Novel Therapies of Hepatitis B and D

Abstract

Hepatitis B virus (HBV) infection is a global public health issue and is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis D virus (HDV) requires the hepatitis B surface antigen (HBsAg) to replicate. The eradication of HBV, therefore, can also cure HDV. The current therapies for chronic hepatitis B and D are suboptimal and cannot definitely cure the viruses. In order to achieve functional or complete cure of these infections, novel therapeutic agents that target the various sites of the viral replicative cycle are necessary. Furthermore, novel immunomodulatory agents are also essential to achieve viral clearance. Many of these new promising compounds such as entry inhibitors, covalently closed circular DNA (cccDNA) inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators and nucleic acid polymers are in various stages of clinical developments. In this review article, we provided a comprehensive overview of the structure and lifecycle of HBV, the limitations of the current therapies and a summary of the novel therapeutic agents for both HDV and HBV infection.

Keywords: Hepatitis B virus (HBV); Hepatitis D virus (HDV); NRTIs; capsid assembly modulators; cccDNA inhibitors; entry and exit inhibitors; immunomodulators; interferon; novel therapies; siRNAs.

Figure 1

Electron microscope image has been taken from CDC’s public domain, and it is free of copyrights.

Figure 2

HBV life cycle in a hepatocyte. Entry inhibitors target the NTCP receptor on hepatocytes and hence prevent the entry of virion into the cell altogether. cccDNA inhibitors either act by targeting the HBx protein which leads to smc5/6 degrading cccDNA or by using the CRISPR/Cas9 nucleases system to break apart the cccDNA. Silencing RNAs (siRNAs) play a role in the destruction of newly formed RNAs. Antisense oligonucleotides (ASO) work against the mRNAs and stop them from reaching the translation step. Capsid assembly modulators cause the production of defected or empty nucleocapsids which fail to further produce new cccDNA or virions. Nucleic acid polymers (NAPs) block the assembly and the secretion of spherical SVP. The release of subviral filaments and virions is not affected [12]. Immunomodulators boost the immune system to attack the virus. HSPG: Heparan Sulfate Proteoglycans, NTCP: Sodium Taurocholate Cotransporting Polypeptide, EGFR: Epidermal Growth Factor Receptor, NPS: Nuclear Pore Complex, rcDNA: relaxed circular DNA, cccDNA: covalently closed circular DNA, ORFs: Open Reading Frames, dslDNA: double-stranded linear DNA, siRNAs: small interfering RNA, ASO: Anti-sense Oligonucleotide, S, M, L HBsAg: Small, Medium, Large HBsAg, ER: Endoplasmic Reticulum, ESCRT-MVBs pathway: Endosomal Sorting Complex Required for Transport.

Figure 3

Development and approval of the HBV Therapy.

Figure 4

Restoration and induction of HBV specific T cells. Therapeutic vaccines consist of various HBV antigens which are processed by APCs. These APCs present the antigens either to new T cells inducing their function or exhausted T cells restoring their function (Left). Check point inhibitors block the interaction of PD-1 with PD-L1 thus boosting T cells function (Right).