Serum hepatitis B core-associated antigen (HBcrAg) is associated with covalently closed circular DNA transcriptional activity in patients with chronic hepatitis B
Barbara Testoni1, 2, †
, FannyLebossé1, 2, 3, †
, Caroline Scholtes 1, 2, 4
, FrançoiseBerby1
,Clothilde Miaglia1,2,3
, Miroslava Subic3
, Alessandro Loglio5
, Floriana Facchetti5
, Pietro Lampertico5
, Massimo Levrero 1, 2, 3, 6
, Fabien Zoulim1, 2, 3, low asterisk, 'Information about the author Fabien Zoulim Email author Fabien Zoulim
PlumX metrics
DOI: https://doi.org/10.1016/j.jhep.2018.11.030 |
showArticle information
Emphasize
• Liver HBV cccDNA is still the cause of the persistence of the virus despite antiviral therapy.
• cccDNA activity, not quantity, is associated with disease progression.
• Serum HBcrAg is highly correlated with intrahepatic cccDNA activity.
• Lower levels of HBcrAg are associated with a more favorable disease process.
Background and purpose
Serum hepatitis B core-associated antigen (HBcrAg) has been proposed to reflect intrahepatic covalently closed circular (ccc) DNA levels. However, the association of HBcrAg with serum and intrahepatic viral markers and liver histology has not been fully investigated in large samples. Our aim was to determine if HBcrAg might be a useful therapeutic marker for patients with chronic hepatitis B.
method
HBcrAg was determined by chemiluminescent enzyme immunoassay in 130 patients (36 hepatitis B e antigen [HBeAg] + and 94 HBeAg-) biopsy confirmed, untreated chronic hepatitis B patients. HBcrAg levels and: a) serum B Hepatitis B virus (HBV)-related DNA, quantification of hepatitis B surface antigen and alanine aminotransferase levels; b) total intrahepatic (t) HBV-DNA, cccDNA, pre-genome (pg) RNA and cccDNA transcriptional activity ( Defined as pgRNA / cccDNA ratio); c) fibrosis and necroinflammatory activity scores.
result
HBeAg+ and HBeAg-patients have significantly elevated levels of HBcrAg and are associated with serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA and cccDNA levels, and transcriptional activity. HBcrAg-negative (<3 LogU / ml) patients had less liver cccDNA and lower cccDNA activity than HBcrAg + group. Principal component analysis combined with unsupervised clustering identified higher HBcrAg levels in the HBeAg-patient subgroup with higher serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA, cccDNA transcriptional activity, and higher fibrosis and Necrotic inflammatory activity scores are related.
in conclusion
Our results indicate that HBcrAg is a surrogate marker for intrahepatic cccDNA and its transcriptional activity. HBcrAg can be used to evaluate new antiviral therapies aimed at achieving a functional cure for HBV infection by directly or indirectly targeting the intrahepatic cccDNA library.
Place summary
Hepatitis B virus causes chronic infection, which develops into severe liver disease and liver cancer. The covalently closed circular DNA (cccDNA) of the virus is responsible for the persistence of infection in hepatocytes. In order to better manage patient treatment and follow-up, and to develop new antiviral therapies that directly target the intrahepatic cccDNA library, serum surrogate markers reflecting viral activity in the liver are urgently needed. In this work, we demonstrate that quantification of hepatitis B core-associated antigens in serum correlates with the amount and activity of cccDNA and can be used to monitor disease progression.
Key words:
Hepatitis B virus (HBV), chronic hepatitis B (CHB), biomarkers, patient management, pregenomic RNA (pgRNA), covalently closed circular DNA (cccDNA)作者: StephenW 时间: 2019-3-17 18:57