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Clinical Trial
. 2026 Jan;63(2):231-241.
doi: 10.1111/apt.70332. Epub 2025 Aug 21.

Long-Term Follow-Up of Patients in a Prospective Study of NA Discontinuation Identifies Different Patterns of HBsAg Loss

Simon J Hume  1   2   3 , Samuel Hall  1   2 , Gareth Burns  4 , Sara Vogrin  2 , Daniel Tassone  1 , Paul Desmond  1 , Dilip Ratnam  5   6 , Miriam T Levy  7   8 , Rohit Sawhney  6   9 , Amanda Nicoll  6   9 , Zina Valaydon  4 , Simone I Strasser  10 , Meng Ngu  11 , Marie Sinclair  12 , Chris Meredith  13 , Gayle V Matthews  14 , Kumar Visvanathan  1   2 , Jacinta A Holmes  1   2 , Alexander J Thompson  1   2
Affiliations
Clinical Trial

Long-Term Follow-Up of Patients in a Prospective Study of NA Discontinuation Identifies Different Patterns of HBsAg Loss

Simon J Hume et al. Aliment Pharmacol Ther. 2026 Jan.

Abstract

Background and aims: Discontinuing nucleos(t)ide analogues (NAs) may lead to functional cure (HBsAg loss) in selected patients with chronic hepatitis B (CHB). We evaluated the rates and predictors of HBsAg loss during long-term follow-up in a prospective cohort.

Methods: This real-world extension study followed participants from a prospective trial of NA discontinuation. All patients had HBeAg-negative CHB without cirrhosis. Efficacy outcomes (including HBsAg loss and decline) and safety outcomes [including hepatitis flare and hepatocellular carcinoma (HCC)] were evaluated.

Results: Amongst 97 participants (85% Asian), with a median follow-up of 7 years, the cumulative incidence of HBsAg loss was 10%, 13% and 22% at 5, 7 and 9 years after stopping NA. HBsAg loss was associated with a lower end-of-treatment (EOT) HBsAg level (HR = 0.28, p < 0.001), older age (HR = 1.14, p = 0.005) and peak off-treatment HBV DNA level (OR = 0.50, p = 0.002). Participants with EOT HBsAg level ≤ 10 IU/mL experienced early HBsAg loss (< 96 weeks) without ALT flares whilst those with EOT HBsAg level ≥ 10 IU/mL experienced late (≥ 96 weeks) HBsAg loss, often following ALT flares (5/8 cases). No cases of hepatic decompensation, liver transplantation or death occurred. Median liver stiffness did not increase. HCC was diagnosed in three individuals (4.4/1000 person-years).

Conclusion: The rate of functional cure increased during long-term follow-up but remained low. EOT HBsAg strongly predicted the likelihood and timing of HBsAg loss. ALT flares were associated with HBsAg decline, and in some cases, with delayed HBsAg loss.

Trial registration: The clinical study was supported by the National Health and Medical Research Council of the study clinical trial ID is NCT02581033.

Keywords: alt flare; chronic hepatitis b; functional cure; hbsag level; hbsag loss; hepatitis flare; long‐term follow‐up; nucleos(t)ide analogue discontinuation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Study flow diagram.
FIGURE 2
FIGURE 2
Cumulative incidence of (A) HBsAg loss, (B) HBsAg loss stratified by EOT HBsAg level, (C) ≥ 1 log10 HBsAg reduction, (D) ALT flare, (E) Re‐treatment.
FIGURE 3
FIGURE 3
Box plots comparing the median HBsAg reduction from end of treatment to end of follow‐up, stratified by flare status. P‐value is derived from the paired comparison (Mann–Whitney test) of change in HBsAg (log10 IU/mL) between those who experienced a major flare vs. the remainder of the cohort.
See this image and copyright information in PMC

References

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