New antivirals for the treatment of chronic hepatitis B

ABSTRACT

Introduction: Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers.

Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription. Alongside these antivirals, agents that enhance anti-HBV specific immune responses are being tested, including TLR agonists, checkpoint inhibitors and therapeutic vaccines.

Expert opinion: The achievement of a ‘functional cure’ for chronic HBV infection, with sustained HBsAg clearance and undetectable viremia once medications are stopped, represents the next step in the pace towards HBV elimination. Hopefully, the combination of new drugs that eliminate or functionally inactivate the genomic HBV reservoirs (cccDNA and integrated HBV-DNA) along with agents that enhance or activate immune responses against HBV will lead to a ‘definitive cure’ for chronic HBV infection.

KEYWORDS:

• Hepatitis B
• capsid inhibitors
• cccDNA
• entry inhibitors
• immunomodulators
• RNAi
• TAF
• novel therapy
• nucleos(t)ide analogues
• polymerase inhibitors
• therapeutic vaccines
• TLR7 agonist

Article highlights

• Current treatment of HBV infection with nucleos(t)ide analogs provides long-term serum HBV-DNA suppression, significantly ameliorating liver damage and extrahepatic complications; however, the risk of liver cancer remains increased.

• New antivirals that target distinct steps of the HBV life cycle including entry, assembly and/or release inhibitors, along with drugs acting on HBV reservoirs (cccDNA disruptors or transcription blockers) hopefully would lead to serum HBsAg clearance, the next step in HBV therapeutics or functional cure.

• Adding immune-modulators that enhance specific anti-HBV immune responses hold promise as adjunctive therapy with antivirals for eliminating the HBV reservoir, the definite HBV cure (eradication).

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded