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.

Table 2 Summary of published studies on hepatitis B surface antigen seroclearance (functional cure) in chronic hepatitis B

Ref.	Year	Study type	n	Cohort and treatment	HBsAg seroclearance rate
Lau et al[36]	2005	RCT	814	HBeAg+ CHB on PEG-IFN α	2.95% at 6 months post-treatment
Marcellin et al[39]	2013	RCT	537	HBeAg- CHB on PEG-IFN α	3% (6 months), 9% (3 years), 12% (5 years)
Bourlière et al[53]	2017	RCT	185	HBeAg- CHB: NA vs NA + PEG-IFN	3.2% vs 7.8% at 96 weeks
Ahn et al[55]	2018	RCT	740	TDF + PEG-IFN vs TDF mono	9.1% vs 0% at 72 weeks
Zhou et al[32]	2019	Meta-analysis	48972	Untreated CHB	1.17% per year
Yeo et al[33]	2019	Meta-analysis	42588	Untreated CHB	1.02% per year
Yip et al[45]	2019	Retrospective	20263	CHB on TDF/ETV	2.1% (mean FU: 4.8 years)
Yeo et al[34]	2020	Prospective cohort	11262	Untreated CHB	1.31% per year
Yang et al[52]	2020	RCT	144	CHB on ETV vs ETV + PEG-IFN	1.8% vs 4.1%
Fonseca et al[56]	2020	Meta-analysis	8719	CHB on IFN+NA vs IFN vs NA (48-130 weeks)	4.8% to 6.5% vs 3.6% to 6.5% vs 0.27% to 0.58%
Song et al[43]	2021	Meta-analysis	1029	IHCs on PEG-IFN	47% at 48 weeks
Hsu et al[47]	2021	Retrospective	4769	CHB on TDF/ETV	0.22% per year
Chan et al[48]	2024	RCT	1298	CHB on TAF	≤ 1.2% at 5 years

HBsAg: Hepatitis B surface antigen; RCT: Randomized controlled trial; HBeAg: Hepatitis B e antigen; CHB: Chronic hepatitis B; PEG-IFN: Pegylated interferon; NA: Nucleos(t)ide analogue; TDF: Tenofovir disoproxil fumarate; ETV: Entecavir; TAF: Tenofovir alafenamide; FU: Follow up; IFN: Interferon; IHCs: Inactive hepatitis B carriers.

Table 3 Predictors of hepatitis B surface antigen clearance in chronic hepatitis B

Category	Subcategory	Predictor variables
Spontaneous clearance	Host factors	Male sex; older age (hazard ratio 1.16-1.21)
	Viral factors	HBeAg-negative status; genotype C infection; lower HBV DNA (≤ 20000 IU/mL); low quantitative HBsAg (≤ 1000 IU/mL)
PEG-IFN therapy	Host factors	Younger age; female sex; ALT elevation at week 12
	Treatment factors	Combination therapy (PEG-IFN + NAs) more effective than PEG-IFN alone
	Viral factors	Genotype A; low baseline HBsAg and HBV DNA; early HBsAg decline (at week 12 or 24)
NAs therapy	Treatment factors	Early HBeAg seroconversion (before age 18); initiating high-barrier NA before seroconversion
	Viral factors	Low HBsAg (< 1000 IU/mL) at 18 months post-seroconversion
NA discontinuation in HBeAg-negative CHB	Treatment factors	End-of-treatment HBsAg < 100 IU/mL; ALT/qHBsAg ratio ≥ 0.2
	Viral factor	Low HBsAg glycan isomer (≤ 3.5 Log ng/mL) associated with 5-fold higher 10-year clearance
Prediction models	Nomogram	BMI, HBeAg status, qHBsAg, HBV DNA (C-index 0.91)
	HepBLOSS-1 & HepBLOSS-2	Age, sex, HBsAg, HBV DNA; AUROC 0.81-0.89; > 50% 10-year clearance in high-risk groups
	HBRN-SQuARe	Sex, age, race, qHBsAg; AUROC 0.99 (1 year), 0.95 (3 years) in untreated HBeAg-negative CHB

HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; qHBsAg: Quantitative hepatitis B surface antigen; PEG-IFN: Pegylated interferon; NAs: Nucleos(t)ide analogues; ALT: Alanine aminotransferase; BMI: Body mass index; CHB: Chronic hepatitis B; AUROC: Area under the receiver operating characteristic curve; C-index: Concordance index; HepBLOSS: Hepatitis B Long-term Outcome Scoring System; HBRN-SQuARe: Hepatitis B Research Network-Surface Quantitative Antigen Risk estimator.