Long-term kinetic of HBsAg proteins in patients with HBeAg-negative infection or hepatitis over up to 9 years

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Background: Intrahepatic viral activity in patients with HBeAg-negative HBV infection (ENI) or chronic hepatitis B (CHB) has recently been linked to silened cccDNA activity after prolonged infection. While intrahepatic studies are of upmost importance, surrogate markers are in high demand. Lower ratios of large (LHBs) and middle (MHBs) HBsAg proteins have been associated with inactive HBV infection or treatment response. Aim: We investigated the dynamics of HBsAg proteins during long-term treatment with Tenofovir Disoproxil Fumarate (TDF) or during spontaneous HBsAg loss in patients with chronic HBV infection. Methods: Serum samples from two patient cohorts with either HBeAg-negative ENI (n=38) or CHB (n=96) were analyzed. The CHB cohort included patients prospectively enrolled during first-line (n=24, group A) or second-line (n=72, group B) TDF treatment. The untreated ENI cohort was retrospectively analyzed, including patients who either lost HBsAg spontaneously (n=19) or remained positive (n=19). HBsAg protein levels and viral markers were quantified at baseline and repeatedly every 1-3 years over up to 9 years. Results: In CHB patients, median HBsAg (log ng/mL) slightly declined over time from 3.8 (group A) and 3.3 (group B) at baseline to 3.4 and 2.8 after 8 years, respectively (p=n.s.). Importantly, LHBs (%) decreased markedly from baseline values of 9.3% and 9.5% to 4.2% and 4.3% at 3 years, without further decline thereafter. MHBs (%) strongly declined from baseline (13.3% and 10.9%) to 3.7% and 3.0% at 8 years of TDF therapy. Untreated ENI patients had significantly lower baseline HBsAg levels (log ng/mL: 3.0 with and 2.9 without HBsAg loss), LHBs (3.1% and 4.1%), and MHBs (1.2% and 1.3%) compared to CHB patients (p<0.001). During follow-up, total HBsAg, LHBs, and MHBs levels consistently declined in patients achieving HBsAg loss. Notably, MHBs dropped from 1.2% at baseline to 0.5% after 4-6 years, becoming undetectable early. Conversely, patients without HBsAg loss showed stable or slightly increased MHBs (1.3% to 3.3%) during follow-up. Conclusion: Long-term TDF treatment in CHB patients led to significant declines in LHBs and MHBs percentages, reflecting reduced viral replication activity. Untreated ENI patients exhibited markedly lower baseline LHBs and MHBs levels, with spontaneous HBsAg loss accompanied by a pronounced decline of HBsAg proteins, particularly early disappearance of MHBs. Publication History Article published online: 04 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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