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CN 22-1108/R
Volume 42 Issue 7
Jul.  2026
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Article Navigation >  Journal of Clinical Hepatology  > 2026  >  42(7): 1532-1540

Multidimensional diagnostic biomarkers for functional cure of chronic hepatitis B

DOI: 10.12449/JCH260708
  • 1.

    Department of Hepatology，Center of Infectious Diseases and Pathogen Biology，The First Hospital of Jilin University，Changchun 130021，China

  • 2.

    Jilin Provincial Key Laboratory of Metabolic Liver Diseases，Changchun 130021，China

  • 3.

    China-Singapore Belt and Road Joint Laboratory on Liver Disease Research，Changchun 130021，China

Research funding:

National Science and Technology Major Project of China (2025ZD01905902);

National Key Research and Development Program of China (2024YFE0213800)

More Information
  • Corresponding author: Niu Junqi， junqiniu@aliyun.com （ORCID： 0000-0002-1696-6008）; Gao Yanhang， yanhang@jlu.edu.cn （ORCID： 0000-0001-8590-6706）
  • Received Date: 2026-05-03
  • Accepted Date: 2026-05-13
  • Published Date: 2026-07-25
    Abstract
  • Chronic hepatitis B （CHB） is a significant public health issue worldwide. The persistent presence of covalently closed circular DNA of the hepatitis B virus （HBV） and the integration of the viral genome are the main obstacles limiting the achievement of virological cure in CHB. Functional cure has now become an important goal in antiviral therapy for CHB， and its accurate determination and efficacy prediction rely on a comprehensive assessment of multidimensional diagnostic markers. This article systematically reviews the research advances in diagnostic markers associated with functional cure in CHB， focusing on the clinical value of serological and virological indicators （HBsAg quantification and HBV DNA）， genomic， transcriptomic， proteomic， and metabolomic markers， and indicators associated with host innate immunity and adaptive immunity. Furthermore， it discusses future research directions such as the establishment of unified detection standards and the construction of predictive models combining multiple markers， in order to promote the precise assessment and individualized management of functional cure in CHB.

     

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    • References(39)
  • [1]
    World Health Organization. Global hepatitis report 2024: Action for access in low- and middle-income countries[EB/OL].( 2024-04-09)[ 2026-04-28]. https://www.who.int/publications/i/item/9789240091672. https://www.who.int/publications/i/item/9789240091672
    [2]
    Hsu Y C, Huang D Q, Nguyen M H. Global burden of hepatitis B virus: Current status, missed opportunities and a call for action[J]. Nat Rev Gastroenterol Hepatol, 2023, 20( 8): 524- 537. DOI: 10.1038/s41575-023-00760-9.
    [3]
    Ito T, Nguyen M H. Perspectives on the underlying etiology of HCC and its effects on treatment outcomes[J]. J Hepatocell Carcinoma, 2023, 10: 413- 428. DOI: 10.2147/JHC.S347959.
    [4]
    Infectious Disease Prevention and Control Branch of Chinese Preventive Medicine Association. Chinese expert consensus on clinical practice of chronic hepatitis B functional(clinical) cure[J]. Chin J Viral Dis, 2026, 16( 1): 16- 27. DOI: 10.16505/j.2095-0136.2025.0080.

    中华预防医学会感染性疾病防控分会. 中国慢性乙型肝炎功能性(临床)治愈临床实践专家共识[J]. 中国病毒病杂志, 2026, 16( 1): 16- 27. DOI: 10.16505/j.2095-0136.2025.0080.
    [5]
    Gan W Q, Gao N, Gu L, et al. Reduction in intrahepatic cccDNA and integration of HBV in chronic hepatitis B patients with a functional cure[J]. J Clin Transl Hepatol, 2023, 11( 2): 314- 322. DOI: 10.14218/JCTH.2022.00177.
    [6]
    Xu H, Locarnini S, Wong D, et al. Role of anti-HBs in functional cure of HBeAg+ chronic hepatitis B patients infected with HBV genotype A[J]. J Hepatol, 2022, 76( 1): 34- 45. DOI: 10.1016/j.jhep.2021.07.031.
    [7]
    Fan R, Zhao S R, Niu J Q, et al. High accuracy model for HBsAg loss based on longitudinal trajectories of serum qHBsAg throughout long-term antiviral therapy[J]. Gut, 2024, 73( 10): 1725- 1736. DOI: 10.1136/gutjnl-2024-332182.
    [8]
    Li S, Shi L C, Huang C, et al. Impact of hepatitis B surface antigen quantification on achieving a functional cure in patients with chronic hepatitis B: A systematic review and meta-analysis[J]. Ann Hepatol, 2025, 30( 2): 101921. DOI: 10.1016/j.aohep.2025.101921.
    [9]
    Tseng T C, Huang S C, Pan M H, et al. Hepatitis B surface antigen level identifies patients with inactive chronic hepatitis B from Asia with HCC risk below surveillance threshold[J]. Gut, 2025, 74( 11): 1896- 1904. DOI: 10.1136/gutjnl-2025-334911.
    [10]
    Leung R H, Hui R W, Mak L Y, et al. ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B[J]. J Hepatol, 2024, 81( 2): 218- 226. DOI: 10.1016/j.jhep.2024.03.022.
    [11]
    Zhang Y, Wang L F, Chen J, et al. Traditional and novel virologic markers for functional cure and HBeAg loss with pegylated interferon in chronic hepatitis B: A systematic review and meta-analysis[J]. J Clin Transl Hepatol, 2026, 14( 2): 159- 167. DOI: 10.14218/JCTH.2025.00443.
    [12]
    Zhuang Hui. Are there only a few steps away from the prime time for hepatitis B virus RNA as a routine marker to guide decision making in treatment of chronic hepatitis B?[J]. J Clin Hepatol, 2022, 38( 2): 285- 287. DOI: 10.3969/j.issn.1001-5256.2022.02.008.

    庄辉. HBV RNA作为常规指标指导慢性乙型肝炎治疗决策是否只有几步之遥?[J]. 临床肝胆病杂志, 2022, 38( 2): 285- 287. DOI: 10.3969/j.issn.1001-5256.2022.02.008.
    [13]
    Hershkovich L, Cotler S J, Shekhtman L, et al. HBV serum RNA kinetics during nucleic acid polymers based therapy predict functional cure[J]. Antiviral Res, 2025, 234: 106061. DOI: 10.1016/j.antiviral.2024.106061.
    [14]
    Testoni B, Lebossé F, Scholtes C, et al. Serum hepatitis B core-related antigen(HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients[J]. J Hepatol, 2019, 70( 4): 615- 625. DOI: 10.1016/j.jhep.2018.11.030.
    [15]
    Wang B, Carey I, Bruce M, et al. HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg-positive patients treated with nucleos(t)ide analogues[J]. J Viral Hepat, 2018, 25( 8): 886- 893. DOI: 10.1111/jvh.12889.
    [16]
    Qiu Y, Tang Q, Liu X Q, et al. Hepatitis B core-related antigen as a promising serological marker for monitoring hepatitis B virus cure[J]. World J Hepatol, 2025, 17( 1): 98658. DOI: 10.4254/wjh.v17.i1.98658.
    [17]
    Han L, Wang Z, Kang L, et al. Predicting relapse after achieving a functional cure for chronic hepatitis B(CHB) using baseline HBsAg and end-of-treatment HBsAb levels[J]. Sci Rep, 2025, 15( 1): 13873. DOI: 10.1038/s41598-025-86555-1.
    [18]
    Zhu D M, Liu L C, Yang D, et al. Clearing persistent extracellular antigen of hepatitis B virus: An immunomodulatory strategy to reverse tolerance for an effective therapeutic vaccination[J]. J Immunol, 2016, 196( 7): 3079- 3087. DOI: 10.4049/jimmunol.1502061.
    [19]
    Wang W X, Jia R, Gao Y Y, et al. Quantitative anti-HBc combined with quantitative HBsAg can predict HBsAg clearance in sequential combination therapy with PEG-IFN-α in NA-suppressed chronic hepatitis B patients[J]. Front Immunol, 2022, 13: 894410. DOI: 10.3389/fimmu.2022.894410.
    [20]
    Zeng J Y, Zheng C X, Zheng Y C, et al. Predictive value of hepatic, hematological, and immunological markers and their temporal dynamics in chronic hepatitis B functional cure[J]. Microbiol Spectr, 2025, 13( 10): e0178025. DOI: 10.1128/spectrum.01780-25.
    [21]
    Li M H, Zhang L X, Xie S, et al. Dynamic changes of cytokine profiles and virological markers associated with HBsAg loss during peginterferon alpha-2a treatment in HBeAg-positive chronic hepatitis B patients[J]. Front Immunol, 2022, 13: 892031. DOI: 10.3389/fimmu.2022.892031.
    [22]
    Luo M Q, Hou J, Mai H M, et al. TRIM26 inhibits hepatitis B virus replication by promoting HBx degradation and TRIM26 genetic polymorphism predicts PegIFNα treatment response of HBeAg-positive chronic hepatitis B Patients[J]. Aliment Pharmacol Ther, 2022, 56( 5): 878- 889. DOI: 10.1111/apt.17124.
    [23]
    Wang L, Zou Z Q, Wang K. Clinical relevance of HLA gene variants in HBV infection[J]. J Immunol Res, 2016, 2016: 9069375. DOI: 10.1155/2016/9069375.
    [24]
    Ye B, Liu X, Li X, et al. T-cell exhaustion in chronic hepatitis B infection: Current knowledge and clinical significance[J]. Cell Death Dis, 2015, 6( 3): e1694. DOI: 10.1038/cddis.2015.42.
    [25]
    Yu Xiaoqi, Zhang Xinxin. Effect of hepatitis B virus integration on functional cure[J]. J Clin Hepatol, 2025, 41( 1): 24- 29. DOI: 10.12449/JCH250104.

    俞晓琦, 张欣欣. 乙型肝炎病毒基因整合对功能性治愈的影响[J]. 临床肝胆病杂志, 2025, 41( 1): 24- 29. DOI: 10.12449/JCH250104.
    [26]
    Wang Z M, Liu N, Yang Y, et al. The novel mechanism facilitating chronic hepatitis B infection: Immunometabolism and epigenetic modification reprogramming[J]. Front Immunol, 2024, 15: 1349867. DOI: 10.3389/fimmu.2024.1349867.
    [27]
    Narmada B C, Khakpoor A, Shirgaonkar N, et al. Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity[J]. J Hepatol, 2024, 81( 1): 42- 61. DOI: 10.1016/j.jhep.2024.02.017.
    [28]
    Cortese M, Zhang L, Pan D, et al. Identification of liver-associated gene signatures from serum exosomes in patients with chronic hepatitis B[J]. J Hepatol, 2023, 78( s1): S1055. DOI: 10.1016/S0168-8278(23)03152-5
    [29]
    Gan W Q, Chen X, Wu Z Q, et al. The relationship between serum exosome HBV-miR-3 and current virological markers and its dynamics in chronic hepatitis B patients on antiviral treatment[J]. Ann Transl Med, 2022, 10( 10): 536. DOI: 10.21037/atm-22-2119.
    [30]
    Zhu C L, Song H, Xu F X, et al. Hepatitis B virus inhibits the expression of complement C3 and C4, in vitro and in vivo[J]. Oncol Lett, 2018, 15( 5): 7459- 7463. DOI: 10.3892/ol.2018.8223.
    [31]
    Lin K, Qiu R X, Wu S H, et al. Multiomics analyses reveal that fatty acid metabolism and TCA cycle contribute to the achievement of functional cure in chronic hepatitis B[J]. J Proteome Res, 2025, 24( 1): 268- 281. DOI: 10.1021/acs.jproteome.4c00747.
    [32]
    Shu Y W, Li S M, Du Y Q, et al. Anti-HBV treatment partially restores the dysfunction of innate immune cells and unconventional T cells during chronic HBV infection[J]. Front Immunol, 2025, 16: 1611976. DOI: 10.3389/fimmu.2025.1611976.
    [33]
    Pathania A S, Bhat S A, Adepoju L A, et al. Hepatic macrophages in chronic hepatitis B: Balancing immunity and pathology[J]. Biology, 2025, 15( 1): 76. DOI: 10.3390/biology15010076.
    [34]
    Zhang P, Wang W X, Li J, et al. CD300A+ CD8+ T cells as predictive biomarkers for achieving functional cure in chronic hepatitis B patients undergoing pegylated interferon-alpha therapy[J]. Aliment Pharmacol Ther, 2025, 62( 5): 512- 525. DOI: 10.1111/apt.70214.
    [35]
    Hoogeveen R C, Dijkstra S, Bartsch L M, et al. Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection[J]. J Hepatol, 2022, 77( 5): 1276- 1286. DOI: 10.1016/j.jhep.2022.05.041.
    [36]
    Gu Q, Mao M X, Liu Y, et al. Activated circulating T follicular helper 17 cells positively correlated with anti-HBV humoral immunity in chronic hepatitis B patients[J]. Front Microbiol, 2025, 16: 1708034. DOI: 10.3389/fmicb.2025.1708034.
    [37]
    Gu S Q, Tang L B, Guo L, et al. Circulating HBsAg-specific B cells are partially rescued in chronically HBV-infected patients with functional cure[J]. Emerg Microbes Infect, 2024, 13( 1): 2409350. DOI: 10.1080/22221751.2024.2409350.
    [38]
    Wu Y L, Wang X X, Lin X, et al. Quantitative of serum hepatitis B core antibody is a potential predictor of recurrence after interferon-induced hepatitis B surface antigen clearance[J]. J Microbiol Immunol Infect, 2021, 54( 2): 238- 244. DOI: 10.1016/j.jmii.2019.09.004.
    [39]
    Chen X Y, Zhang B X, Song X, et al. Serum sPD-1 and sPD-L1 as predictive biomarkers for HBsAg clearance in HBeAg-negative CHB patients undergoing IFN-based therapy[J]. Aliment Pharmacol Ther, 2024, 60( 5): 593- 603. DOI: 10.1111/apt.18131.
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