HBsAg glycan isomer predicts on-treatment HBsAg decline in low-HBsAg chronic hepatitis B on nucleos(t)ide therapy

Background Early decline in HBsAg levels during nucleos(t)ide-analog (NA) therapy predicts subsequent HBsAg loss, but stratification tools are limited. We assessed whether a novel baseline HBV biomarker—the HBsAg glycan-isomer (HBsAgGi)—predicts 12-month HBsAg decline. Methods We retrospectively analysed genotype C chronic hepatitis B patients who initiated entecavir, tenofovir-disoproxil-fumarate, or tenofovir-alafenamide and had serum available for HBsAgGi measurement. Early decliners were defined as those with ≥ 0.10 log10 IU/mL HBsAg reduction after 1 year. Baseline clinical and virological parameters were compared between decliners and non-decliners and within HBsAg < 3,000 and ≥ 3,000 IU/mL strata. Results Of 201 screened individuals, 106 had samples for HBsAgGi testing. In this cohort, HBsAg levels continued to fall annually over 5 years in early decliners, whereas non-decliners showed almost no long-term HBsAg reduction. In univariate analyses, higher baseline HBsAg, HBV DNA, HBeAg-positivity, and HBcrAg were associated with 1-year HBsAg decline, whereas HBsAgGi was not; none remained significant in multivariable models. However, among patients with baseline HBsAg < 3,000 IU/mL, HBsAgGi alone differentiated decliners from non-decliners. After adjustment for baseline HBsAg and HBcrAg, lower HBsAgGi remained independently associated with ≥ 0.10 log10 IU/mL HBsAg decline at 1 year. In patients with baseline HBsAg ≥ 3,000 IU/mL, decliners had higher rates of HBeAg positivity and higher baseline HBsAg and HBcrAg. Traditional HBV markers were tightly correlated, whereas HBsAgGi showed only weak-to-modest correlations. Conclusions Baseline HBsAgGi adds prognostic value in patients with low HBsAg, identifying those more likely to achieve on-therapy HBsAg decline and potentially informing selection for intensified or combination HBV therapies.