Future anti-HBV strategies.

Although current oral antivirals can maintain viral suppression and reduce the risk of liver-related complications, lifelong therapy is associated with high cost, risk of breakthrough and potential toxicity. There is a need to develop a finite course of treatment which can provide sustained off-treatment virological and clinical response. The likely marker of such a clinical HBV CURE would be HBsAg clearance, but in addition cccDNA elimination would be required to prevent future reactivation (ie complete HBV cure). Chronic HBV infection is characterised by high viral and antigen burden and inadequate host immune responses, both of which will need to be overcome to achieve HBV CURE. Innovative approaches to restore innate and adaptive immune responses against HBV currently in clinical development include therapeutic vaccines, TLR-7 and TLR-8 agonists. In future, strategies to reverse T-cell exhaustion such as checkpoint inhibitors may be feasible. Currently, the only antivirals in clinical use are the HBV polymerase inhibitors. However, many other steps of HBV virion life cycle can be targeted by small molecules, including inhibitors of HBV entry, nucleocapsid formation and virion assembly and release. siRNAs could inhibit many different steps by blocking multiple HBV transcripts. But, the ultimate goal will be to successfully eradicate or silence cccDNA. It is likely that successful HBV cure will require combination of immunomodulatory, antiviral and cccDNA silencing strategies. Efficacy, safety, route of administration and cost will ultimately determine the impact of these new regimens on the burden of HBV.