Association of hepatitis B surface antigen loss with clinical outcomes among patients with chronic hepatitis B infection: a retrospective cohort study in the United States

Introduction: Chronic hepatitis B virus infection (CHB) is a major public health concern and liver-related complications are a leading cause of mortality in this population. The impact of loss of hepatitis B surface antigen (HBsAg), a marker of functional cure for CHB, on clinical outcomes remains unclear in a US population.

Objectives: Assess the association between HBsAg loss and clinical outcomes (compensated cirrhosis [CC], decompensated liver disease [DLD], hepatocellular carcinoma [HCC], all-cause mortality [ACM]) in a diverse cohort of US adults with prevalent CHB.

Methods: Retrospective cohort study was conducted using data from the Optum electronic health records database for CHB patients between 1 Jan 2012 and 31 Dec 2019 who had≥1 positive HBsAg test. Exposure was HBsAg loss (≥1 negative HBsAg test). The first negative test was defined as the loss index date among the exposed; a comparator index date was imputed for the unexposed. Outcomes including CC, DLD, HCC and ACM were assessed from loss/comparator index date to end of follow-up. Inverse probability of treatment weighting (IPTW) was used to balance the distribution of baseline characteristics between exposed and unexposed patients. Doubly robust IPTW-weighted Cox proportional hazard models were applied to estimate the hazard ratios (HRs) and according 95% confidence intervals (CIs) between HBsAg loss and clinical outcomes.

Results: A total of 15,760 patients with CHB were included, among which 667 (4%) experienced HBsAg loss. Exposed patients were numerically older (median 49 vs 43 years of age) than unexposed patients and had numerically higher proportions of patients who were Caucasian (44% vs 20%), obese (32% vs 21%), and hypertensive (32% vs 18%). Over a median follow-up of 25 months in both cohorts, HBsAg loss was significantly associated with an 89% reduced risk of HCC (adjusted HR [aHR]: 0.11, 95% CI: 0.01–0.76) and a 62% reduced risk of ACM (aHR: 0.38, 95% CI: 0.20–0.74). Those with HBsAg loss also had a lower (but non-significant) risk of CC (aHR: 0.84, 95% CI: 0.52–1.35) and DLD (aHR: 0.74, 95% CI: 0.37–1.48).

Conclusion: HBsAg loss was associated with a lower risk of HCC and ACM in a diverse population of patients with CHB in the US. The risk of CC and DLD also appeared lower after HBsAg loss, but did not reach significance. Further investigation into sub-groups of interest is needed to better understand the potential impact of HBsAg loss on these outcomes.

Funding GSK, Study 223767

 

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Publication History

Article published online:
04 September 2025