Hepatitis B functional cure: Current and future perspective

Table 1 Barriers to achieving functional cure in chronic hepatitis B

Category	Barrier	Description /mechanism
Viral factors	cccDNA persistence	cccDNA forms a stable nuclear minichromosome, serving as a reservoir for HBV transcription
	High antigen load	Continuous production of HBsAg and HBcAg from cccDNA promotes immune tolerance and T cell exhaustion
	HBV-mediated immune suppression	HBsAg and HBeAg interfere with PRR signaling, hindering innate immune responses via IRF3 and NF-κB inhibition
	HBx-induced cell cycle modulation	HBx protein disrupts hepatocyte proliferation and prevents cccDNA dilution during cell division
Host factors	Epigenetic control of cccDNA	Host enzymes (e.g., HDAC1, Smc5/6) modify cccDNA chromatin, affecting its transcriptional activity
	Effective innate immunity	Kupffer cells, dendritic cells, and monocytes show impaired PRR signaling and reduced IFN production
	NK cell dysfunction	NK cells display reduced cytotoxicity, lower IFN-γ secretion, and contribute to CD8+ T cell depletion
	T cell exhaustion	HBV-specific CD4+ and CD8+ T cells overexpress inhibitory receptors (PD-1, CTLA-4), resulting in functional impairment
	B cell dysfunction	Atypical memory B cells (e.g., PD-1+, FcRL5+) fail to generate effective anti-HBs antibodies
	Expansion of immunosuppressive cells	Regulatory T cells and myeloid-derived suppressor cells suppress antiviral immune responses
Therapeutic gaps	No cccDNA-targeting therapies	Current antivirals suppress replication but do not eliminate or silence cccDNA effectively
	Limited immunotherapeutic tools	PEG-IFN and NAs yield low HBsAg clearance; novel immunotherapies are investigational

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HBcAg: Hepatitis B core antigen; HBeAg: Hepatitis B e antigen; cccDNA: Covalently closed circular DNA; HBx: Hepatitis B Virus X protein; PRR: Pattern recognition receptor; IRF3: Interferon regulatory factor 3; HDAC1: Histone deacetylase 1; IFN-γ: Interferon-gamma; PD-1: Programmed cell death protein 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; FcRL5: Fc Receptor–Like 5; NK cells: Natural killer cells; PEG-IFN: Pegylated interferon; NAs: Nucleos(t)ide.