Stemming the Tide of Hepatitis B Virus–Related Hepatocellular Carcinoma?

Abstract

Infection with hepatitis B virus (HBV) is a major global public health problem, with an estimated prevalence of 350 million chronic carriers worldwide, and 1.5 million in the United States. The majority of HBV-infected individuals are concentrated in Asia and subSaharan Africa, but the incidence is rising is Western countries as a result of changing migration patterns. Chronic HBV infection can lead to liver cirrhosis, hepatic decompensation, and premature death. As many as 25% of HBV-infected patients will develop hepatocellular carcinoma (HCC), which is the fourth most common solid tumor worldwide. As much as a 50% reduction in the incidence of HBV transmission has been achieved in certain countries through widespread vaccination programs. Reduction in the morbidity and mortality of HBV-related HCC has been achieved as a result of intensive screening programs and through antiviral treatment with agents such as lamivudine and interferon. Because the majority of HCC cases worldwide are HBV-associated, HCC is truly a preventable malignancy. Given the considerable number of patients who are at risk for developing chronic HBV infection and its deadly sequelae, the costs associated with screening and treatment are similarly enormous. The challenge, therefore, is to select those patients most likely to benefit from HBV treatment and HCC screening to maximize the benefit-cost ratio of such programs. Any opportunity to optimize selection of patients for HBV treatment and HCC screening, and thereby reduce the incidence of HCC, should result in a significant public health benefit. HBV has been classified into eight genotypes, designated by capital letters A through H. HBV genotypes have distinct geographic distributions, with genotypes B and C being the most prevalent in Asia. Several studies have demonstrated that genotype C is associated with a higher prevalence of hepatitis B e antigen (HBeAg), more active hepatitis, and more advanced liver disease than genotype B. In a cross-sectional study of 270 Taiwanese HBV carriers with various forms of liver disease, genotype C was more prevalent in patients with cirrhosis and in those with HCC older than 50 years compared with age-matched asymptomatic carriers. Furthermore, HBV genotype C has been shown to be an independent risk factor for development of HCC. In a study of 426 Chinese patients infected with HBV, 25 patients developed HCC during a median follow-up of 121 weeks. Cirrhosis and HBV genotype C infection were independently associated with HCC development. In a study of 4,841 Taiwanese male hepatitis B s antigen (HBsAg) carriers, there were 154 cases of HCC diagnosed during a 14-year follow-up period. HBV DNA levels and HBV genotypes were determined for all patients with HCC and 316 control subjects. Results indicated that the risk of HCC increased with increasing HBV viral load. Moreover, genotype C was associated with an increased risk of HCC compared with other HBV genotypes (adjusted odds ratio [OR] 5.11; 95% CI, 3.20 to 8.18). In that study, the association of HBV genotype C and HBV viral load with HCC risk appeared to be additive. The adjusted OR of HCC for those carrying genotype C and with viral load in the highest quintile was 26.49 (95% CI, 10.41 to 67.42) compared with those carrying other HBV genotypes and lower viral loads. These and other recent studies have been paramount in our understanding of the factors that influence clinical outcome in HBV infection. However, it appears that HBV genotype is only one of the elements associated with hepatocarcinogenesis. Mutations in the basic core promoter (BCP) and precore regions carry an increased risk of HCC. In a cross-sectional, retrospective study of 160 chronic HBV carriers and 200 patients with HCC, advanced age, male sex, the precore A1896 mutation, the BCP T1762/A1764 mutation, and a high HBV load were significantly associated with development of HCC. There has also been recent interest in studying the relationship among HBV genotypes, subgenotypes, and mutations encountered in HBV carriers. Whether these have additive or synergistic effects on the risk of HCC development remains unclear. It has been reported that patients with genotype B have a higher chance of harboring precore mutations when compared with patients with genotype C. In the same study, core promoter mutations, T1653 mutations, HBV DNA levels of at least 4 log10 copies/mL, and cirrhosis were shown on to be independent risk factors for HCC. HBV genotype C has been classified into four subgenotypes: HBV/C1-C4. The designation of the two most widely disseminated subgenotypes is controversial. HBV/C1 (or Cs) is commonly found in Southeast Asia. HBV/C2 (or Ce) is found in East Asia including Japan and China. There are limited data on the clinical implications and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 2 JANUARY 1