Hepatitis B virus core-related antigen levels predict
progression to liver cirrhosis in hepatitis B carriers
Toshifumi Tada,* Takashi Kumada,* Hidenori Toyoda,* Natsuko Kobayashi,* Tomoyuki Akita
and Junko Tanaka
*Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Gifu, and
Department of Epidemiology, Infectious Disease Control and
Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Hiroshima, Japan
Fibrosis-4 index, hepatitis B, hepatitis B virus
core-related antigen, liver cirrhosis.
Accepted for publication 6 September 2017.
Toshifumi Tada, Department of
Gastroenterology and Hepatology, Ogaki
Municipal Hospital, 4-86 Minaminokawa, Ogaki,
Gifu 503-8502, Japan.
Declaration of conflict of interest: The authors
declare no conﬂicts of interest.
Ethical approval: The study protocol was ap-
proved by the institutional ethics committee of
Ogaki Municipal Hospital in January 2011. This
study was in compliance with the Declaration of
Informed consent: Written informed consent
for the use of stored serum samples was ob-
tained from all patients.
Financial support: This work was supported by
Health and Labour Sciences Research Grants
(Research on Hepatitis) from the Ministry of
Health, Labour, and Welfare of Japan.
Background and Aim: Several hepatitis B virus (HBV) markers have been identiﬁed as
risk factors for progression to liver cirrhosis in patients with chronic HBV infection. The
predictive impact of HBV markers on progression to cirrhosis in HBV carriers was
Methods: A total of 529 hepatitis B e antigen seroconverters with ﬁbrosis-4 (FIB-4) index
≤ 3.6 not on nucleos(t)ide analogue therapy were included. Univariate and multivariate
analyses of associations between HBV markers and progression to cirrhosis were per-
formed. In addition, the hazard ratio (HR) spline curves for continuous HBV markers were
Results: Eighty-four patients progressed to cirrhosis (FIB-4 index > 3.6) during the
follow-up period. Hepatitis B surface antigen (HBsAg), HBV DNA, HBV core-related
antigen (HBcrAg), and basal core promoter status, but not genotype and precore status,
were signiﬁcantly associated with progression to cirrhosis in univariate Cox proportional
hazards models. Multivariate Cox proportional hazards models adjusted for HBV
genotype, HBsAg, HBV DNA, HBcrAg, precore status, and basal core promoter status in-
dicated that HBsAg ≥ 3.0 log IU/mL (HR, 0.53; 95% conﬁdence interval [CI], 0.30–0.94)
and HBcrAg ≥ 3.7 log U/mL (HR, 3.28; 95% CI, 1.60–6.75) are independently associated
with progression to cirrhosis. In the HR spline curve analysis, HR and 95% CI gradually
increased as HBcrAg levels increased. Conversely, HRs and 95% CIs for HBsAg and
HBV DNA did not show this tendency as their levels increased.
Conclusions: Elevated HBcrAg levels in HBV carriers increases the risk for progression to
cirrhosis. HBcrAg is an excellent predictor of the development of cirrhosis.
Chronic hepatitis B (CHB) affects over 350 million people world-
wide. Long-term complications of infection include liver cirrhosis
and hepatocellular carcinoma (HCC), which together cause over
500 000 deaths annually.
Hepatitis B surface antigen
(HBsAg)-positive patients have a 70-fold increased risk of devel-
oping HCC than their HBsAg-negative counterparts.
B virus (HBV) infection is endemic in South-East Asia, China,
Taiwan, Korea, and sub-Saharan Africa, where up to 85–95% of
patients with HCC are HBsAg positive.
The risk of progression
to cirrhosis and HCC is variable and depends on the host’s im-
mune response. The 5-year cumulative incidence of cirrhosis
ranges from 8% to 20% in untreated CHB patients. Among those
with cirrhosis, the 5-year cumulative risk of hepatic decompensa-
tion is 20%.
The annual risk of HCC in patients with cirrhosis
has been reported to be 2–5%.
Previous studies have shown that serum levels of HBV DNA
and HBsAg are associated with disease progression in patients
In particular, patients with serum HBV DNA levels
≥ 3.3 log IU/mL (2000 IU/mL) at baseline have an increased like-
lihood of developing hepatitis B e antigen (HBeAg)-negative hep-
atitis, cirrhosis, and HCC during long-term follow-up.
these viral parameters, HBV core-related antigen (HBcrAg), a new
biomarker of HBV infection, is associated with HCC develop-
HBcrAg comprises HBV core antigen and HBeAg; both
are products of the precore/core gene and have the ﬁrst 149 amino
acids of HBV core antigen in common. Serum HBcrAg concentra-
tions are well correlated with intrahepatic levels of covalently
closed circular DNA (cccDNA).
It has been reported that
HBcrAg is a useful marker for guiding cessation of nucleos(t)ide
analogue (NA) therapy and evaluating disease activity.
recently reported that HBcrAg is a useful predictor of
Journal of Gastroenterology and Hepatology 33 (2018) 918–925
© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd