Based on the recommendation of the International Coalition to Eliminate hepatitis B virus (ICE-HBV), we intend to mimic the spontaneous resolution of HBV infection to achieve a functional cure of chronic hepatitis B virus (HBV) infection. To this end, we propose sequential targeting of the innate and adaptive host immune responses. Long-term suppression of HBV replication and hepatitis B surface antigen (HbsAg) production will be achieved first by inducing a strong innate immune response. The clinically validated viral superinfection therapy (SIT) will be administered, which employs an attenuated, non-lytic, double-stranded RNA (dsRNA) infectious bursal disease virus (IBDV) that provides an exceptionally strong interferon (IFN) response. Then, the exhausted HBV-specific T cell function will be restored by blocking the cytotoxic T lymphocyte-associated antigen-4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) receptors with immune checkpoint inhibitors (ICIs). In order to minimize any risk of toxicity, off-label low doses of nivolumab (0.5 mg/kg) plus ipilimumab (0.3 mg/kg) will be administered, the safety and efficacy of which has already been demonstrated in 131 unselected stage IV cancer patients. We predict that this combination therapy will provide sustained off-treatment virological and clinical responses during a relatively short treatment period.

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