Hepatitis B virus: promising drug targets and therapeutic implications

ABSTRACT

Introduction: Current therapy for infection with hepatitis B virus (HBV) rarely clears the virus, and viremia commonly resurges following treatment withdrawal. To prevent serious complications of the infection, research has been aimed at identifying new viral and host targets that can be exploited to inactivate HBV replication.

Areas covered: This paper reviews the use of these new molecular targets to advance anti-HBV therapy. Emphasis is on appraising data from pre-clinical and early clinical studies described in journal articles published during the past 10 years and available from PubMed.

Expert opinion: The wide range of viral and host factors that can be targeted to disable HBV is impressive and improved insight into HBV molecular biology continues to provide the basis for new drug design. In addition to candidate therapies that have direct or indirect actions on HBV covalently closed circular DNA (cccDNA), compounds that inhibit HBsAg secretion, viral entry, destabilize viral RNA and effect enhanced immune responses to HBV show promise. Preclinical and clinical evaluation of drug candidates, as well as investigating use of treatment combinations, are encouraging. The field is poised at an interesting stage and indications are that reliably achieving functional cure from HBV infection is a tangible goal.

KEYWORDS:

• Hepatitis B virus
• cccDNA
• drug targets
• host factors
• viral targets

ARTICLE HIGHLIGHTS

• Recent research shows that there is a wide range of viral and host factors that can be targeted to inhibit HBV replication.

• Promising candidate therapies have direct or indirect actions on the stable HBV replication intermediate comprising cccDNA.

• HBV-targeting siRNAs, inhibitors of viral protein function, such as CpAMs, NAPs and entry inhibitors, have shown impressive efficacy and rapidly progressed to evaluation in clinical trials.

• Pre-clinical assessment of drugs that enhance anti-HBV immune responses is also encouraging.

• Advancing more effective anti-HBV agents is gaining momentum and achieving a functional cure, possibly with drug combinations, seems imminent

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by the Poliomyelitis Research Foundation; South African Medical Research Council, Extramural research unit; South African National Research Foundation, Unique Grant Numbers:118022 and 120383.