Aiming for Functional Cure With Established and Novel Therapies for Chronic Hepatitis B

Abstract

Chronic hepatitis B virus (HBV) infection remains difficult to cure due to the persistent, self-replenishing nature of the viral genome and impaired host immune responses. Current treatment goals for chronic hepatitis B (CHB) are to prevent or significantly delay liver-related adverse outcomes and death, and two types of treatments are available: nucleos(t)ide analogues (NAs) and interferons (IFNs). NAs effectively suppress HBV replication, and IFNs improve serological response rates, thereby decreasing the risk of adverse outcomes. However, their efficacy in attaining serological responses, especially functional cure (i.e., loss of serum hepatitis B surface antigen), is very limited. Various strategies such as stopping antiviral therapy or combining therapies have been investigated to enhance response, but efficacy is only modestly improved. Importantly, the development of novel direct-acting antivirals and immunomodulators is underway to improve treatment efficacy and enhance rates of functional cure. The present review provides an overview of the treatment goals and indications, the possibility of expanding indications, and the safety and efficacy of different treatment strategies involving established and/or novel therapies as we continue our search for a cure.

FIG. 1

Treatment indications of CHB infection. Color‐coded by recommendations (red: Treat; blue: Do not treat, monitor ALT and HBV‐DNA levels every 3‐6 months, and annual serology tests; yellow: Monitor, exclude other causes of ALT elevation, and assess disease severity, treating if significant hepatic fibrosis or inflammation).

FIG. 2

Combination strategies with approved therapies aiming for a functional cure of CHB infection.

FIG. 3

Discontinuation of NA treatment in patients with HBeAg‐positive CHB infection (A) and HBeAg‐negative CHB infection (B).

FIG. 4

Targets for novel direct‐acting antivirals and immunomodulators in chronic HBV infection. Abbreviation: rcDNA, relaxed circular DNA.