Hepatitis B e antigen (HBeAg) seroclearance and HBeAg seroconversion are critical milestones indicating reduced viral replication and a lower risk of disease progression to cirrhosis and hepatocellular carcinoma (HCC). Despite entecavir (ETV) and tenofovir alafenamide (TAF) being two first-line agents used for the treatment of patients with chronic hepatitis B (CHB), their comparative efficacy in attaining HBeAg seroclearance or HBeAg seroconversion is still unclear. Consequently, we aimed to directly compare the incidence of HBeAg seroclearance and HBeAg seroconversion in CHB patients treated with ETV or TAF.

This retrospective study included 244 patients who initiated therapy with ETV ( n =145) or TAF ( n =99) from 2017 to 2025. Multivariate Cox proportional hazards analysis was conducted to identify the factors independently associated with HBeAg seroclearance and seroconversion. Kaplan-Meier survival analysis was performed to compare the incidence of HBeAg seroclearance and seroconversion between the ETV and TAF groups.

A 1:1 propensity score matching yielded 99 patients in each treatment group. The median HBeAg levels were 2.37 log ₁₀ IU/ml and 2.44 log ₁₀ IU/ml in the ETV and TAF groups respectively. After a follow-up period of 288 weeks, a total of 47 patients attained HBeAg seroclearance, comprising 20 patients from the ETV group and 27 patients from the TAF group, respectively. Additionally, 37 patients achieved HBeAg seroconversion, with 17 and 20 patients from the ETV and TAF treatment, respectively. The incidence of HBeAg seroclearance was significantly higher in TAF-treated patients than in ETV-treated patients (27.3% vs. 20.2%; p = 0.016), whereas the incidence of HBeAg seroconversion was comparable between the two groups (20.2% vs. 17.2%; p =0.075). Notably, compared with ETV, patients treated with TAF (HR=2.04; 95% CI: 1.84-6.47; p < 0.001) showed a significantly higher rate of HBeAg seroclearance. Higher baseline HBsAg levels (HR=0.50; 95% CI: 0.41-0.73; p < 0.001), and higher baseline HBeAg levels (HR=0.48; 95% CI: 0.43-0.75; p < 0.001) were associated with lower rates of HBeAg seroclearance, whereas elevated serum ALT levels (HR=1.001; 95% CI: 1.001-1.002; p < 0.001) were associated with higher rates of HBeAg seroclearance. In addition, factors significantly associated with HBeAg seroconversion included higher baseline HBsAg levels (HR=0.50; 95% CI: 0.45-0.78; p < 0.001) and higher baseline HBeAg levels (HR=0.51; 95% CI: 0.39-0.75; p < 0.001), which were linked to lower rates of HBeAg seroconversion, whereas elevated serum ALT levels (HR=1.001; 95% CI: 1.001-1.002; p < 0.001) were associated with higher rates of HBeAg seroconversion.

Higher incidence of HBeAg seroclearance was observed with TAF compared with ETV in HBeAg-positive CHB patients. Baseline HBsAg, HBeAg, and ALT levels were identified as significant predictors for both HBeAg seroclearance and HBeAg seroconversion.