Although safe and effective vaccines for hepatitis B virus (HBV) have been available for more than two decades, infection by this organism remains a burden to global public health, resulting in 600,000 to 1 million deaths per year worldwide [1]. Clinically, HBV infection can manifest in acute/fulminant hepatitis or in various chronic conditions, including an inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [2]. Approximately 15-40% of HBV carriers who acquire the virus early in life eventually develop HBV-related cirrhosis or HCC [3].

being a virus of the family Hepadnaviridae, HBV is the smallest human DNA virus, carrying a genome only 3,200 nucleotides in length [4]. The partially double-stranded circular DNA harbors four overlapping open reading frames encoding the S (surface), C (core), P (polymerase), and X genes (Fig. 1). Because the viral reverse transcriptase has a high error rate, the HBV genome evolves quickly over time, with an estimated nucleotide substitution rate of 1.4-3.2 × 10^-5/site per year [4]. This unique replication strategy accounts for the majority of the point mutations, deletions, and insertions observed in the HBV genome. The lengthy evolution of HBV has led to the present existence of various genotypes, subgenotypes, mutants, recombinants, and even quasispecies of HBV [5].

HBV is endemic in Asia and the Pacific islands, Africa, Southern Europe, and Latin America. The community prevalence of the HBV surface antigen (HBsAg) encoded by gene S ranges from 2 to 20% [1]. In Asian countries, the majority of HBV infections are acquired perinatally or in early childhood by the age of 2 years through vertical (mother-to-child) transmission; however, horizontal transmission is the main route of infection in African and Western countries [1].

Disease progression in patients with chronic hepatitis B varies widely. Several viral factors, including the HBV genotype, viral load, and specific viral mutations, have been documented to be strongly associated with disease progression and outcomes (Table 1). The annual incidence of cirrhosis is estimated to be 2-6% in those who test positive for the HBV e antigen (HBeAg) and 8-10% in those who test negative. The annual incidence of HCC is less than 1% for patients without cirrhosis and 2-3% for patients with cirrhosis [2,3].

Analyses of the divergence of HBV genomic sequences has led to the identification of 10 HBV genotypes (A through J) and several subtypes, where separate genotypes and subtypes are defined as strains exhibiting an entire genome sequence divergence of more than 8% or 4-8%, respectively [6]. The geographic distribution of HBV genotypes A-H and their subtypes is shown in Table 2. Genotype A is highly prevalent in sub-Saharan Africa (subtype A1), Northern Europe (subtype A2), and Western Africa (subtype A3). Genotypes B and C are prevalent in the Asian Pacific region. However, the prevalence rates of genotypes B and C vary among the different Asian countries (Table 3) [7]. For example, HBV-C is more common than HBV-B in China, Japan, and Korea, whereas HBV-B is the more common genotype in Taiwan and Vietnam [8]. Of particular note is the fact that almost all chronic hepatitis B patients in Korea are infected with HBV-C [7].

Genotype B has six subtypes, B1-B6. B1 is found in Japan; B2-B5 and B7 are found in East Asia, and B6 is found in indigenous populations living in Arctic regions, including Alaska, Northern Canada, and Greenland. Genotype C, which has subtypes C1-C5, is found primarily in East and Southeast Asia. Genotype D, which has subtypes D1-D5, is prevalent in Africa, Europe, the Mediterranean region, and India. Genotype E is restricted to West Africa. Genotype F, which has 4 subtypes (F1-F4), is found in Central and South America. Genotype G has been reported in France, Germany, and the United States. Genotype H is found in Central America [9,10]. Recently, genotype I was isolated in Vietnam and Laos [11], and genotype J was identified in Japan [12].

Current evidence for the impact of HBV genotype on the short- and long-term adverse outcomes of chronic HBV infection is summarized in Table 4. Most retrospective and case-control studies have indicated that patients infected with HBV-C have more severe liver disease, including cirrhosis and HCC, than those with infected with HBV-B [2,8,13]. In a recent community-based prospective cohort study of 2762 Taiwanese HBV carriers, HBV-C was associated with a higher risk of HCC than was HBV-B; the adjusted hazard ratio was 2.35 (95% confidence interval [CI], 1.68 to 3.30; p < 0.001) [14]. These findings confirm that HBV-C is associated with a higher risk of HCC development than HBV-B is.

HBV genotype also affects the clinicopathologic features of patients with resectable HCC. Of 193 patients with resectable HBV-related HCC in Taiwan, those infected with HBV-B had a higher rate of solitary tumor than did those infected with HBV-C (94% vs. 86%; p = 0.048), but they also had more satellite nodules (22% vs. 12%; p = 0.05). These features may contribute to the recurrence patterns and prognosis of HBV-related HCC patients infected with HBV-B or -C infection [15,16]. Death related to liver disease occurs more often in patients with HBV-D and -F than in those with HBV-A [17,18].

The importance of HBV genotype on the development of HCC has prompted the recent development of a clinical HBV scoring system, a nomogram including several independent risk predictors, including sex, age, family history of HCC, alcohol consumption, serum alanine aminotransferase (ALT) level, HBeAg status, serum HBV DNA level, and HBV genotype [19]. Based on clinical characteristics that can be determined noninvasively, this easy-to-use nomogram has been found to accurately predict HCC risk in HBV-infected persons and could facilitate communication between physicians and their patients, particularly in the Asian Pacific region.

The pathogenic differences among various HBV genotypes have been partially clarified. Intracellular expression levels of HBV DNA and HBV core antigen (HBcAg), as well as the extracellular levels of HBV DNA and HBeAg, have been found to be higher for HBV-B and -C genotypes than for HBV-A and -D. The intracellular accumulation of HBV DNA and viral antigens may play a role in inducing liver cell damage. Additionally, the higher replication capacity of the C genotype may explain why it is the genotype associated with the most severe HBV-induced liver disease [20,21].

In recent in vitro studies, we found that; 1) the expression of intracellular HBV core protein increased in strains of the C genotype when mutations were made in the precore or basal core promoter regions affecting HBeAg expression; 2) the expression of intracellular HBV surface protein was lower for a precore wild-type HBV-C strain than for HBV-B; 3) the precore mutation was associated with a decreased level of extracellular HBV DNA; 4) less HBsAg was secreted by HBV-C than by HBV-B; and 5) less HBeAg was secreted by HBV-B than by HBV-C [22]. The in vivo and in vitro manifestations of HBV-B and -C are compared in Table 5.

Investigations of the molecular epidemiology and clinical implications of HBV genotypes have resulted in clinically significant advances over the past decade, particularly with regards to genotypes found in the Asian Pacific region. Accumulating evidence [40] suggests that a patient with chronic HBV infection should receive HBV genotyping unless he or she lives in a country known to harbor only one HBV genotype. This measure will help practicing physicians to identify those patients who are at increased risk of disease progression to end-stage liver disease and those who can benefit most from interferon-based therapy [41,42].