Toward a Functional Cure for Hepatitis B

Abstract

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Core protein inhibitors: Opportunities and challenges at the forefront of hepatitis B cure: Editorial on “Phase 1 trial of the safety, pharmacokinetics, and antiviral activity of EDP-514 in untreated viremic chronic hepatitis B patients”

“…As a result, a diverse array of investigational drugs is presently in development and undergoing clinical trials, including direct-acting antivirals such as entry inhibitors, RNA interference agents (small interfering RNA [siRNA] or antisense oligonucleotides), HBsAg release inhibitors, capsid assembly modulators (CAMs) -also known as core protein inhibitors -and immune modulators. 1 Among these agents, core protein inhibitors emerge as promising drugs due to the pivotal role of the core protein in HBV persistence across various stages of the viral cycle. There are two types of core protein inhibitors: Type 1, involved in aberrant capsid formation, and Type 2, responsible for generating an empty capsid.…”

“…10 Studies have demonstrated that adding a core protein inhibitor to NUCs leads to a more potent reduction in viral activity compared to NUCs alone, 11,12 and HBsAg seroclearance has been observed with the combination of a core protein inhibitor with siRNA and pegIFN-α. 1 Considering that many current CHB patients are already undergoing NUCs treatment, the efficacy of sequential therapy, as one modality for combining different approaches, with the newer agents is also expected.…”