Role of Hepatitis B Viral Load and Basal Core Promoter Mutation in Hepatocellular Carcinoma in Hepatitis B Carriers
JID
Role of Hepatitis B Viral Load and Basal Core Promoter Mutation in Hepatocellular Carcinoma in Hepatitis B Carriers
Chun-Jen Liu 2
Bing-Fang Chen 3
Pei-Jer Chen 1 2
Ming-Yang Lai 1 2
Wen-Ling Huang 2
Jia-Horng Kao 0 1 2 4
Ding-Shinn Chen 1 2
0 Hepatitis Research Center
1 Graduate Institute of Clinical Medicine
2 Division of Gastroenterology, Department of Internal Medicine
3 School of Medicine, Fu Jen Catholic University , Taipei , Taiwan
4 Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital
Background. Several hepatitis B viral factors correlate with the progression of chronic liver disease. However, the independent and interactive effects of each known viral factor on the development of hepatocellular carcinoma (HCC) remain largely unknown. Methods. In a cross-sectional, retrospective, hospital-based setting, we comprehensively compared viral factors in 160 chronic hepatitis B virus (HBV) carriers and 200 patients with HCC, to clarify the independent and joint effect of each factor. Results. In univariate analysis, statistically significant odds ratios (ORs) were obtained for male sex (P ! .001), advanced age (P ! .001), HBV genotype C infection (P p .005), the precore A1896 mutation (P ! .001), and the basal core promoter (BCP) T1762/A1764 mutation (P ! .001). According to the results of multiple logistic-regression analysis, advanced age, male sex, the precore A1896 mutation, the BCP T1762/A1764 mutation, and an HBV load 105 copies/mL were independently associated with the development of HCC. Compared with patients with an HBV load !105 copies/mL and the BCP A1762/G1764 wild-type strain, the adjusted OR of developing HCC was 30 in patients with an HBV load 105 copies/mL and the BCP T1762/A1764 mutant, irrespective of the presence of the precore A1896 mutation and viral genotype. Conclusions. HBV load and the BCP T1762/A1764 mutation are important in hepatocarcinogenesis.
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Hepatitis B virus (HBV) infection is a global health
problem, and 1350 million people in the world are
chronic carriers of the virus [1]. The clinical
manifestations of HBV infection include acute self-limiting
infection or fulminant hepatic failure, the inactive carrier
state, chronic hepatitis with progression to cirrhosis,
and hepatocellular carcinoma (HCC) [2]. The
pathogenesis of HBV infection is usually through interactions
between the virus and host immune responses to
HBVencoded antigens [3]. Nevertheless, HCC occurs in a
small proportion of hepatitis B surface antigen (HBsAg)
carriers. It has been speculated that HBV-related
hepatocarcinogenesis depends on several predisposing
factors [4]. Apart from host factors, it is important to
identify the relevant viral factors that likely are involved in
the development of HCC.
At present, 8 HBV genotypes (A–H) have been
identified [5–7]. Although the clinical significance of
different HBV genotypes remains to be firmly settled, it
has been shown that genotype C is associated with the
development of HCC [8–11] and has a lower response
rate to conventional interferon therapy than does
genotype B [12, 13]. However, the molecular and
virologic factors that contribute to these clinical and
therapeutic differences among HBV genotypes need further
examination.
Because of the spontaneous error rate of viral reverse
transcriptase, the HBV genome evolves under the
antiviral pressure of host immunity or specific therapy
[14]. These HBV mutants could display an alteration of
epitopes that are important in host immune recognition, enhanced
virulence with the increased replication of HBV, resistance to
antiviral therapies, or facilitated cell attachment/penetration
[15]. Among these mutants, previous studies have revealed
ample evidence that precore stop-codon mutations, as well as
mutations in the basal core promoter (BCP), may be associated
with severe and fulminant outcomes of HBV infection [14, 15].
The predominant mutation of the precore region involves a
GrA change at nt 1896, which creates a premature stop codon
at codon 28. Isolates with an ArT transversion at nt 1762,
together with a GrA transition at nt 1764 (T1762/A1764) in
the BCP (nt 1742–1849) are often present in hepatitis B carriers
with chronic hepatitis, fulminant hepatitis, and HCC and less
often in inactive carriers and immunosuppressed patients [15–
18]. In addition, the BCP T1762/A1764 mutant has been
reported to be associated with a poor response to interferon
therapy in patients with chronic hepatitis B infection [19].
Several recent studies have also indicated that genotype C has a
higher frequency of BCP T1762/A1764 mutations than does
genotype B [12, 20]. Our previous study clearly demonstrated
that HBV carriers with the BCP T1762/A1764 mutant have an
increased risk of developing HCC [21]. In addition to viral
genotype and mutants, recent studies have suggested that high
HBV loads are also associated with the progression of chronic
liver disease (...truncated)