REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection

Nucleic acid polymers (NAPs) are broad spectrum antiviral agents whose antiviral activity in hepatitis B virus (HBV) infection is derived from their ability to block the release of the hepatitis B virus surface antigen (HBsAg). This pharmacological activity blocks replenishment of HBsAg in the circulation, allowing host mediated clearance. This effect has important clinical significance as the clearance of circulating HBsAg dramatically potentiates the ability of immunotherapies to restore functional control of HBV infection which persists after antiviral therapy is removed. These effects are reproducible in preclinical evaluations and in several clinical trials that have evaluated the activity of the lead NAP, REP 2139, in monotherapy and in combination with immunotherapy in hepatitis B e antigen (HBeAg) negative and HBeAg positive HBV infection and also in HBeAg negative HBV/hepatitis D virus (HDV) coinfection. These antiviral effects of REP 2139 are achieved in the absence of any direct immunostimulatory effect in the liver and also without any discernible direct interaction with viral components. The search for the host protein interaction with NAPs that drives their antiviral effects is ongoing, and the interaction targeted by REP 2139 within infected cells has not yet been elucidated. This article provides an updated review of available data on the effects of REP 2139 in HBV and HDV infection and the ability of REP 2139-based combination therapy to achieve functional control of HBV and HDV infection in patients.