Role of Hepatitis B Viral Load and Basal Core Promoter Mutation in Hepatocellular Carcinoma in Hepatitis B Carriers

Journal of Infectious Diseases, May 2006

BackgroundSeveral 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 MethodsIn 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 ResultsIn univariate analysis, statistically significant odds ratios (ORs) were obtained for male sex (P<.001), advanced age (P<.001), HBV genotype C infection (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 ConclusionsHBV load and the BCP T1762/A1764 mutation are important in hepatocarcinogenesis

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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. - 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)


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Chun-Jen Liu, Bing-Fang Chen, Pei-Jer Chen, Ming-Yang Lai, Wen-Ling Huang, Jia-Horng Kao, Ding-Shinn Chen. Role of Hepatitis B Viral Load and Basal Core Promoter Mutation in Hepatocellular Carcinoma in Hepatitis B Carriers, Journal of Infectious Diseases, 2006, pp. 1258-1265, 193/9, DOI: 10.1086/502978