Current and Future Management of Chronic Hepatitis D

Area of Science:

• Virology
• Hepatology
• Infectious Diseases

Background:

• Hepatitis D virus (HDV) is a defective RNA virus requiring hepatitis B surface antigen (HBsAg) for replication.
• HDV causes a severe form of chronic viral hepatitis, posing significant therapeutic challenges.
• Current treatments for chronic hepatitis D are limited, with interferon-α being the only approved drug for decades.

Purpose of the Study:

• To examine the unconventional nature of HDV's life cycle.
• To review the current management strategies for chronic hepatitis D.
• To highlight novel therapeutic approaches emerging from a deeper understanding of HDV.

Main Methods:

• Review of HDV's unique biological characteristics, including its reliance on HBsAg and host cell machinery.
• Analysis of the HDV replication cycle, focusing on entry via NTCP and lack of a viral polymerase.
• Examination of emerging drug classes targeting specific steps in the HDV life cycle.

Main Results:

• HDV's dependence on HBsAg and host RNA polymerase II presents unique therapeutic vulnerabilities.
• Farnesylation of large delta antigen (HDAg) and hepatocyte entry via NTCP are critical steps.
• Three novel drug classes—NTCP receptor inhibitors, farnesyltransferase inhibitors, and nucleic acid polymers—are under clinical evaluation.

Conclusions:

• The unconventional biology of HDV necessitates novel therapeutic strategies beyond traditional antiviral targets.
• Targeting specific interactions in the HDV life cycle, such as NTCP entry and farnesylation, shows promise.
• Emerging therapies offer new hope for managing chronic hepatitis D, a historically difficult-to-treat condition.