**1. Introduction**

Hepatitis B virus (HBV) is a blood-borne virus that infects the liver. Until the discovery of the virus in the 1960s [1], it was transmitted sexually and by transfusion of contaminated blood and blood fractions. Today, the virus has been virtually eliminated from the blood supply by a simple blood test while infection has been prevented by a highly efficacious vaccine [2, 3]. Prior to establishment of vaccination programs in various countries, infants born to infected mothers replicating virus often acquired the virus at birth by exposure to contaminated maternal blood.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More than 90% of these children became HBV carriers, characterized by the persistence of virus or virus antigens in their blood for years to decades. These children were a high risk for the development of chronic liver disease (CLD), which progressed from hepatitis, to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [4]. Fortunately, newborns in many countries receive the HBV vaccine at birth, which helps to prevent mother-to-infant transmission as well as protect from exposure later in life. Among unvaccinated adults engaging in unprotected sex, roughly 5–10% become carriers, and these individuals are also at high risk for the development of CLD and HCC. Although estimates vary, there are ~300–350 million carriers of HBV worldwide [5]. HCC is the sixth most prevalent cancer worldwide, with about 600,000 newly diagnosed cases annually, and the second leading cause of cancer deaths [6]. Interferon, and in more recent years, powerful nucleoside analogs, have successfully treated patients with chronic hepatitis B, but presently there is no cure [7, 8]. HCC is curable by surgical resection, but this is often accompanied by relapse. Dozens of drugs, alone or in combination, have been evaluated in clinical trials for patients with advanced HCC, but only the multi-kinase inhibitors, Sorafenib and regorafenib, and the immune checkpoint inhibitor nivolumab, have been useful in modestly extending the lifespan of such patients [9, 10]. Given that the carrier state and CLD are the major risk factors for HCC [11], there is strong rationale to better understand the host-virus relationship that contributes to the pathogenesis of chronic infection.

**3. Contributions of hepatitis B surface, core and e antigens to the** 

HBV is a small virus consisting of only four open reading frames (ORF) [15]. One ORF encodes a family of envelope polypeptides (**Figure 1**). The major envelope polypeptide, HBsAg, triggers neutralizing antibody which is central to virus clearance after acute exposure and is the major component of the HBV vaccine [2]. HBsAg polypeptides are transmembrane proteins and glycoproteins that are on the envelope of virus particles, and are also secreted as small, spherical and variably long filamentous subviral particles that lack the virus nucleocapsid and HBV DNA. It is thought that these subviral particles, which are produced at concentrations several logs above that of infectious virus particles, absorb neutralizing antibody and trigger immunological tolerance, both of which promote virus persistence in the blood. Moreover, in patients with CLD, there does not seem to be any correlation between intrahepatic HBsAg expression patterns and inflammatory infiltrates [16, 17], nor have HBsAg specific T cell clones been isolated from such patients [18]. In addition, T cell sensitization to HBsAg in acute and chronic HBV infection is usually undetectable [19],

Pathogenesis of Hepatitis B Virus Associated Chronic Liver Disease

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**Figure 1.** Genetic organization of HBV showing the ORFs (in color). The positions of enhancer 1 (EN1) and 2 (EN2) are also shown. The direct repeat 1 (DR1) and 2 (DR2) sequences at the ends of the long and short DNA strands are also indicted. The pregenomic RNA (3.5 kb) is greater than genome length, while the 2.1 and 2.4 kb subgenomic mRNAs encode surface antigen polypeptides, and the 0.7 kb mRNA encodes the X protein. Reproduced from [20] with permission.

**pathogenesis of chronic infection**

**3.1. Hepatitis B surface antigen (HBsAg)**
