Research progress of biomarkers of hepatitis B virus and clinical significance_Journal of Biomedical Engineering

Authors：

WANG Xin ^1,2 , TANG Xiaoqiong ^1,2 , HAN Ning ^1,2 ,  TANG Hong ^1,2

1. Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
2. Divison of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

Keywords：

Hepatitis B virus; Biomarkers; HBcrAg; HBV RNA

DOI：

10.7507/1001-5515.202309041

Video：

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The infection of Hepatitis B virus (HBV) can result in severe consequences, including chronic hepatitis, liver fibrosis, cirrhosis, and even liver cancer. Effective antiviral treatment has the potential to slow down the progression of the disease. HBV serum biomarkers play a crucial role in the dynamic management of chronic hepatitis B (CHB) patients. However, the conventional hepatitis B virus markers, such as hepatitis B serologic testing and HBV DNA, are insufficient to meet the clinical requirements. This review provided a comprehensive overview of the current research on the quantification of HBsAg and anti-HBc, HBV RNA and HBV core-associated antigen, which summarized the crucial role these markers play in the administration of antiviral medications, predicting the efficacy of treatment and anticipating the likelihood of virologic rebound following drug cessation, as well as assessing disease progression in CHB patients.

Citation： WANG Xin, TANG Xiaoqiong, HAN Ning, TANG Hong. Research progress of biomarkers of hepatitis B virus and clinical significance. Journal of Biomedical Engineering, 2023, 40(6): 1242-1248. doi: 10.7507/1001-5515.202309041 Copy

1.	Global HIV, Hepatitis and Sexually Transmitted Infections Programmes. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016-2021: actions for impact. Geneva: WHO, 2022.
2.	Yoo S, Kim J Y, Lim Y S, et al. Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. J Hepatol, 2022, 77(4): 939-946.
3.	Terrault N A, Lok A S, Wahed A S, et al. Randomized trial of tenofovir with or without peginterferon alfa followed by protocolized treatment withdrawal in adults with chronic hepatitis B. Am J Gastroenterol, 2023, 118(7): 1214-1225.
4.	Li M, Zhang L, Lu Y, et al. Early serum HBsAg kinetics as predictor of HBsAg loss in patients with HBeAg-negative chronic hepatitis B after treatment with pegylated interferonα-2a. Virol Sin, 2021, 36(2): 311-320.
5.	Brakenhoff S M, De Man R A, Boonstra A, et al. Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss. Aliment Pharmacol Ther, 2021, 53(2): 314-320.
6.	Hall S A L, Burns G S, Anagnostou D, et al. Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels. Aliment Pharmacol Ther, 2022, 56(2): 310-320.
7.	Sonneveld M J, Chiu S M, Park J Y, et al. Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels. J Hepatol, 2022, 76(5): 1042-1050.
8.	Xie Y, Li M, Ou X, et al. Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation. BMC Gastroenterol, 2023, 23(1): 224.
9.	Sonneveld M J, Park J Y, Kaewdech A, et al. Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels: A multicenter study (CREATE). Clin Gastroenterol Hepatol, 2022, 20(4): e784-e793.
10.	Brakenhoff S M, De Knegt R J, Van Campenhout M J H, et al. End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients. J Microbiol Immunol Infect, 2023, 56(1): 31-39.
11.	Gan Q, Huang Y, Zhu C, et al. qHBsAg for the identification of liver histological abnormalities in HBeAg-negative chronic hepatitis B patients with normal and mildly elevated ALT levels. Can J Gastroenterol Hepatol, 2022, 2022: 8695196.
12.	Yao K, Wang J, Wang L, et al. Association of anti-HBc and liver inflammation in HBeAg-negative chronic hepatitis B virus-infected patients with normal ALT and detectable HBV DNA. J Med Virol, 2022, 94(2): 659-666.
13.	Brakenhoff S M, De Knegt R J, Oliveira J, et al. Levels of antibodies to hepatitis B core antigen are associated with liver inflammation and response to peginterferon in patients with chronic hepatitis B. J Infect Dis, 2022, 227(1): 113-122.
14.	Wang X, Gao X, Wu R, et al. Serum qAnti-HBc combined with ALT and HBsAg predicts significant hepatic inflammation in HBeAg-positive immune active patients. J Gastroenterol Hepatol, 2022, 37(9): 1806-1814.
15.	Fan R, Sun J, Yuan Q, et al. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues. Gut, 2016, 65(2): 313-320.
16.	Hou F Q, Song L W, Yuan Q, et al. Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon. Theranostics, 2015, 5(3): 218-226.
17.	Zhao X A, Wang J, Liu J, et al. Baseline serum hepatitis B core antibody level predicts HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B after antiviral treatment. Antiviral Res, 2021, 193: 105146.
18.	Fang Y Q, Xu X Y, Hou F Q, et al. A baseline model including quantitative anti-HBc to predict response of peginterferon in HBeAg-positive chronic hepatitis B patients. Antivir Ther, 2021, 26(6-8): 126-133.
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. Front Immunol, 2022, 13: 894410.
20.	Chi H, Li Z, Hansen B E, et al. Serum level of antibodies against hepatitis B core protein is associated with clinical relapse after discontinuation of nucleos(t)ide analogue therapy. Clin Gastroenterol Hepatol, 2019, 17(1): 182-191. e1.
21.	Chen E Q, Wang M L, Tao Y C, et al. Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA. J Viral Hepat, 2019, 26(5): 586-595.
22.	Wang J, Yu Y, Li G, et al. Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients. J Hepatol, 2018, 68(1): 16-24.
23.	Wang X, Chi X, Wu R, et al. Serum HBV RNA correlated with intrahepatic cccDNA more strongly than other HBV markers during peg-interferon treatment. Virol J, 2021, 18(1): 4.
24.	Carey I, Gersch J, Wang B, et al. Pregenomic HBV RNA and hepatitis B core-related antigen predict outcomes in hepatitis B e antigen-negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy. Hepatology, 2020, 72(1): 42-57.
25.	Farag M S, Van Campenhout M J H, Pfefferkorn M, et al. Hepatitis B virus RNA as early predictor for response to pegylated interferon alpha in HBeAg-negative chronic hepatitis B. Clin Infect Dis, 2021, 72(2): 202-211.
26.	Van Campenhout M J H, Van Bömmel F, Pfefferkorn M, et al. Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B. J Viral Hepat, 2020, 27(6): 610-619.
27.	Luo H, Tan N, Kang Q, et al. Hepatitis B virus pregenomic RNA status can reveal the long-term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues. J Viral Hepat, 2020, 27(3): 323-328.
28.	Van Bömmel F, Bartens A, Mysickova A, et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology, 2015, 61(1): 66-76.
29.	Seto W K, Liu K S, Mak L Y, et al. Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation. Gut, 2021, 70(4): 775-783.
30.	Fan R, Zhou B, Xu M, et al. Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucles(t)ide analogue therapy. Clin Gastroenterol Hepatol, 2020, 18(3): 719-727. e7.
31.	Thompson A J, Jackson K, Bonanzinga S, et al. Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants. Hepatol Commun, 2023, 7(8): e0188.
32.	Huang C, Li Q, Xu W, et al. Serum HBV RNA levels predict significant liver fibrosis in patients with chronic HBV infection. Discov Med, 2020, 29(157): 119-128.
33.	Liu S, Deng R, Zhou B, et al. Association of serum hepatitis B virus RNA with hepatocellular carcinoma risk in chronic hepatitis B patients under nucleos(t)ide analogues therapy. J Infect Dis, 2022, 226(5): 881-890.
34.	Xiao Y, Cao J, Zhang Z, et al. Hepatitis B virus pregenomic RNA reflecting viral replication in distal non-tumor tissues as a determinant of the stemness and recurrence of hepatocellular carcinoma. Front Microbiol, 2022, 13: 830741.
35.	Chen E Q, Feng S, Wang M L, et al. Serum hepatitis B core-related antigen is a satisfactory surrogate marker of intrahepatic covalently closed circular DNA in chronic hepatitis B. Sci Rep, 2017, 7(1): 173.
36.	Lee H A, Lee H W, Park Y, et al. Hepatitis B core-related antigen is useful for predicting phase and prognosis of hepatitis B e antigen-positive patients. J Clin Med, 2022, 11(6): 1729.
37.	Hwang S Y, Yoo S H, Chang H Y, et al. Baseline and on-treatment HBcrAg levels as predictors of HBeAgseroconversion in chronic hepatitis B patients treated with antivirals. J Viral Hepat, 2023, 30(1): 39-45.
38.	Wang M L, Liao J, Wei B, et al. Comparison of hepatitis B virus core-related antigen and hepatitis B surface antigen for predicting HBeAg seroconversion in chronic hepatitis B patients with pegylated interferon therapy. Infect Dis (Lond), 2018, 50(7): 522-530.
39.	Wang M L, Deng R, Chen E Q, et al. Performance of serum HBcrAg in chronic hepatitis B patients with 8-year nucleos(t)ide analogs therapy. Clin Res Hepatol Gastroenterol, 2019, 43(3): 301-309.
40.	Huang D, Wu D, Wang P, et al. End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB. J Hepatol, 2022, 77(1): 42-54.
41.	Fan R, Peng J, Xie Q, et al. Combining hepatitis B virus RNA and hepatitis B core-related antigen: Guidance for safely stopping nucleos(t)ide analogues in hepatitis B e antigen-positive patients with chronic hepatitis B. J Infect Dis, 2020, 222(4): 611-618.
42.	Papatheodoridi M, Papachristou E, Moschidis Z, et al. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy. J Viral Hepat, 2022, 29(11): 948-957.
43.	Mak L Y, Wong D, Kuchta A, et al. Hepatitis B virus pre-genomic RNA and hepatitis B core-related antigen reductions at week 4 predict favourable hepatitis B surface antigen response upon long-term nucleos(t)ide analogue in chronic hepatitis B. Clin Mol Hepatol, 2023, 29(1): 146-162.
44.	Liang L Y, Wong V W, Toyoda H, et al. Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients. J Gastroenterol, 2020, 55(9): 899-908.
45.	Kaneko S, Kurosaki M, Inada K, et al. Hepatitis B core-related antigen predicts disease progression and hepatocellular carcinoma in hepatitis B e antigen-negative chronic hepatitis B patients. J Gastroenterol Hepatol, 2021, 36(10): 2943-2951.
46.	Hosaka T, Suzuki F, Kobayashi M, et al. Ultrasensitive assay for hepatitis B core-related antigen predicts hepatocellular carcinoma incidences during entecavir. Hepatol Commun, 2022, 6(1): 36-49.
47.	Chang K C, Lin M T, Wang J H, et al. HBcrAg predicts hepatocellular carcinoma development in chronic B hepatitis related liver cirrhosis patients undergoing long-term effective anti-viral. Viruses, 2022, 14(12): 2671.
48.	Tseng T C, Hosaka T, Liu C J, et al. Hepatitis B core-related antigen stratifies the risk of liver cancer in HBeAg-negative patients with indeterminate phase. Am J Gastroenterol, 2022, 117(5): 748-757.

1. Global HIV, Hepatitis and Sexually Transmitted Infections Programmes. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016-2021: actions for impact. Geneva: WHO, 2022.
2. Yoo S, Kim J Y, Lim Y S, et al. Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. J Hepatol, 2022, 77(4): 939-946.
3. Terrault N A, Lok A S, Wahed A S, et al. Randomized trial of tenofovir with or without peginterferon alfa followed by protocolized treatment withdrawal in adults with chronic hepatitis B. Am J Gastroenterol, 2023, 118(7): 1214-1225.
4. Li M, Zhang L, Lu Y, et al. Early serum HBsAg kinetics as predictor of HBsAg loss in patients with HBeAg-negative chronic hepatitis B after treatment with pegylated interferonα-2a. Virol Sin, 2021, 36(2): 311-320.
5. Brakenhoff S M, De Man R A, Boonstra A, et al. Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss. Aliment Pharmacol Ther, 2021, 53(2): 314-320.
6. Hall S A L, Burns G S, Anagnostou D, et al. Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels. Aliment Pharmacol Ther, 2022, 56(2): 310-320.
7. Sonneveld M J, Chiu S M, Park J Y, et al. Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels. J Hepatol, 2022, 76(5): 1042-1050.
8. Xie Y, Li M, Ou X, et al. Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation. BMC Gastroenterol, 2023, 23(1): 224.
9. Sonneveld M J, Park J Y, Kaewdech A, et al. Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels: A multicenter study (CREATE). Clin Gastroenterol Hepatol, 2022, 20(4): e784-e793.
10. Brakenhoff S M, De Knegt R J, Van Campenhout M J H, et al. End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients. J Microbiol Immunol Infect, 2023, 56(1): 31-39.
11. Gan Q, Huang Y, Zhu C, et al. qHBsAg for the identification of liver histological abnormalities in HBeAg-negative chronic hepatitis B patients with normal and mildly elevated ALT levels. Can J Gastroenterol Hepatol, 2022, 2022: 8695196.
12. Yao K, Wang J, Wang L, et al. Association of anti-HBc and liver inflammation in HBeAg-negative chronic hepatitis B virus-infected patients with normal ALT and detectable HBV DNA. J Med Virol, 2022, 94(2): 659-666.
13. Brakenhoff S M, De Knegt R J, Oliveira J, et al. Levels of antibodies to hepatitis B core antigen are associated with liver inflammation and response to peginterferon in patients with chronic hepatitis B. J Infect Dis, 2022, 227(1): 113-122.
14. Wang X, Gao X, Wu R, et al. Serum qAnti-HBc combined with ALT and HBsAg predicts significant hepatic inflammation in HBeAg-positive immune active patients. J Gastroenterol Hepatol, 2022, 37(9): 1806-1814.
15. Fan R, Sun J, Yuan Q, et al. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues. Gut, 2016, 65(2): 313-320.
16. Hou F Q, Song L W, Yuan Q, et al. Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon. Theranostics, 2015, 5(3): 218-226.
17. Zhao X A, Wang J, Liu J, et al. Baseline serum hepatitis B core antibody level predicts HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B after antiviral treatment. Antiviral Res, 2021, 193: 105146.
18. Fang Y Q, Xu X Y, Hou F Q, et al. A baseline model including quantitative anti-HBc to predict response of peginterferon in HBeAg-positive chronic hepatitis B patients. Antivir Ther, 2021, 26(6-8): 126-133.
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. Front Immunol, 2022, 13: 894410.
20. Chi H, Li Z, Hansen B E, et al. Serum level of antibodies against hepatitis B core protein is associated with clinical relapse after discontinuation of nucleos(t)ide analogue therapy. Clin Gastroenterol Hepatol, 2019, 17(1): 182-191. e1.
21. Chen E Q, Wang M L, Tao Y C, et al. Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA. J Viral Hepat, 2019, 26(5): 586-595.
22. Wang J, Yu Y, Li G, et al. Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients. J Hepatol, 2018, 68(1): 16-24.
23. Wang X, Chi X, Wu R, et al. Serum HBV RNA correlated with intrahepatic cccDNA more strongly than other HBV markers during peg-interferon treatment. Virol J, 2021, 18(1): 4.
24. Carey I, Gersch J, Wang B, et al. Pregenomic HBV RNA and hepatitis B core-related antigen predict outcomes in hepatitis B e antigen-negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy. Hepatology, 2020, 72(1): 42-57.
25. Farag M S, Van Campenhout M J H, Pfefferkorn M, et al. Hepatitis B virus RNA as early predictor for response to pegylated interferon alpha in HBeAg-negative chronic hepatitis B. Clin Infect Dis, 2021, 72(2): 202-211.
26. Van Campenhout M J H, Van Bömmel F, Pfefferkorn M, et al. Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B. J Viral Hepat, 2020, 27(6): 610-619.
27. Luo H, Tan N, Kang Q, et al. Hepatitis B virus pregenomic RNA status can reveal the long-term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues. J Viral Hepat, 2020, 27(3): 323-328.
28. Van Bömmel F, Bartens A, Mysickova A, et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology, 2015, 61(1): 66-76.
29. Seto W K, Liu K S, Mak L Y, et al. Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation. Gut, 2021, 70(4): 775-783.
30. Fan R, Zhou B, Xu M, et al. Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucles(t)ide analogue therapy. Clin Gastroenterol Hepatol, 2020, 18(3): 719-727. e7.
31. Thompson A J, Jackson K, Bonanzinga S, et al. Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants. Hepatol Commun, 2023, 7(8): e0188.
32. Huang C, Li Q, Xu W, et al. Serum HBV RNA levels predict significant liver fibrosis in patients with chronic HBV infection. Discov Med, 2020, 29(157): 119-128.
33. Liu S, Deng R, Zhou B, et al. Association of serum hepatitis B virus RNA with hepatocellular carcinoma risk in chronic hepatitis B patients under nucleos(t)ide analogues therapy. J Infect Dis, 2022, 226(5): 881-890.
34. Xiao Y, Cao J, Zhang Z, et al. Hepatitis B virus pregenomic RNA reflecting viral replication in distal non-tumor tissues as a determinant of the stemness and recurrence of hepatocellular carcinoma. Front Microbiol, 2022, 13: 830741.
35. Chen E Q, Feng S, Wang M L, et al. Serum hepatitis B core-related antigen is a satisfactory surrogate marker of intrahepatic covalently closed circular DNA in chronic hepatitis B. Sci Rep, 2017, 7(1): 173.
36. Lee H A, Lee H W, Park Y, et al. Hepatitis B core-related antigen is useful for predicting phase and prognosis of hepatitis B e antigen-positive patients. J Clin Med, 2022, 11(6): 1729.
37. Hwang S Y, Yoo S H, Chang H Y, et al. Baseline and on-treatment HBcrAg levels as predictors of HBeAgseroconversion in chronic hepatitis B patients treated with antivirals. J Viral Hepat, 2023, 30(1): 39-45.
38. Wang M L, Liao J, Wei B, et al. Comparison of hepatitis B virus core-related antigen and hepatitis B surface antigen for predicting HBeAg seroconversion in chronic hepatitis B patients with pegylated interferon therapy. Infect Dis (Lond), 2018, 50(7): 522-530.
39. Wang M L, Deng R, Chen E Q, et al. Performance of serum HBcrAg in chronic hepatitis B patients with 8-year nucleos(t)ide analogs therapy. Clin Res Hepatol Gastroenterol, 2019, 43(3): 301-309.
40. Huang D, Wu D, Wang P, et al. End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB. J Hepatol, 2022, 77(1): 42-54.
41. Fan R, Peng J, Xie Q, et al. Combining hepatitis B virus RNA and hepatitis B core-related antigen: Guidance for safely stopping nucleos(t)ide analogues in hepatitis B e antigen-positive patients with chronic hepatitis B. J Infect Dis, 2020, 222(4): 611-618.
42. Papatheodoridi M, Papachristou E, Moschidis Z, et al. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy. J Viral Hepat, 2022, 29(11): 948-957.
43. Mak L Y, Wong D, Kuchta A, et al. Hepatitis B virus pre-genomic RNA and hepatitis B core-related antigen reductions at week 4 predict favourable hepatitis B surface antigen response upon long-term nucleos(t)ide analogue in chronic hepatitis B. Clin Mol Hepatol, 2023, 29(1): 146-162.
44. Liang L Y, Wong V W, Toyoda H, et al. Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients. J Gastroenterol, 2020, 55(9): 899-908.
45. Kaneko S, Kurosaki M, Inada K, et al. Hepatitis B core-related antigen predicts disease progression and hepatocellular carcinoma in hepatitis B e antigen-negative chronic hepatitis B patients. J Gastroenterol Hepatol, 2021, 36(10): 2943-2951.
46. Hosaka T, Suzuki F, Kobayashi M, et al. Ultrasensitive assay for hepatitis B core-related antigen predicts hepatocellular carcinoma incidences during entecavir. Hepatol Commun, 2022, 6(1): 36-49.
47. Chang K C, Lin M T, Wang J H, et al. HBcrAg predicts hepatocellular carcinoma development in chronic B hepatitis related liver cirrhosis patients undergoing long-term effective anti-viral. Viruses, 2022, 14(12): 2671.
48. Tseng T C, Hosaka T, Liu C J, et al. Hepatitis B core-related antigen stratifies the risk of liver cancer in HBeAg-negative patients with indeterminate phase. Am J Gastroenterol, 2022, 117(5): 748-757.

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Research progress of biomarkers of hepatitis B virus and clinical significance

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