Toward a Functional Cure for Hepatitis B

Gut Liver. 2024 Jul 15;18(4):593-601. doi: 10.5009/gnl240023. Epub 2024 Mar 27.

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.

Keywords: Direct-acting antivirals; Hepatitis B surface antigen loss; Immune modulatory therapies; Nucleos(t)ide analogues; Pegylated interferon-α.

Publication types

  • Review

MeSH terms

  • Antiviral Agents* / therapeutic use
  • DNA, Viral
  • Drug Therapy, Combination
  • Hepatitis B Surface Antigens*
  • Hepatitis B virus* / drug effects
  • Hepatitis B virus* / immunology
  • Hepatitis B virus* / physiology
  • Hepatitis B, Chronic* / drug therapy
  • Hepatitis B, Chronic* / immunology
  • Humans
  • Interferon-alpha* / therapeutic use
  • Polyethylene Glycols / therapeutic use
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Interferon-alpha
  • Hepatitis B Surface Antigens
  • Polyethylene Glycols
  • DNA, Viral