Emerging Therapies for Chronic Hepatitis B and the Potential for a Functional Cure

Area of Science:

• Hepatology
• Virology
• Immunology

Background:

• Chronic hepatitis B virus (HBV) infection affects 296 million globally, posing significant health risks.
• Current therapies (pegylated interferon and nucleoside analogues) suppress HBV but rarely achieve functional cure (HBsAg loss).
• Relapse post-therapy is common due to persistent viral DNA (cccDNA and integrated HBV DNA).

Purpose of the Study:

• To review the efficacy of novel direct-acting antivirals (DAAs) and immunomodulators for chronic HBV.
• To assess their potential in achieving sustained hepatitis B surface antigen (HBsAg) loss (functional cure).
• To explore combination therapies and future treatment strategies.

Main Methods:

• Review of current literature on novel DAAs (entry inhibitors, capsid modulators, RNAi, ASOs, nucleic acid polymers) and immunomodulators (T-cell agonists, checkpoint inhibitors, vaccines, antibodies).
• Analysis of studies evaluating HBsAg loss rates with these novel agents, alone or in combination with existing therapies.
• Assessment of the impact on viral suppression, hepatitis B surface antigen (HBsAg) loss, and durability post-therapy.

Main Results:

• Some DAAs, particularly RNAi, ASOs, and nucleic acid polymers combined with standard therapy, significantly reduce HBsAg levels and achieve sustained HBsAg loss in up to 40% of patients.
• Novel immunomodulators may restore HBV-specific T-cell responses but have not consistently led to sustained HBsAg loss.
• Finite nucleoside analogue therapy shows increased HBsAg loss rates up to 39% over 5 years.

Conclusions:

• Novel DAAs and immunomodulators offer improved strategies for chronic HBV functional cure.
• Combination therapies hold potential for enhancing HBsAg loss rates.
• Directly targeting cccDNA remains a critical goal, though currently in early development stages. Further research is needed for safety and durability.