The premise of capsid assembly modulators towards eliminating HBV persistence

ABSTRACT

Introduction

The burden of chronic hepatitis B virus (HBV) results in almost a million deaths per year. The most common treatment for chronic hepatitis B infection is long-term nucleoside analogs (NUC) or one-year interferon-alpha (pegylated or non-pegylated) therapy before or after NUC therapy. Unfortunately, these therapies rarely result in HBV functional cure because they do not eradicate HBV from the nucleus of the hepatocytes, where the covalently closed circular DNA (cccDNA) is formed and/or where the integrated HBV DNA persists in the host genome. Hence, the search continues for novel antiviral therapies that target different steps of the HBV replication cycle to cure chronically infected HBV individuals and eliminate HBV from the liver reservoirs.

Areas covered

The authors focus on capsid assembly modulators (CAMs). These molecules are unique because they impact not only one but several steps of HBV viral replication, including capsid assembly, capsid trafficking into the nucleus, reverse transcription, pre-genomic RNA (pgRNA), and polymerase protein co-packaging.

Expert opinion

Mono- or combination therapy, including CAMs with other HBV drugs, may potentially eliminate hepatitis B infections. Nevertheless, more data on their potential effect on HBV elimination is needed, especially when used daily for 6–12 months.

KEYWORDS:

• antiviral therapy
• CAM - capsid assembly modulator
• cccDNA
• core inhibitor
• DAA – directly acting antiviral
• hepatitis B
• HBV
• drug resistance

Article highlights

• Today, the hepatitis B virus (HBV) results in almost a million deaths per year.

• Current antiviral therapies are inadequate and do not eliminate HBV from liver reservoirs, leading to lifetime treatment and the potential development of hepatocellular carcinoma (HCC).

• Novel HBV direct-acting antivirals targeting different steps of the HBV replication cycle are being studied experimentally and clinically toward a functional cure, including the loss of HBsAg and other HBV markers.

• Data on long-term treatment of chronically HBV-infected individuals with new capsid assembly modulators alone or in combination with nucleoside analogs (NUC) are limited.

• In the absence of simple cell-based assays, a computational approach to predict HBV resistance mutations to CAMs has been successfully developed and validated.

Acknowledgments

We thank Drs. James J. Kohler and Lefteris Michailidis for the helpful review of the paper

Declaration of interest

RF Schinazi, F Amblard, L Bassit, and Emory University, are entitled to equity and royalties related to anti-HBV products licensed to Aligos Therapeutics, Inc., being further evaluated in the research described in this review. Emory University has reviewed and approved the terms of this arrangement per its conflict-of-interest policies. 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 or other relationships to disclose.

Additional information

Funding

This work was supported by funding from the National Institutes of Health (AI-132833 to RF Schinazi), (AI-148740 to JC Gumbart and L Bassit), and the Emory Center for AIDS Research (5P30-AI-50409 to RF Schinazi).