Combination of infectious bursal disease virus with ultra-low doses of nivolumab plus ipilimumab could provide functional cure in chronic hepatitis B virus infections

The hepatitis B virus (HBV) infects close to 300 million people worldwide. Each year, HBV causes 884,000 deaths from liver cancer and cirrhosis. Since HBV is considered a carcinogen, about 80 million people may die from hepatocellular carcinoma. While the World Health Organization (WHO) called for the elimination of HBV by 2030, currently, not a single country is on track to meet WHO’s targets. Based on the International Coalition to Eradicate HBV recommendation, a sequential combination of two clinically validated modalities is recommended for the functional cure of chronic hepatitis Bpatients. This combination therapy mimics the spontaneous resolution of HBV infection by activating both innate and adaptive immune responses. HBV replication is suppressed by a paradigm-changing broad-spectrum postinfection antiviral superinfection therapy (SIT) that could provide a functional cure during a finite treatment course. The drug candidate for SIT is the infectious bursal disease virus (IBDV), which is a double-stranded RNA attenuated avian vaccine virus. The nonlytic IBDV elicits a strong IFN-β and IFN-λ response that separates the antiviral effect from inflammation. Exhausted HBV-specific T-cell responses are restored by blocking CTLA-4 and PD-1 receptors with ultra-low doses of immune checkpoint inhibitors, nivolumab (0.5mg/kg) and ipilimumab (0.3mg/kg). The proof of principle of the new therapy is proposed in virally suppressed HBeAg-negative patients.