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Review
. 2022 Jun;76(6):1249-1262.
doi: 10.1016/j.jhep.2021.11.024.

How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?

Grace L H Wong  1 , Ed Gane  2 , Anna S F Lok  3
Affiliations
Review

How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?

Grace L H Wong et al. J Hepatol. 2022 Jun.

Abstract

Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.

Keywords: Antiviral; Antiviral treatment; Immune modulation; cccDNA; entecavir; hepatitis B surface antigen clearance; nucleos(t)ide analogue; tenofovir.

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Conflict of interest statement

Conflict of interest Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche, and received research grant from Gilead Sciences. Ed Gane has served as an advisory committee member and/or speaker for AbbVie, Abbott Diagnostics, Aligos, Arbutus, Arrowhead, Assembly, Avalia, Clear B Therapeutics, Dicerna, Enanta, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche and Vir Bio. Anna Lok has served as an advisory committee member / consultant for Arbutus, ClearB, Enanta, Enochian, GNI, Janssen, TARGET, and Viravaxx, and received research grants from Gilead and TARGET. Please refer to the accompanying ICMJE disclosure forms for further details.

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