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

Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center

Marta Davila

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas M.D. Anderson Cancer Center

James L. Abbruzzese

Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center

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.^1,2 The majority of HBV-infected individuals are concentrated in Asia and sub-Saharan Africa,³ 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.^4-8

As much as a 50% reduction in the incidence of HBV transmission has been achieved in certain countries through widespread vaccination programs.^2,9-14 Reduction in the morbidity and mortality of HBV-related HCC has been achieved as a result of intensive screening programs^15,16 and through antiviral treatment with agents such as lamivudine^17-19 and interferon.^20-23 Because the majority of HCC cases worldwide are HBV-associated, HCC is truly a preventable malignancy.^24-31

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.^32-38 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.^39,40 Several studies have demonstrated that genotype C is associated with a higher prevalence of hepatitis B e antigen (HBeAg),^41,42 more active hepatitis,^43-46 and more advanced liver disease than genotype B.^47,48 In a cross-sectional study of 270 Taiwanese HBV carriers with various forms of liver disease,⁴⁷ 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,⁴⁹ 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.⁵⁰ 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.^51-55 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.⁵⁵

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 virologic differences of the different subgenotypes. In a study of 241 HBV-infected patients, including 34 with HCC, mutations in V1753, T1856, and C1858 were specifically associated with HBV/C1 (Cs). Conversely, T1858 and A1896 were specifically associated with HBV/C2 (Ce).⁵⁵ Among HCC patients, those who were infected with HBV/C2 (Ce) were older and had significantly lower albumin levels and platelet counts, and higher levels of alpha-fetoprotein, suggestive of more advanced disease.⁵⁵ In a matched cross-sectional control study of 118 carriers of HBV/C1(Cs) and 210 carriers of HBV/C2(Ce), independent predictive factors for HCC were subgenotype C2(Ce), mutations in T1653, V1753, and T1762/A1764; age at least 50 years, male sex, and HBeAg positivity.

The current study by Chan et al⁵⁶ examines the effect on the risk of HCC of HBV DNA, HBV genotypes and subgenotypes. One thousand six adult patients with known HBV exposure were followed prospectively in an HCC surveillance program. Other specific eligibility criteria for this study were not stated. Routine serum chemistries, tumor marker studies, and frequent abdominal imaging were obtained. Patients were followed for 7.7 years, and the primary outcome measure was the relationship among HBV DNA, HBV genotype, other clinical variables, and the development of HCC. Seven hundred sixty-nine patients had positive polymerase chain reaction for HBV genotyping. Higher HBV DNA, presence of cirrhosis, older age, male sex, low serum albumin, presence of ascites, and previous antiviral treatment were associated with increased risk of HCC. On multivariate analysis, patients infected with HBV subgenotype Ce had the highest risk of HCC.

This is the first prospective cohort study that specifically examines HBV subgenotypes and the risk of HCC. All patients were recruited from community screening programs in an HBV endemic area. Prior studies have been cross sectional and have involved smaller number of patients. One of the strengths of the study is that participants underwent detailed assessment of liver function at entry and on follow-up. No information is given in regard to HBeAg status and presence of mutations. However, the authors are to be commended on the careful analysis of HBV genotypes/subgenotypes and the correlation with clinical outcomes in this group of patients.

The study provides valuable information, but we must remember that genotypes/subgenotypes are one of several viral factors, as well as host factors, that are critically involved in hepatocarcinogenesis. This study should guide other prospective studies on the subject, but it may be premature to recommend that determination of HBV genotype/subgenotype should alter current HCC screening guidelines.^57-59 We believe further studies are needed in the area of antiviral treatment and the relationship between HBV genotypes and treatment response.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Melanie B. Thomas, James L. Abbruzzese

Collection and assembly of data: Melanie B. Thomas, Marta Davila

Data analysis and interpretation: Melanie B. Thomas, Marta Davila, James L. Abbruzzese

Manuscript writing: Melanie B. Thomas, Marta Davila, James L. Abbruzzese

Final approval of manuscript: Melanie B. Thomas, Marta Davila, James L. Abbruzzese

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Thomas, M. B. Articles by Abbruzzese, J. L. Search for Related Content PubMed Articles by Thomas, M. B. Articles by Abbruzzese, J. L. Social Bookmarking                            What's this?