is important to treat HBV infection at an early stage. Active treatment is recommended for the immunoactive hepatitis B surface-antigen-positive and -negative phase, but not during the immune-inactive phase or immune-tolerant phase; instead, follow-up is recommended. However, these patients should be monitored through regular blood tests to accurately diagnose the immune-inactive or -tolerant phases. The treatment regimen should be determined based on the age, sex, family history of liver cancer, and liver fibrosis status of patients. Early treatment is often recommended due to various problems during the immune-tolerant phase. This review compares the four major international practice guidelines, including those from the Japanese Society of Hepatology, and discusses strategies for chronic hepatitis B treatment during the immune-tolerant, immune-inactive, and resolved phases. Finally, recommended hepatitis B antiviral therapy and follow-up protocols are discussed.
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Affiliation(s)
- Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Ken Nishino
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
| | - Ken Haruma
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama 700-8505, Japan
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27
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Hayashi S, Nagaoka K, Tanaka Y. Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins. Int J Mol Sci 2021; 22:11051. [PMID: 34681709 PMCID: PMC8540379 DOI: 10.3390/ijms222011051] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of the pathogenesis of HBV infection and in clinical laboratory techniques have enabled the establishment of disease-specific tests, prediction of the progression of liver diseases, including HCC, and auxiliary diagnosis of HCC, using blood-based methods instead of biopsies of liver or HCC tissues. Viral factors such as the HBV genotype, HBV genetic mutations, HBV DNA, and HBV-related antigens, as well as host factors, such as tumor-associated proteins and post-translational modifications, especially glycosylated proteins, can be blood-based, disease-specific biomarkers for HCC development in HBV-infected patients. In this review, we describe the clinical applications of viral biomarkers, including the HBV genome and glycosylated proteins, for patients at a risk of HBV-related HCC, based on their molecular mechanisms. In addition, we introduce promising biomarker candidates for practical use, including colony stimulating factor 1 receptor (CSF1R), extracellular vesicles, and cell-free, circulating tumor DNA. The clinical use of such surrogate markers may lead to a better understanding of the risk of disease progression and early detection of HCC in HBV-infected patients, thereby improving their prognosis.
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Affiliation(s)
| | | | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (S.H.); (K.N.)
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28
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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: 21] [Impact Index Per Article: 5.3] [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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29
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Inoue T, Matsui T, Tanaka Y. Novel strategies for the early diagnosis of hepatitis B virus reactivation. Hepatol Res 2021; 51:1033-1043. [PMID: 34272919 DOI: 10.1111/hepr.13699] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) reactivation under systemic chemotherapy or immunosuppressive therapy is a serious complication among HBV-resolved patients. Some medications, such as more than 2 weeks of corticosteroid therapy, can influence HBV reactivation; therefore, screening tests that measure hepatitis B surface antigen (HBsAg), hepatitis B core antibody, and hepatitis B surface antibody before therapy are required. Additionally, because HBV reactivation has been reported in patients positive for HBsAg treated with immune checkpoint inhibitors (ICIs), the prophylactic administration of nucleos(t)ide analogues prior to administering ICIs is recommended for HBsAg-positive patients. Under these circumstances, highly sensitive novel biomarkers are expected to be used for the early diagnosis of HBV reactivation. A fully automated high-sensitivity HBsAg assay (detection limit: 5 mIU/ml) by Lumipulse HBsAg-HQ, with 10-fold higher sensitivity than that of conventional assays, is currently used. Furthermore, ultra-sensitive HBsAg assays using a semi-automated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA; detection limit: 0.5 mIU/ml) have been developed. Recently, a fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg; cut-off value: 2.1 Log U/mL) has been developed and reported. The utility of ICT-CLEIA and iTACT-HBcrAg for the diagnosis of HBV reactivation appears comparable to the use of HBV DNA. In this review, we provide the latest information related to medications that influence HBV reactivation and recently developed novel biomarkers that predict and monitor HBV reactivation.
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Grants
- 19H03640 the Ministry of Education, Culture, Sports, Science, and Technology
- AMED JP20fk0310101, JP21fk0310101 the Japan Agency for Medical Research and Development
- 19H03640 Ministry of Education, Culture, Sports, Science, and Technology
- AMED JP20fk0310101, JP21fk0310101 Japan Agency for Medical Research and Development
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Yasuhito Tanaka
- Department of Virology & 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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30
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Hosaka T, Suzuki F, Kobayashi M, Fujiyama S, Kawamura Y, Sezaki H, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H. Ultrasensitive Assay for Hepatitis B Core-Related Antigen Predicts Hepatocellular Carcinoma Incidences During Entecavir. Hepatol Commun 2021; 6:36-49. [PMID: 34532993 PMCID: PMC8710789 DOI: 10.1002/hep4.1819] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/15/2021] [Accepted: 08/22/2021] [Indexed: 01/05/2023] Open
Abstract
Serum hepatitis B core‐related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e‐antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow‐up of 11.0 years, 22 patients developed HCC (11.8/1,000 person‐years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log‐rank test; P < 0.001). In 110 patients (61.1%) with ≥4.0 log U/mL at baseline (high HBcrAg cohort), HBcrAg declined to ≤2.9 log U/mL at year 1 in 25 patients (22.7%). The adjusted hazard ratio for HCC incidence was significantly lower in patients with HBcrAg ≤2.9 log U/mL at year 1 than in those in the high HBcrAg cohort. Conclusion: Measurement of HBcrAg by ultrasensitive assay has better potential for predicting HCC during antiviral treatment than the current HBcrAg assay.
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Affiliation(s)
| | | | | | | | | | - Hitomi Sezaki
- Department of HepatologyToranomon HospitalTokyoJapan
| | - Norio Akuta
- Department of HepatologyToranomon HospitalTokyoJapan
| | | | | | | | - Yasuji Arase
- Department of HepatologyToranomon HospitalTokyoJapan
| | - Kenji Ikeda
- Department of HepatologyToranomon HospitalTokyoJapan
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