New treatments to reach functional cure: Rationale and challenges for emerging immune-based therapies

The landscape for chronic HBV therapy is rapidly evolving. The latest generation of antiviral drugs provide robust virus suppression with a high barrier to resistance that facilitates long-term treatment. However, low rates of HBsAg loss demonstrate that additional strategies are needed to consistency achieve a functional cure. The immune system can clear HBV and establish long-term control over the virus. Sufficiently boosting HBV immunity in chronic patients has been very difficult due to immune exhaustion, immune dysregulation, and inhibitory pathways suppressing the immune response. Therapeutic vaccines employing new technology, vectors and new immunomodulatory drugs that can elicit direct antiviral effects and cancel inhibitory mechanism may be able to overcome exhaustion. This review will discuss the justification for immunotherapy, lessons from previous trials and new vaccines/drugs in early stage clinical trials. The challenges of correlating immune responses induced by these drugs to clinical efficacy will also be addressed.