HBsAg isoforms predict HBsAg seroclearance and finite treatment in patients with chronic hepatitis B after cessation of long term nucleos(t)ide analogue.

BACKGROUND AND AIMS: We examined the role of HBsAg isoforms to predict HBsAg seroclearance or finite treatment among patients with chronic hepatitis B (CHB) infection who stopped long-term nucleoside analogue (NUC). METHODS: This prospective study recruited patients with HBeAg-negative non-cirrhotic CHB on ≥3 years of first-line NUC with NUC cessation. NUC was resumed upon clinical relapse (CR) or major virological rebound (mVR). HBV biomarkers were measured at baseline, CR or mVR (if any), and end-of-follow-up. The primary outcome was HBsAg seroclearance (defined as <0.05 IU/mL). Patients were followed up for ≥1 year after NUC cessation (without CR/mVR) or ≥1 year after ALT normalization (with CR/mVR), whichever was later. Finite treatment was defined as a state of no virological relapse (VR), i.e., persistent HBV DNA <2000 IU/mL or HBsAg seroclearance. RESULTS: Among 51 patients who completed study (median age 50.1, 62.7% male, baseline qHBsAg 298 IU/mL with 25.5% <100 IU/mL, median NUC duration 7.38 years; median follow-up 91 weeks), 6 patients developed HBsAg seroclearance at weeks 20, 24, 48, 81, 91 and 96, with an event rate of 11.7%. Baseline small HBsAg [SHBs] was predictive of HBsAg seroclearance (HR 0.205, 95% CI 0.082-0.514) and identified 62.5% patients who achieved HBsAg seroclearance when combined with criteria of quantitative HBsAg (qHBsAg) <100 IU/mL. Fifteen patients fulfilled finite treatment criteria, which was associated with low baseline SHBs (HR 3.471, 95% CI 1.132-10.647) and the presence of hepatic steatosis (HR 4.077, 95% CI 1.374-12.098). No patients developed hepatic decompensation. CONCLUSION: Baseline small HBs (SHBs) levels, in addition to quantitative HBsAg levels, were predictive of HBsAg seroclearance. SHBs levels and hepatic steatosis were associated with finite treatment following nucleoside analogue cessation. IMPACT AND IMPLICATIONS: Stopping long-term nucleoside analogue (NUC) is one of the strategies to enhance host control to hepatitis B virus and target for functional cure. In addition to quantitative HBsAg (qHBsAg) levels, we explored the role of HBsAg isoforms in predicting off-therapy outcomes in this prospective cohort study involving Asian patients with chronic hepatitis B infection. Low small HBs, a surrogate marker of integrated DNA-derived HBsAg, was predictive of off-NUC HBsAg seroclearance and identified 62.5% patients who would develop HBsAg seroclearance when combined with qHBsAg <100 IU/mL. Finite treatment, defined as either HBsAg seroclearance or viral load maintained below 2,000 IU/mL after NUC cessation, was associated with low baseline SHBs and presence of hepatic steatosis. Combining qHBsAg <100 IU/mL with low baseline SHBs identified 87.5% patients who could achieve finite treatment. These findings are most compelling to hepatologists and other clinicians managing patients with chronic hepatitis B infection on NUC or researchers conducting clinical trials. The findings are of academic relevance to researchers to investigate the correlation between SHBs expression with intrahepatic viral reservoir as well as the immunological basis behind virological control after NUC cessation. However, the study was limited by a relatively small sample size and the inclusion of purely Asian patients, requiring confirmation in larger cohorts for validation of findings before incorporation into clinical guidelines.