Functional cure of chronic hepatitis B-hope or hype?

Abstract

Chronic hepatitis B constitutes a substantial disease burden worldwide. The steps advocated by the World Health Organization in 2016 to eradicate hepatitis B by 2030 has failed to achieve significant progress, especially with respect to immunization coverage and linkage to care. The lack of governmental and public awareness regarding the long-term implications of hepatitis B burden cause underfunding of developmental projects. The presently approved treatment modalities have limited efficacy in complete viral eradication, hence the need for newer molecules to achieve functional cure (sustained undetectable hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA in peripheral blood after a finite period of therapy). However, preliminary results from trials of novel therapies show their inadequacy to achieve this end by themselves but better performance with a low baseline serum HBsAg with nucleos(t)ide analogues (NA) treatment which need to be combined with/without pegylated interferon as an immunomodulator. Such therapy is limited by cost and adverse events and need to show incremental benefit over the standard of care (long-term NA therapy) with respect to efficacy and drug toxicities, making the development process tenuous. Thus, while such therapies continue to be tested, strategies should still focus on prevention of transmission by non-pharmaceutical measures, vaccination and increasing linkage to care.

Keywords: Clinical trial; Drugs; Functional cure; Hepatitis B; Novel therapies; Therapy.

Figure 1

Hepatitis B virus life cycle and novel drug targets. NTCP: Sodium taurocholate co-transporting polypeptide; rcDNA: Relaxed circular DNA; cccDNA: Covalently closed circular DNA; CRISPR: Clustered regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; mRNA: Messenger RNA; pgRNA: Pregenomic RNA; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B envelope antigen; HBcAg: Hepatitis B core antigen; HBcrAg: Hepatitis B core related antigen; TALEN: Transcription Activator-like Effector Nucleases; ZFP: Zinc-Finger Proteins; CpAM: Capsid assembly modulators; siRNA: Short interfering RNA; ASO: Antisense oligonucleotides; NAP: Nucleic acid polymer; HBx: Hepatitis B X protein; HBs: Hepatitis B S protein; HDAc: Histone deacetylase; FXR: Farnesoid X receptor; PegIFN: Pegylated interferon; NA: Nucleotide analogue.