Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load.
Journal
Alimentary pharmacology & therapeutics
ISSN: 1365-2036
Titre abrégé: Aliment Pharmacol Ther
Pays: England
ID NLM: 8707234
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
27
10
2020
received:
29
09
2020
accepted:
04
01
2021
pubmed:
20
1
2021
medline:
20
4
2021
entrez:
19
1
2021
Statut:
ppublish
Résumé
Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication. To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19 999 IU/mL) due to their moderate risk of disease progression. A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40 U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10 KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load. Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9 years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20 000 IU/mL after 3 years of follow-up. In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10 KU/mL defines a low-risk group for disease progression.
Sections du résumé
BACKGROUND
Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication.
AIM
To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19 999 IU/mL) due to their moderate risk of disease progression.
METHODS
A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40 U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10 KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load.
RESULTS
Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9 years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20 000 IU/mL after 3 years of follow-up.
CONCLUSIONS
In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10 KU/mL defines a low-risk group for disease progression.
Substances chimiques
DNA, Viral
0
Hepatitis B Core Antigens
0
Hepatitis B e Antigens
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
908-918Informations de copyright
© 2021 John Wiley & Sons Ltd.
Références
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546-1555.
Kao J-H. Hepatitis B: from control to cure. J Formosan Med Assoc. 2018;117(10):868-870.
Tseng T-C, Liu C-J, Chen C-L, et al. Serum hepatitis B virus-DNA levels correlate with long-term adverse outcomes in spontaneous hepatitis B e antigen seroconverters. J Infect Dis. 2012;205:54-63.
Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686.
Tseng T-C, Liu C-J, Yang H-C, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut. 2015;64:292-302.
Tseng T-C, Liu C-J, Su T-H, et al. Fibrosis-4 index predicts cirrhosis risk and liver-related mortality in 2075 patients with chronic HBV infection. Aliment Pharmacol Ther. 2018;47:1480-1489.
Chu CM, Chen YC, Tai DI, Liaw YF. Level of hepatitis B virus DNA in inactive carriers with persistently normal levels of alanine aminotransferase. Clin Gastroenterol Hepatol. 2010;8:535-540.
Bonacci M, Lens S, Mariño Z, et al. Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the Grey Zone. Aliment Pharmacol Ther. 2018;47:1397-1408.
Oliveri F, Surace L, Cavallone D, et al. Long-term outcome of inactive and active, low viraemic HBeAg-negative-hepatitis B virus infection: Benign course towards HBsAg clearance. Liver Int. 2017;37:1622-1631.
Zhou K, Wahed AS, Cooper S, et al. Phase transition is infrequent among North American adults with e-antigen-negative chronic hepatitis B and low-level viremia. Am J Gastroenterol. 2019;114:1753-1763.
Wong DK, Seto WK, Cheung KS, et al. Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA. Liver Int. 2017;37:995-1001.
Testoni B, Lebosse 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 Hepatol. 2019;70:615-625.
Tada T, Kumada T, Toyoda H, et al. HBcrAg predicts hepatocellular carcinoma development: an analysis using time-dependent receiver operating characteristics. J Hepatol. 2016;65:48-56.
Tseng TC, Liu CJ, Hsu CY, et al. High level of hepatitis B core-related antigen associated with increased risk of hepatocellular carcinoma in patients with chronic HBV infection of intermediate viral load. Gastroenterology. 2019;157:1518-1529, e3.
To WP, Mak LY, Wong DK, et al. Hepatitis B core-related antigen levels after HBeAg seroconversion is associated with the development of hepatocellular carcinoma. J Viral Hepat. 2019;26:1473-1480.
Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560-1599.
European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;2017:370-398.
Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1-98.
Tseng TC, Liu CJ, Yang HC, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142:1140-1149.
Tseng TC, Liu CJ, Su TH, et al. Fibrosis-4 index helps identify HBV carriers with the lowest risk of hepatocellular carcinoma. Am J Gastroenterol. 2017;112:1564-1574.
Tseng T-C, Liu C-J, Chang CT, et al. HEV superinfection accelerates disease progression in patients with chronic HBV infection and increases mortality in those with cirrhosis. J Hepatol. 2020;72:1105-1111.
Tseng T-C, Liu C-J, Chen C-L, et al. Risk stratification of hepatocellular carcinoma in hepatitis B virus e antigen-negative carriers by combining viral biomarkers. J Infect Dis. 2013;208:584-593.
Tseng T-C, Liu C-J, Chen C-L, et al. Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. Aliment Pharmacol Ther. 2015;41:949-960.
Hung C-H, Lu S-N, Wang J-H, et al. Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis. J Gastroenterol. 2003;38:153-157.
Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol. 2012;57:196-202.
Tseng T, Liu C, Su T, et al. Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. Gastroenterology. 2011;141(2):517-525.e2.
Tseng TC, Liu CJ, Yang HC, et al. Determinants of spontaneous surface antigen loss in hepatitis B e antigen-negative patients with a low viral load. Hepatology. 2012;55:68-76.
Yeh SH, Tsai CY, Kao JH, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol. 2004;41:659-666.
Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads. Hepatology. 2013;57:441-450.
Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11:550-560.
Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11:561-570.
Karim ME, Gustafson P, Petkau J, et al. Marginal structural Cox models for estimating the association between beta-interferon exposure and disease progression in a multiple sclerosis cohort. Am J Epidemiol. 2014;180:160-171.
Zeng G, Gill US, Kennedy PTF. Prioritisation and the initiation of HCC surveillance in CHB patients: lessons to learn from the COVID-19 crisis. Gut. 2020;69(11):1907-1912.
Boettler T, Newsome PN, Mondelli MU, et al. Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper. JHEP Rep. 2020;2:100113.
Tada T, Kumada T, Toyoda H, Kobayashi N, Akita T, Tanaka J. Hepatitis B virus core-related antigen levels predict progression to liver cirrhosis in hepatitis B carriers. J Gastroenterol Hepatol. 2018;33:918-925.