Hepatitis B virus primary infection may be asymptomatic or may cause an acute illness with symptoms including jaundice, dark urine, fatigue, and digestive-associated complaints. Hepatitis B prevalence is highest in sub-Saharan Africa and East Asia (≥8 %, see Fig. 1b), where transmission from generation to generation occurs. High rates of chronic infections are also found in the Amazon and the southern parts of Eastern and Central Europe. In the Middle East and the Indian subcontinent, an estimated 2–5 % of the general population is chronically infected, whereas <1 % of the population in Western Europe and North America is chronically infected (Fig. 1b). What had been noted for a long time is that the liver cancer incidence is higher in areas with high HBV prevalence (see Fig. 1).

In individuals chronically infected by HBV, the need for efficient antiviral therapy remains clear when a viral replication is observed to control the risk of progression and delay liver transplantation, which represents the only end-stage treatment. Indeed, patients having advanced chronic hepatitis B (CHB) can now be successfully treated using nucleos(t)ide analogs (NA) or pegylated interferon (PEG-IFN). Therefore, beside vaccination, prevention of the progression of the disease to cirrhosis and liver decompensation, leading to end-stage liver disease and/or to hepatocellular carcinoma, by inhibiting viral replication, represents a logical approach to improve survival.

During chronic infection, liver regeneration (renewal of the pool of cell) and architecture reconstruction (due to stimulation of stellate cells) will lead to activation of cell cycle and fibrogenesis, respectively (Fig. 2). Collagen scar tissue, in response to liver injury, may lead to nodular reconstruction pattern of fibrosis, progressively interrupting the normal communication between portal space and subhepatic venous circulation leading to liver cirrhosis. This advanced state of nodular fibrosis is often present in the West countries before the emergence of HCC and corresponds to a risk factor by itself. In a Western series of 30 patients without cirrhosis, all patients had some non-tumorous pathological changes such as iron overload and large cell dysplasia in their liver [7]. In contrast, in developing countries, cirrhosis is typically overshadowed by the signs of the tumor, unfortunately when it has reached an advanced stage. Indeed, analyzing 14 trials (six Asian and eight non-Asian) [8], Hsu and coworkers found that median survival rate of HCC reflecting natural history was 3.57 ± 1.88 month in Asian trials versus 5.96 ± 1.46 in non-Asian trials.

Both HBV and hepatitis delta virus (HDV) use heparan sulfate membrane-anchored molecules and the Na taurocholate cotransporting polypeptide (NTCP) receptor to infect hepatocytes [9, 10]; L-HBsAg protein, coded by HBV PreS1/PreS2/S gene, is required for infection. The replication of the two viral genomes is fully independent in the nucleus of the cell. HBV DNA genome replicates through an RNA intermediate depending on its own viral polymerase having a reverse transcriptase activity, which is the step that will be inhibited by nucleoside/nucleotide analogs. Even under this therapy, the HBV DNA genome will persist as an episome in the nucleus of the infected cell. HBV genome can also integrate into the cellular genome (see below).

During viral replication, the intracytoplasmic reverse transcription step of the viral polymerase introduces errors that are not corrected due to the lack of a 3′→5′ exonuclease activity leading to mutations. In a chronically infected patient, more than 10E11 viral particles are produced per day, and viral polymerase introduces non-corrected errors every 10E4 to 10E5 nucleotides. Viral load and punctual mutations might also be involved in HCC. For example, the REVEAL study indicated clearly that the serum HBV DNA level is significantly and independently associated with incidence of HCC. In addition, viral genetic features such as core promotor mutations A1762T/G1764A mutant or precore G1896A were documented as predictor of HCC risk [11].

Eight different genotypes, A to H, have been described. Recently, a ninth “genotype” evidenced in North-West China, India, Laos, and Vietnam and tentatively termed “I” was suggested, although it is still subject to debate, as being a recombinant strain having a genotype C backbone. Finally, a tenth genotype provisionally assigned to genotype “J” was proposed for a Japanese patient’s HBV isolate.

Genotype-specific HBV genomes have sizes ranging from 3,182 nt (HBV/D) to 3,248 nt (HBV/G). This has consequences on the size of the viral proteins. Genotypes and subgenotypes might also be associated to specific geographic distributions reflecting ancient evolution. However, associated to human migrations, this picture may evolve. Furthermore, in some specific area, the recombinant strain represents the dominant variant such as the HBV/CD recombinant in Tibet [12]. Indeed, high endemy and coexistence of different genotypes in borders will favor a recombination process such as the recently described HBV/DE recombinant in Niger and India [13, 14].

Whether or not a specific viral genotype/subgenotype is linked to a specific pathogenic power or treatment sensitivity is a field of active research. However, there are still conflicting results. In addition, emerging strains might take benefit of the possibility of recombination to acquire resistance to the only available antiviral class of drugs or to escape from vaccine. Another important point relies on the fact that 78 % of chronic carriers live in Asia. This high percentage might by itself contribute to a high number of severe cases in this part of the world where genotype B and C are predominant. In the countries where genotypes A and D coexist, it has been suggested that patients infected by genotype A might evolve more rapidly during chronic infection than those infected with genotype D. Furthermore, different studies seem to sustain that patients infected with genotype C would progress to cirrhosis and liver cancer earlier than those infected by genotype B at the age of 30; however, at the age of 45 years, the same proportion of patients had been evolving to cirrhosis and liver cancer whatever the genotype was [15]. Other studies in the Amazonian basin indicated that the F genotype was frequently associated to severe acute hepatitis. In such cases, most of hospitalized patients were co- or superinfected by the hepatitis delta virus genotype 3 (HDV-3).

In contrast, several authors have found no link between HBV genotypes and the severity of hepatitis. For example, a study conducted in Uzbekistan didn’t demonstrate any difference of the severity of the liver histology between infections by HBV genotype D and A. Another recent study considering all case of liver damage (asymptomatic HBsAg carriers, acute or chronic hepatitis, cirrhosis, and hepatocellular carcinoma) also found no concrete link between genotype A or D and the severity of the hepatitis or response to treatment [38]. In summary, if there is not yet enough clear data to attribute to a specific genotype a clear predictive severity value, there is increasing evidence that in Asia, genotype C might be more frequently associated to HCC than genotype B. It is also important to evaluate these genotypes in function of the therapeutic response as this could represent predictive criteria. In a trial of PEG-IFN, patients infected with genotypes A and B had a higher rate of HBeAg loss (about 45 %) as compared to patients infected with genotype C or D (about 26 %).

HBV encodes a small regulatory protein known as the HBx protein that stimulates HBV viral transcription and replication. HBx is a small polypeptide of 154 amino acids (16.5 kDa) encoded by the X gene which is highly conserved among mammalian hepadnaviruses. Designed as a probable “viral oncoprotein,” HBx favors HBV virus replication by exerting pleiotropic activities, such as destabilization of orderly cellular functions of cell cycle regulation, deregulation of different signaling pathways and DNA repair. Accumulation of such dysfunctions and alterations in cells may lead to viral persistence and hepatocarcinogenesis. In fact, during natural HBV infection, HBx is essential to initiate and maintain HBV [16]. In spite of HBx low expression levels both in acute and chronic infections, HBx induces humoral and cellular immune responses [17].