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Covalently closed circular DNA: The ultimate therapeutic target for curing HBV infections

Maria Guadalupe Martinez1, Anders Boyd2, Emmanuel Combe1

  • 1INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France.

Journal of Hepatology
|May 29, 2021
PubMed

Insights

Current treatments control chronic hepatitis B but don't cure it. New therapies targeting the hepatitis B virus (HBV) minicircle, covalently closed circular DNA (cccDNA), show promise for a complete HBV cure.

Area of Science:

  • Hepatology and Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • Chronic hepatitis B (CHB) treatments like interferon and nucleos(t)ide analogues manage the infection but do not eliminate it.
  • A complete cure for CHB is hindered by the inability to target the viral covalently closed circular DNA (cccDNA) minichromosome within infected hepatocytes.
  • Functional cure (loss of HBsAg and undetectable HBV DNA) is an interim goal, but complete eradication requires direct cccDNA targeting.

Purpose of the Study:

  • To review emerging technologies capable of directly targeting and eliminating the cccDNA pool in infected hepatocytes.
  • To explore strategies for achieving a complete cure for chronic hepatitis B, moving beyond current control measures.
  • To discuss novel approaches for non-cytolytic targeting of cccDNA for a definitive hepatitis B virus (HBV) cure.

Main Methods:

  • Review of current and emerging therapeutic strategies for HBV.
  • Analysis of technologies aimed at degrading, mutating, or silencing cccDNA.
  • Discussion of clinical trial data for novel cccDNA-targeting agents.

Main Results:

  • Current therapies offer symptomatic relief but fail to eradicate HBV due to persistent cccDNA.
  • Several innovative technologies are under investigation for their potential to directly eliminate or inactivate cccDNA.
  • Early clinical trials are exploring functional cure, but complete cure necessitates effective cccDNA clearance.

Conclusions:

  • Achieving a complete cure for chronic hepatitis B requires direct targeting of the cccDNA minichromosome.
  • Cutting-edge technologies offer potential pathways for non-cytolytic cccDNA degradation, mutation, or silencing.
  • Further research and clinical development are crucial to realize the potential of these novel therapies for a definitive HBV cure.

Keywords:
HBV curecccDNAchronic hepatitis Bdirect-acting antivirals

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