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

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 and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-a (PEG-IFNa) 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 PEGIFNa 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. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Automated summary

Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Current therapies for HBV rarely achieve cure, but novel antiviral and immunomodulatory strategies show promise in increasing the chance of cure through personalized approaches. The development of safe, effective, and affordable curative therapies must be coupled with standardized virologic and immunologic assays to confirm target engagement and to assess response.