Control of viral transcripts as a concept for future HBV therapies

Chronic hepatitis B virus infections affect over 250 million people world-wide, and, at present, are not curable. Of those, over 800 000 are expected to die yearly from complications including cirrhosis and primary hepatocellular carcinoma (HCC). A viral episomal DNA intermediate, covalently closed circular DNA (cccDNA) can persist in nuclei of infected hepatocytes and trigger production of infectious virus. Current standard of care treatments against chronic HBV infections primarily rely on nucleoside analogs (NA) that inhibit de novo virus production by inhibiting the viral reverse transcriptase and, as a consequence, reducing virus titers. However, they cannot cure infections, because they do not directly target cccDNA persistence. Nevertheless, NA therapies can halt progression of liver disease including cirrhosis and can reduce the development of hepatocellular carcinoma (HCC). A cure for chronic hepatitis B (CHB) must reduce the load of cccDNA or permanently silence transcription from cccDNA, and ensure sustained activation of an adaptive immune response that prohibits reactivation and spread of residual virus in the liver. As discussed in this review, novel technologies enabling genetic destruction of cccDNA and advances in our understanding of HBV transcriptional control provide exciting opportunities for the future development of curative therapies desperately needed to reduce the burden of chronic HBV infections.