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Review
. 2023 Jan;164(1):42-60.e6.
doi: 10.1053/j.gastro.2022.10.008. Epub 2022 Oct 12.

Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure

David Yardeni  1 , Kyong-Mi Chang  2 , Marc G Ghany  3
Affiliations
Review

Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure

David Yardeni et al. Gastroenterology. 2023 Jan.

Abstract

The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.

Keywords: Antiviral; Functional Cure; Screening; Treatment.

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Figures

Figure 1:
Figure 1:. HBV lifecycle and targets of drug development
Viral entry is a multi-step process beginning with viral attachment to the hepatocyte surface via a loose interaction with heparan sulfate proteoglycans[145]. This is followed by stronger interaction between the pre-S1 domain and the hepatocyte bile salt transporter, the sodium taurocholate co-transporting polypeptide (NTCP) which facilitates entry[146]. The NTCP receptor confers species specificity to HBV. Viral entry is thought to occur via endocytosis. Following entry, there is uncoating and release of the partially double-stranded, relaxed circular DNA genome (rcDNA), which is transported to the hepatocyte nucleus where host cellular enzymes repair the rcDNA to form the covalently closed circular DNA (cccDNA). cccDNA serves as the transcriptional template for all mRNAs including the pre-genomic RNA, which also serves as the template for genome replication. Viral transcription and translation are under the control of viral promoters and enhancers. Four viral transcripts, polymerase, core, surface, and X are transported to the cytoplasm where they are translated into 7 viral proteins. In the cytoplasm, core proteins self-assemble and through an encapsidation reaction, the pgRNA and viral polymerase are packaged to form the nucleocapsid. Viral replication occurs within the nucleocapsid through a reverse transcription step. The mature viral capsids containing rcDNA are then enveloped with the small, medium, and large (S, M, L) surface proteins in the endoplasmic reticulum and secreted from the infected cell as intact virions, (Dane particle), or transported back to the nucleus to replenish the cccDNA pool. Several sub-viral filamentous and spherical particles that are devoid of viral DNA are also produced in vast excess of the Dane particle. 1)Targeting viral entry; 2) Targeting covalently closed circular DNA (cccDNA) via elimination or silencing; 3) Targeting viral transcription 4) Targeting the HBV core protein; 5) Targeting the HBV polymerase; and 6) Targeting hepatitis B surface antigen (HBsAg) secretion.
Figure 2:
Figure 2:. Immune subsets involved in HBV pathogenesis and approaches for immune-modulatory therapy.
Multiple immune subsets participate in virus control and disease pathogenesis in chronic hepatitis B. Adaptive immune modulatory approaches in exploration include augmentation of antiviral T and B cells by therapeutic vaccination, checkpoint inhibition (e.g. blockade of PD1/PDL1 or CTLA4/CD28 interactions) as well as supplementation by providing engineered T-cells or antibodies. Innate immune modulatory include IFN alpha (already in clinical use with pleiotropic antiviral and immune modulatory effects) in addition to evolving clinical and pre-clinical evaluations for cellular antiviral pathways including agonists for toll like receptors (e.g TLR7/8), RIG-I,* STING agonists and lymphotoxins. *No longer in clinical development
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