Abstract: Objective To compare the efficacy and safety of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment for chronic hepatitis B (CHB) patients who have persistently normal serum alanine aminotransferase (ALT) levels, and to provide evidence for antiviral treatment strategies in this population. Methods The clinical data of 94 patients with CHB treated in No.904 Hospital of the Joint Logistics Support Force between January 2020 and December 2024 were retrospectively analyzed. According to the initial antiviral regimen, patients were divided into an ETV group (n=50) and a TDF group (n=44). Virological response parameters, noninvasive liver fibrosis indices, immunological responses, and safety outcomes at 12 months of treatment were compared between the two groups. Results The median time to achieve complete virological response (CVR) was shorter in the TDF group than that in the ETV group [6.0 (5.0, 10.0) months vs. 7.5 (5.0, 11.0) months, P<0.05]. At 12 months of treatment, there were no significant differences between the two groups in the rate of HBV DNA negativity (84.1% vs. 76.0%, P>0.05) or the CVR rate (79.5% vs. 72.0%, P>0.05). Similarly, no significant differences were observed in the incidence of low-level viremia (LLV) (13.6% vs. 14.0%, P>0.05) or the duration of LLV between the two groups. Regarding immunological response, the proportions of patients achieving HBsAg declines of ≥0.3, ≥0.5, and ≥1.0 lg IU/mL were significantly higher in the TDF group than those in the ETV group (61.4% vs. 40.0%, 50.0% vs. 28.0%, and 22.7% vs. 8.0%, respectively; all P<0.05), and the mean magnitude of HBsAg reduction was also greater in the TDF group [(0.27±0.12) lg IU/mL vs. (0.18±0.09) lg IU/mL, P<0.05]. No significant difference was observed in the HBeAg seroconversion rate between the two groups. The safety analysis showed that renal function and bone metabolism-related parameters remained generally stable in the ETV group, whereas the incidences of eGFR<90 mL/min/1.73 m², proteinuria, and hypophosphatemia were higher those in the TDF group (all P<0.05); however, no serious adverse events were observed this group of patients. Conclusion Chronic hepatitis B patients with persistently normal ALT levels can effectively achieve virological suppression and hepatic benefits from antiviral therapy. TDF demonstrates certain advantages in early virological response and HBsAg decline, whereas ETV shows a more stable long-term safety profile. Initiation of antiviral therapy and selection of agents for CHB patients with normal ALT levels should be individualized by balancing virological benefits and safety considerations.

Key words: Chronic hepatitis B with normal ALT, Entecavir, Tenofovir disoproxil fumarate, Complete virological response