New Approaches to Chronic Hepatitis B
Geoffrey Dusheiko et al.
Chronic hepatitis B is caused by the hepatitis B virus (HBV), a hepatotropic DNA virus that can replicate at high levels and cause minimal disease or severe liver injury. The clinical spectrum of chronic hepatitis B ranges from no symptoms to progressive hepatic fibrosis, advanced cirrhosis, and hepatocellular carcinoma. An estimated 296 million people have chronic hepatitis B, of whom 221 million live in low- and middle-income countries.1 Without intervention, deaths from HBV are expected to peak at 1.14 million by 2035.2 Virologic Features of HBV HBV is a partially double-stranded DNA virus. The life cycle and therapeutic targets are shown in Figures 1 and 2. The spherical 42-nm virion comprises an envelope that is outside a 30-nm nucleocapsid that encloses a circular 3.2-kb DNA genome. The lipid bilayer of the virion envelope incorporates the large (42-kD) hepatitis B virus surface protein (LHBs), the medium (33-kD) surface protein (MHBs), and the small (26-kD) surface protein (SHBs). The minus-strand HBV DNA genome is synthesized by reverse transcription of the 3.5-kb pregenomic RNA (pgRNA), after copackaging of the pgRNA and HBV polymerase inside the icosahedral nucleocapsids. The RNA primer can remain bound to the direct repeat 1 region to prime linear double-stranded DNA synthesis.3 Linear double-stranded integrants of the HBV DNA genome are integrated into the hepatocyte genome at sites of DNA breaks. The linear genomes do not circularize, and integrated HBV DNA is therefore unable to produce progeny virus. However, the randomly dispersed integrated HBV genomes act as a source of subgenomic RNA transcripts encoding LHBs, MHBs, SHBs, and possibly HBx. Integration could favor viral persistence, since the hepatitis B surface antigen (HBsAg) burden transcribed from integrated genomes may contribute to T-cell and B-cell exhaustion. Insertion into hepatocellular DNA may contribute to the pathogenesis of hepatocellular carcinoma by invoking a cismediated oncogenic mechanism, driving downstream cellular transcription, or through trans-mediated expression of viral proteins, particularly HBx.4,5