J Hepatol. 2018 Dec 6. pii: S0168-8278(18)32582-0. doi: 10.1016/j.jhep.2018.11.030. [Epub ahead of print]
Serum Hepatitis B core-related antigen (HBcrAg) correlates with covalently-closed circular DNA transcriptional activity in chronic hepatitis B patients.
Barbara T1, Fanny L2, Caroline S3, Françoise B4, Clothilde M2, Miroslava S5, Alessandro L6, Floriana F6, Pietro L6, Massimo L7, Fabien Z8.
Author information
1
INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France.
2
INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France.
3
INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Virology, Croix Rousse Hospital, Hospices Civils de Lyon, France.
4
INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France.
5
Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France.
6
Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
7
INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France; Department of Internal Medicine - DMISM and the IIT Center for Life Nanoscience (CLNS), Sapienza University, Rome, Italy.
8
INSERM U1052- Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, UMR_S1052, CRCL, 69008 Lyon, France; Department of Hepatology, Croix Rousse hospital, Hospices Civils de Lyon, France. Electronic address: [email protected].
Abstract
BACKGROUND AND AIMS:
Serum Hepatitis B core-related antigen (HBcrAg) has been proposed to reflect the intrahepatic cccDNA levels, but a comprehensive investigation of its correlation with serum and intrahepatic viral markers and liver histology in a large number of patients is still lacking.
METHODS:
HBcrAg was measured by chemiluminescent enzyme immunoassay (Fujirebio Lumipulse® G HBcrAg) in 130 [36 HBeAg(+) and 94 HBeAg(-)] biopsy proven, untreated, CHB patients. HBcrAg levels were correlated with: a) serum HBV-DNA, quantitative (q)HBsAg and alanine aminotransferase (ALT) levels; b) intrahepatic total (t)HBV-DNA, cccDNA, pgRNA and cccDNA transcriptional activity (defined as pgRNA/cccDNA ratio); c) fibrosis and necroinflammatory activity scores.
RESULTS:
HBcrAg levels were significantly higher in HBeAg(+) vs HBeAg(-) patients and correlated with serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA and cccDNA levels and transcriptional activity. Patients who scored negative for HBcrAg (< 3 LogU/mL) had less liver cccDNA and lower cccDNA activity as compared to the HBcrAg(+) group. Principal component analysis coupled to unsupervised clustering identified a subgroup of HBeAg(-) patients with higher HBcrAg levels associated to higher serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA, cccDNA transcriptional activity and to higher scores of fibrosis and necro-inflammatory activity.
CONCLUSIONS:
Our results indicate that HBcrAg is a surrogate marker of both intrahepatic cccDNA and its transcriptional activity that can be useful in the evaluation of new antiviral therapies aiming at a functional cure of HBV infection either by targeting directly or indirectly the intrahepatic cccDNA pool.
LAY SUMMARY:
Hepatitis B virus causes a chronic infection which develops in severe liver disease and liver cancer. The viral covalently-closed-circular DNA (cccDNA) is responsible for the persistence of the infection in hepatocytes. To better manage patient treatment and follow up, and to develop new antiviral treatments directly targeting the intrahepatic pool of cccDNA, serum surrogate markers reflecting the viral activity in the liver are urgently needed. In this work, we demonstrate that quantification of HBcrAg in serum correlates with cccDNA amount and activity and could be used to monitor of disease progression.