Comparison of Hepatitis B e Antigen Clearance Rates between Tenofovir Alafenamide and Entecavir in Treatment-Naive Hepatitis B e Antigen-Positive Chronic Hepatitis B Patients over 48–96 Weeks: A Retrospective Cohort Study

INTRODUCTION AND OBJECTIVES: Hepatitis B e antigen (HBeAg) clearance is a critical event for predicting long-term prognosis. However, direct comparative data on HBeAg clearance between tenofovir alafenamide (TAF) and entecavir (ETV) are limited, especially for the mid-term (48-96 weeks) in real-world settings. This retrospective cohort study aimed to compare HBeAg clearance rates at 48 and 96 weeks in treatment-naïve, HBeAg-positive chronic hepatitis B (CHB) patients receiving TAF versus ETV therapy and to identify factors associated with HBeAg clearance. PATIENTS AND METHODS: A retrospective cohort study was conducted on HBeAg-positive CHB patients who initiated TAF or ETV therapy between June 2020 and October 2024. Patients were assessed at baseline, week 48, and week 96. Propensity score matching (PSM) was used to balance baseline characteristics between the groups. The HBeAg clearance rate at 96 weeks was analyzed using intention-to-treat (ITT) analysis. Multivariate Cox regression identified factors associated with HBeAg clearance. Kaplan-Meier analysis compared cumulative clearance rates, and generalized estimating equations assessed HBeAg dynamics. RESULTS: Of 425 initially screened HBeAg-positive CHB patients, 251 were included in the 48-week analysis (ETV: 119; TAF: 132) and 101 in the 96-week analysis (ETV: 41; TAF: 60). A 1:1 PSM created balanced groups of 77 patients each for the 48-week comparison. At 48 weeks, the HBeAg clearance rate was significantly higher in the TAF group than in the ETV group: 22.1% versus 6.5% (χ2 = 7.636, p = 0.006); at 96 weeks, the HBeAg clearance rate in the intention-to-treat analysis was 27.3% (21/77) in the TAF group versus 12.99% (10/77) in the ETV group (p = 0.027); both groups showed reduced HBeAg levels from baseline. However, the TAF group had significantly lower levels at week 48 than the ETV group (ETV: 7.94 [0.85∼179.66] vs. TAF: 4.60 [0.20∼70.51]; p = 0.025). The reduction in HBeAg was also greater in the TAF group (ETV: -82.10 [-189.65, -5.99] vs. TAF: -149.77 [-267.46, -15.17]; p = 0.041). For the 96-week analysis, 1:2 PSM yielded 66 matched patients (ETV: 24, TAF: 42). The HBeAg clearance rate was significantly higher in the TAF group (13/42, 31.0%) than in the ETV group (2/24, 8.3%) (χ2 = 4.450, p = 0.035). At week 96, qHBeAg levels were significantly lower in the TAF group (2.85 [0.33∼33.38]) than in the ETV group (57.35 [4.78∼257.45]) (p = 0.001). The TAF group also showed a greater magnitude of reduction from baseline (ETV: -81.66 [-170.58 ∼ -1.13] vs. TAF: -260.66 [-398.15 ∼ -50.31], p < 0.001). Multivariate Cox analysis identified TAF treatment (vs. ETV) (HR = 6.37, 95% CI: 2.10-19.26, p = 0.001), baseline anti-HBe positivity (HR = 3.87, 95% CI: 1.40-10.67, p = 0.009), and baseline qHBeAg (HR = 0.65, 95% CI: 0.44-0.95, p = 0.025) as independent predictors of HBeAg clearance. CONCLUSIONS: For HBeAg-positive CHB patients, TAF demonstrated superior efficacy to ETV in achieving HBeAg clearance over 48-96 weeks. This effect was more pronounced in patients with lower baseline qHBeAg levels or already existing anti-HBe positivity.