Present and future therapies of hepatitis B: From discovery to cure

Abstract

Hepatitis B virus (HBV) is a significant global pathogen, infecting more than 240 million people worldwide. While treatment for HBV has improved, HBV patients often require lifelong therapies and cure is still a challenging goal. Recent advances in technologies and pharmaceutical sciences have heralded a new horizon of innovative therapeutic approaches that are bringing us closer to the possibility of a functional cure of chronic HBV infection. In this article, we review the current state of science in HBV therapy and highlight new and exciting therapeutic strategies spurred by recent scientific advances. Some of these therapies have already entered into clinical phase, and we will likely see more of them moving along the development pipeline.

Conclusion: With growing interest in developing and efforts to develop more effective therapies for HBV, the challenging goal of a cure may be well within reach in the near future.

Figure 1

HBV life cycle and targets of therapeutic development. The complete HBV life cycle including entry, trafficking, cccDNA formation, transcription, encapsidation, replication, assembly and secretion is shown here. The functions of the HBV gene products are incorporated into the life cycle. Drugs or biologics, in clinical use or development, targeting various steps of the HBV life cycle are illustrated in red. See text for details of these drugs.

Figure 2

Innate and adaptive HBV-specific immune responses and immune-based therapeutic development. Immune cells involved in innate and adaptive immune responses activated by HBV infection and their mechanisms of antiviral actions are shown. They are virus-specific CD8⁺ T cells that inhibit viral replication by both direct killing of infected hepatocytes and cytokine-mediated antiviral mechanisms; virus-specific CD4⁺ T cells, which provide essential help for CD8⁺ T-cell priming and effector functions as well as antiviral cytokines; regulatory T cells, which suppress virus-specific T-cell functions; B cells, which mature to plasma cells producing neutralizing antibodies and potentially participate in antigen presentation; NK cells, which display antiviral but also regulatory activity by eliminating activated virus-specific CD8⁺ T cells ; NK-T cells that sense viral-infected hepatocytes, produce antiviral cytokines and activate adaptive immune responses; other immune cells in the liver that play important roles in the activation and coordination of the innate and adaptive responses such as Kupffer cells, myeloid and plasmacytoid dendritic cells. TNF-L: TNF-like molecules, e.g., lymphotoxin-β. Therapeutic approaches designed to activate various pathways of the innate and adaptive immunities are illustrated in red. See text for details of these approaches.