The roadmap towards cure of chronic hepatitis B virus infection

Global elimination of HBV is feasible thanks to the availability of a safe, effective and inexpensive vaccine. However, this will not help almost 300 million adults living with chronic HBV infection. Current therapy can reduce complications but is administered life-long and is associated with risk of breakthrough and potential cumulative toxicity. There is therefore great interest in developing new therapies which can achieve sustained disease remission after a finite course of treatment i.e. an HBV CURE. Steps of HBV life cycle other than the polymerase that are targeted by new direct antiviral therapies include HBV entry, HBV capsid assembly, HBV mRNA transcription and translation and HBsAg secretion. As chronic HBV infection is characterised by high viral load and antigen burden and inadequate host immune responses innovative approaches to restore innate and adaptive immune responses against HBV, are currently in clinical development. These include therapeutic vaccines and TLR agonists. It is likely that HBV Cure will require combinations of novel immunomodulatory and antiviral approaches. In the future, strategies which directly silence or eliminate cccDNA could provide a single agent cure. Efficacy, safety, route of administration and cost will ultimately determine the impact of these new regimens on the burden of HBV. Abbreviations: ACTG: AIDS Clinical Trials Group network; ALT: alanine aminotransferase; ASGPR: Asialoglycoprotein Receptor; ASO: anti-sense oligonucleotide; CAM: capsid assembly modulator; CAM-A: capsid assembly modulator with abhorrent structure; CAM-N: capsid assembly modulator with normal structure; cccDNA: covalently closed circular DNA; CHB: chronic hepatitis B; c-Raf-1/MAP: cellular Rapidly Accelerated Fibrosarcoma-1/mitogen-activated protein kinase; DR1 and DR2: direct repeat sequences 1 and 2; ETV: entecavir; FDA: Food and Drug Administration; GalNAc: N-acetylgalactosamine; HBcrAg: hepatitis B core-related antigen; HBeAg: hepatitis B e antigen; HBIG: hepatitis B immunoglobulin; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HBV DNA: hepatitis B virus deoxyribonucleic acid; HCC: hepatocellular carcinoma; HDV: hepatitis delta virus; ir-AE: immune-related adverse events; LNA: locked nucleic acid; MAD: multiple ascending dose; mRNA: messenger ribonucleic acid; NAPs: nucleic acid polymers; NTCP: sodium taurocholate co-transporting polypeptide; PD-1: programmed death receptor 1; PD-L1: programmed death receptor ligand 1; pgRNA: pregenomic ribonucleic acid; R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisolone; RISC: RNA-induced silencing complex; RNAi: ribonucleic acid interference; SAD: single ascending dose; siRNA: short (small) interfering ribonucleic acid; STOPs: S-antigen traffic-inhibiting oligonucleotide polymers; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil; USD: United States dollars; WHO: World Health Organization.