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"Yasuhito Tanaka"

Original Article

Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues
Rui Huang, Dae Won Jun, Hidenori Toyoda, Yao-Chun Hsu, Huy Trinh, Akito Nozaki, Toru Ishikawa, Tsunamasa Watanabe, Haruki Uojima, Daniel Q. Huang, Takashi Honda, Yasuhito Tanaka, Philip Vutien, Sebastián Marciano, Hiroshi Abe, Masaru Enomoto, Masanori Atsukawa, Hirokazu Takahashi, Kunihiko Tsuji, Koichi Takaguchi, Pei-Chien Tsai, Chia-Yen Dai, Jee-Fu Huang, Chung-Feng Huang, Ming-Lun Yeh, Eileen Yoon, Sung Eun Kim, Sang Bong Ahn, Gi-Ae Kim, Jang Han Jung, Soung Won Jeong, Hyunwoo Oh, Cheng-Hao Tseng, Masatoshi Ishigami, Angela Chau, Mayumi Maeda, Satoshi Yasuda, Makoto Chuma, Takanori Ito, Keigo Kawashima, Joanne Kimiko Liu, Adrian Gadano, Ritsuzo Kozuka, Norio Itokawa, Kaori Inoue, Tomonori Senoh, Jie Li, Wan-Long Chuang, Ramsey Cheung, Chao Wu, Ming-Lung Yu, Mindie H. Nguyen
Clin Mol Hepatol 2025;31(3):1003-1017.
Published online March 17, 2025
DOI: https://doi.org/10.3350/cmh.2024.1070
Background/Aims
Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment.
Methods
We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes.
Results
The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).
Conclusions
Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.

Citations

Citations to this article as recorded by  Crossref logo
  • Type 2 diabetes mellitus as an independent predictor of significant fibrosis in treatment-naïve chronic hepatitis B patients with concurrent hepatic steatosis
    Jie Li, Liang Xu, Fajuan Rui, Sally Tran, Pei-Chien Tsai, Youwen Tan, Hidenori Toyoda, Qing-Lei Zeng, Huy Trinh, Yao-Chun Hsu, Tsunamasa Watanabe, Hiroshi Abe, Hiroyuki Motoyama, Yoko Yoshimaru, Takanori Suzuki, Taeang Arai, Masanori Atsukawa, Phillip Vut
    Hepatology.2026; 83(5): 1273.     CrossRef
  • Advancing metabolic risk profiling in chronic hepatitis B: Reply to correspondence on “Metabolic health in antiviral era of chronic hepatitis B”
    Shang-Chin Huang, Jia-Horng Kao
    Clinical and Molecular Hepatology.2026; 32(1): e117.     CrossRef
  • Metabolic health in antiviral era of chronic hepatitis B: Editorial on “Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues”
    Shang-Chin Huang, Jia-Horng Kao
    Clinical and Molecular Hepatology.2026; 32(1): 423.     CrossRef
  • Diagnosis and management of metabolic dysfunction-associated steatohepatitis in patients with chronic hepatitis B infection
    Talal K Bhatti, Joseph K Lim
    World Journal of Gastroenterology.2026;[Epub]     CrossRef
  • Diabetes Impairs the Virological Response in Patients with Chronic Hepatitis B: Glycemic Control as a Key Modifiable Risk Factor
    Aoyi Li, Yan Han, Guanglin Xiao, Zhiling Deng, Chaojing Wen, Ke Qiu, Taiyu He, Hong Ren
    Journal of Clinical Medicine.2026; 15(5): 1826.     CrossRef
  • Antiviral Therapy Reduces Hepatocellular Carcinoma and Cirrhosis Risk in Chinese Chronic Hepatitis B Patients With Mildly Elevated Alanine Aminotransferase
    Jian Wang, Zhiyi Zhang, Li Zhu, Tao Fan, Ye Xiong, Shaoqiu Zhang, Chao Jiang, Shengxia Yin, Xin Tong, Juan Xia, Xiaomin Yan, Renling Yao, Yu Shi, Xingxiang Liu, Chuanwu Zhu, Chao Wu, Rui Huang
    Clinical Gastroenterology and Hepatology.2026;[Epub]     CrossRef
  • Steatosis paradox: Unraveling pathways of suppressive effect of hepatic steatosis on hepatitis B virus
    Shang-Chin Huang, Jia-Horng Kao
    Biomedical Journal.2026; 49(3): 100969.     CrossRef
  • Impact of Cardiometabolic Risk Factors and Steatotic Liver Disease on Liver‐Related Outcomes in Patients With Chronic Hepatitis C After Curative Antiviral Therapy
    Chung‐Feng Huang, Yi‐Hung Lin, Pei‐Chien Tsai, Ming‐Lun Yeh, Chih‐Wen Wang, Tyng‐Yuan Jang, Po‐Cheng Liang, Yu‐Ju Wei, Nai‐Jen Hou, Ming‐Yen Hsieh, Chao‐Kuan Huang, Tzu‐Chun Lin, Jee‐Fu Huang, Chia‐Yen Dai, Wan‐Long Chuang, Ming‐Lung Yu
    The Kaohsiung Journal of Medical Sciences.2026;[Epub]     CrossRef
  • Absence of steatosis combined with cardiometabolic risk factors confers the highest hepatocellular carcinoma risk in treated chronic hepatitis B
    Hung-Wei Wang, Hsueh-Chou Lai, Wei-Fan Hsu, Sheng-Hung Chen, Yi-Chun Kuo, Cheng-Yuan Peng
    Annals of Medicine.2026;[Epub]     CrossRef
  • Diagnosing and defining MASLD in people living with chronic hepatitis B
    Emily Martyn, Alejandro Arenas-Pinto, Richard Gilson, Nomathemba Chandiwana, Stuart Flanagan, Douglas MacDonald, Emmanuel A. Tsochatzis, W. D. Francois Venter, Jennifer Manne-Goehler, Philippa C. Matthews
    Communications Medicine.2026;[Epub]     CrossRef
  • The Chronic Hepatitis B and Metabolic Dysfunction-Associated Steatotic Liver Disease Paradox: Friend or Foe?
    Shang-Chin Huang, Tai-Chung Tseng
    Gut and Liver.2026; 20(3): 350.     CrossRef
  • Differential HCC risk among HBV indeterminate types at baseline and by phase transition
    Rui Huang, Huy N Trinh, Satoshi Yasuda, Angela Chau, Mayumi Maeda, Ai-Thien Do, Daniel Q Huang, Takanori Ito, Takashi Honda, Masatoshi Ishigami, Ritsuzo Kozuka, Carmen Monica Preda, Cheng-Hao Tseng, Sebastián Marciano, Pei-Chien Tsai, Dong Hyun Lee, Chris
    Gut.2025; 74(11): 1873.     CrossRef
  • Incidence and determinants of achieving HBsAg <100 IU/mL in HBeAg-negative CHB patients with nucleos(t)ide analogue treatment
    Jian Wang, Tao Fan, Zhiyi Zhang, Li Zhu, Shaoqiu Zhang, Ye Xiong, Chun Shan, Chao Jiang, Shengxia Yin, Xin Tong, Renling Yao, Juan Xia, Xiaomin Yan, Yu Shi, Yuxin Chen, Xingxiang Liu, Huali Wang, Haixia Zhang, Chuanwu Zhu, Qun Zhang, Chao Wu, Rui Huang
    Emerging Microbes & Infections.2025;[Epub]     CrossRef
  • Impact of metabolic dysfunction on treatment responses to nucleos(t)ide analogues in chronic hepatitis B: a retrospective multi-center REAL-B cohort study
    Rui Huang, Dae Won Jun, Hidenori Toyoda, Yao-Chun Hsu, Huy Trinh, Akito Nozaki, Toru Ishikawa, Tsunamasa Watanabe, Haruki Uojima, Daniel Q. Huang, Takashi Honda, Yasuhito Tanaka, Philip Vutien, Sebastián Marciano, Hiroshi Abe, Masaru Enomoto, Masanori Ats
    eClinicalMedicine.2025; 87: 103407.     CrossRef
  • Aspirin Use and Risk of HCC and Gastrointestinal Bleeding in Patients With HBV‐Related Cirrhosis: A Landmark Analysis
    Mi Na Kim, Geun U. Park, Seng Chan You, Jae Seung Lee, Hye Won Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn
    Journal of Gastroenterology and Hepatology.2025; 40(11): 2750.     CrossRef
  • Multifunctional Metal Composite Hydrogels for Diabetic Wound Therapy
    Shengnan Zhang, Hui Gao, Kevin H. Mayo, Jingang Mo, Le Deng
    Gels.2025; 11(12): 960.     CrossRef
  • 14,198 View
  • 251 Download
  • 20 Web of Science
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Reviews

Viral hepatitis

Update on the treatment navigation for functional cure of chronic hepatitis B: Expert consensus 2.0
Di Wu, Jia-Horng Kao, Teerha Piratvisuth, Xiaojing Wang, Patrick T.F. Kennedy, Motoyuki Otsuka, Sang Hoon Ahn, Yasuhito Tanaka, Guiqiang Wang, Zhenghong Yuan, Wenhui Li, Young-Suk Lim, Junqi Niu, Fengmin Lu, Wenhong Zhang, Zhiliang Gao, Apichat Kaewdech, Meifang Han, Weiming Yan, Hong Ren, Peng Hu, Sainan Shu, Paul Yien Kwo, Fu-sheng Wang, Man-Fung Yuen, Qin Ning
Clin Mol Hepatol 2025;31(Suppl):S134-S164.
Published online January 22, 2025
DOI: https://doi.org/10.3350/cmh.2024.0780
As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

Citations

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  • Correspondence to editorial on “Switching to besifovir in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate: A randomized trial”
    Hyung Joon Yim, Seong Hee Kang, Young Kul Jung, Jin Mo Yang
    Clinical and Molecular Hepatology.2026; 32(1): e55.     CrossRef
  • Dynamics and Sensitivity of the Lifecycle of Hepatitis B Virus
    Dmitry Grebennikov, Igor Sazonov, Rostislav Savinkov, Matvey Zakharov, Mark Sorokin, Yakov Mokin, Andreas Meyerhans, Gennady Bocharov
    Pathogens.2026; 15(2): 172.     CrossRef
  • ZNF638 represses the transcription of HBV closed circular DNA involving HUSH complex-mediated histone modifications of epigenetic silencing
    Sifan Meng, Jiaqian Li, Yunlong Fang, Binwei Duan, Jing Wang, Yang Si, Feng Li, Qiong Wu, Shan Cheng, Wei Ding
    Cell Communication and Signaling.2026;[Epub]     CrossRef
  • Response to letters to editor "Next-Step Paradigms for Hepatitis B Functional Cure: Insights from the Anchor Combination Therapy Trial" and “Critical Appraisal of the Anchor RCT on Entecavir, Peginterferon Alfa-2b, and GM-CSF Combination Therapy”
    Di Wu, Da Huang, Weiming Yan, Qin Ning
    Hepatology International.2026;[Epub]     CrossRef
  • Response to letter to editor—Machine learning prediction of rapid HBsAg seroclearance at week 24 in inactive carriers treated with pegylated interferon
    Jianxia Dong, Sujun Zheng, Xinyue Chen
    Hepatology International.2026;[Epub]     CrossRef
  • Mechanisms and management of pegylated interferon-α toxicity in chronic hepatitis B
    Liya Zhu, Fei Peng, Dingfang Pi, Jinzhi Lu
    Frontiers in Immunology.2026;[Epub]     CrossRef
  • Long-term antiviral therapy sustains HBsAg decline, increases HBV RNA negativity and enhances the proportion of patients achieving functional cure in chronic hepatitis B
    Ruihan Gao, Shuting Liu, Shiyu Zhang, Xin Zhou, Bin Zhu, Baoju Wang
    Annals of Hepatology.2026; 31(2): 102212.     CrossRef
  • Hepatitis B in Africa: Progress toward World Health Organization 2030 targets, persistent disparities, and COVID-19 setbacks
    Kui Wang, Ruchen Zhou
    Clinical and Molecular Hepatology.2026; 32(2): e211.     CrossRef
  • A Comparative Study of Entecavir and Tenofovir Alafenamide on Quantitative HBsAg Reduction in Patients With CHB
    Jungnam Lee, Young‐Joo Jin
    Journal of Medical Virology.2026;[Epub]     CrossRef
  • Hepatitis B in Children: A Review of Current Knowledge and Future Directions
    Paola Carolina Espin Diaz, Swati Antala
    Current Treatment Options in Pediatrics.2026;[Epub]     CrossRef
  • Functional cure for chronic hepatitis B on hepatocellular carcinoma prevention: Evidence and clinical implications
    Wen Kang, Yu-Shen Liu, Tian-Ping Wang, Shu-Ming Zhang, Yu Li, Ye Zhang
    iLIVER.2026; 5(2): 100235.     CrossRef
  • Efficacy and Safety of Pegylated Interferon as Rescue Therapy for Patients with Chronic Hepatitis B Who Failed to Achieve Functional Cure After Antisense Oligonucleotides or Small Interfering RNA: A Prospective, Multicentre, Open-Label Randomized Controll
    Qiran Zhang, Feng Sun, Shulan Sui, Jianmei Lin, Chuncheng Wu, Jing Yuan, Yingli He, Jia Shang, Tao Han, Ying Zhu, Zuxiong Huang, Chen Chen, Chao Qiu, Xing Wang, Jiming Zhang, Yao Xie, Wenhong Zhang
    Advances in Therapy.2026;[Epub]     CrossRef
  • Residual viral expression in siRNA-treated HBV-replicating cell and mouse models
    Mingzhu Xu, Yuyan Qian, Ziyang Song, Haiyu Wang, Lei Yue, Jiangxia Liu, Yaming Li, Wenjing Zai, Zhenghong Yuan, Jieliang Chen
    Antiviral Research.2025; 240: 106210.     CrossRef
  • Anti-HBV treatment partially restores the dysfunction of innate immune cells and unconventional T cells during chronic HBV infection
    Yiwen Shu, Sumeng Li, Yanqin Du, Xin Zheng
    Frontiers in Immunology.2025;[Epub]     CrossRef
  • Quantitatively Evaluate the Improvement of Functional Cure for the Quality of Life of Chronic Hepatitis B Cases: Evidence from a Cross-Sectional Study in China
    Sihui Zhang, Zhiliang Gao, Hui Li, Yi Kang, Lei Fu, Xuebing Chen, Xiaoyuan Xu, Xinyue Chen, Hui Zhuang, Hui Zheng, Fuqiang Cui
    Healthcare.2025; 13(20): 2590.     CrossRef
  • Discontinuation of nucleos(t)ide analogues after NA-induced HBsAg seroclearance: a single-center 48-week retrospective study
    Yong-Hong Wang, Ya-Chao Tao, Meng-Lan Wang, Cheng-Run Song, Jiang-Nan Peng, En-Qiang Chen
    Journal of Virus Eradication.2025; 11(4): 100617.     CrossRef
  • An RNA interference therapeutic potentially achieves functional cure of chronic hepatitis B virus infection
    Ze-Ao Huang, Yang Yang, Shuo Yang, Guang-Shen Ji, Rui Fu, Zhi-Kang Tian, Yu-Cheng Wu, Geng-Shen Song
    Nature Communications.2025;[Epub]     CrossRef
  • A Study on Serum Protein Tracking in Patients with Low Levels of HBsAg Undergoing Treatment for Chronic Hepatitis B with a Combination of Tenofovir Disoproxil Fumarate and Pegylated Interferon
    Yimin Chen, Min Deng, Mingkai Tong, Peixia Lin, Hua Xuan, Dahai Wei
    Hepatitis Monthly.2025;[Epub]     CrossRef
  • Machine learning model for HBsAg seroclearance after 48-week pegylated interferon therapy in inactive HBsAg carriers: a retrospective study
    Jianxia Dong, Shan Ren, Jing Zhao, Pengxuan Wu, Haitian Yu, Yao Xie, Junliang Fu, Xiaorong Mao, Zhiliang Gao, Bingliang Lin, Qingfa Ruan, Yongfang Jiang, Xiulan Xue, Yueyong Zhu, Haidong Zhao, Haifang Cao, Xinyue Chen, Sujun Zheng
    Virology Journal.2025;[Epub]     CrossRef
  • Functional cure of chronic hepatitis B virus infection: current therapeutic regimens
    Yi-Wei Shi, Rui Pu, Yi-Bo Ding, Wen-Bin Liu, Zi-Shuai Li, Jia-Yi Zhao, Yi-Fan Chen, Guang-Wen Cao
    Hepatoma Research.2025;[Epub]     CrossRef
  • 19,050 View
  • 672 Download
  • 20 Web of Science
  • Crossref

Viral hepatitis

Hepatitis B core-related antigen: A novel and promising surrogate biomarker to guide anti-hepatitis B virus therapy
Takako Inoue, Takehisa Watanabe, Yasuhito Tanaka
Clin Mol Hepatol 2023;29(4):851-868.
Published online March 9, 2023
DOI: https://doi.org/10.3350/cmh.2022.0434
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.

Citations

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  • Similar hepatic outcome by SGLT2i vs. DPP4i for at-risk cohort with CHB & T2DM: A nationwide target trial emulation study
    Byungyoon Yun, Juyeon Oh, Heejoo Park, Jian Lee, Beom Kyung Kim, Jin-Ha Yoon
    Annals of Hepatology.2026; 31(1): 102175.     CrossRef
  • Strategic analysis of hepatitis B virus serological profile and the diagnostic utility of HBcrAg across Osun and Plateau State, Nigeria
    Priscilla Abechi, Uwem E. George, Olamide Y. Aborisade, Arthur O. Oragwa, Oluwatomisin P. Osijonwo, Oluremi I. Ajayi, Olusola A. Ogunsanya, Christian Happi, Onikepe A. Folarin
    Journal of Immunoassay and Immunochemistry.2026; 47(2): 129.     CrossRef
  • High Intrahepatic cccDNA in Resolved HBV Infection: Insights From Living Donor Liver Transplantation With Anti‐HBc‐Positive Grafts
    Sung Kwan Bae, Nobuhisa Akamatsu, Akihiko Ichida, Yujiro Nishioka, Yoshinori Inagaki, Nozomi Miyake, Takeshi Takamoto, Yoshikuni Kawaguchi, Sumihito Tamura, Junichi Arita, Junichi Kaneko, Motoyuki Otsuka, Yasuhito Tanaka, Hiroshi Yotsuyanagi, Kyoji Moriya
    Journal of Gastroenterology and Hepatology.2026; 41(4): 1335.     CrossRef
  • Analysis of HBV Genome Integration in Patients With HBV‐Previously Infected NBNC‐HCC
    Tomoya Saito, Rigel Suzuki, Akhinur Rahman, Kento Mori, Samiul Alam Rajib, Nobuhiro Kobayashi, Yoichi Yamamoto, Sharmin Nahar Sithi, Takaya Ichikawa, Tatsuya Orimo, Tatsuhiko Kakisaka, Lihan Liang, Naganori Nao, Saori Suzuki, Tomokazu Tamura, Yorifumi Sat
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    Egyptian Liver Journal.2026;[Epub]     CrossRef
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    Beom Kyung Kim
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    Beom Kyung Kim
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    Virologica Sinica.2025; 40(4): 579.     CrossRef
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    Yong-Hong Wang, Ya-Chao Tao, Meng-Lan Wang, Cheng-Run Song, Jiang-Nan Peng, En-Qiang Chen
    Journal of Virus Eradication.2025; 11(4): 100617.     CrossRef
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    Takehisa Watanabe, Katsuya Nagaoka
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    Hepatology Research.2024; 54(7): 615.     CrossRef
  • Long-Term Outcomes after Switching to Tenofovir Alafenamide in Patients with Chronic Hepatitis B
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    International Journal of Molecular Sciences.2024; 25(4): 2245.     CrossRef
  • Kinetics and Value of Hepatitis B Core-Related Antigen in Patients with Chronic Hepatitis B Virus Infection during Antiviral Treatment
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Viral hepatitis

Novel biomarkers for the management of chronic hepatitis B
Takako Inoue, Yasuhito Tanaka
Clin Mol Hepatol 2020;26(3):261-279.
Published online June 15, 2020
DOI: https://doi.org/10.3350/cmh.2020.0032
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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