Efficacy and safety of sequential or combined therapy with tenofovir amibufenamide in entecavir-treated patients with low-level viremia: A propensity score-matched cohort study

Background Low-level viremia (LLV) in chronic hepatitis B (CHB) patients receiving entecavir (ETV) therapy is associated with increased risk of hepatic fibrosis progression and hepatocellular carcinoma. Optimal management strategies for LLV remain debated. This study aimed to compare the efficacy and safety of sequential tenofovir amibufenamide (TMF) monotherapy versus ETV plus TMF combination therapy in CHB patients with LLV after prior ETV treatment. Methods This retrospective cohort study enrolled 212 CHB patients with LLV (HBV DNA 20-2000 IU/mL) after ≥ 48 weeks of ETV treatment at the Third People's Hospital of Yunnan Province between January 2022 and December 2024. Patients were allocated to either sequential TMF monotherapy (TMF group, n = 118) or ETV plus TMF combination therapy (combination group, n = 94). Propensity score matching (1:1 ratio, caliper 0.02) was performed to balance baseline covariates, yielding 60 patients per group. Virological response (HBV DNA < 20 IU/mL), HBeAg seroconversion, liver function (ALT, AST), renal function (Cr, eGFR), liver stiffness measurement (LSM), lipid profiles (TC, TG, HDL-C, LDL-C), and adverse events were assessed at 48 weeks. Results After PSM, baseline characteristics were well-balanced between groups. At week 48, the combination group demonstrated significantly higher HBV DNA undetectable rate (86.67% vs. 63.33%, χ²=8.711, P = 0.003) and HBeAg seroconversion rate (58.33% vs. 36.67%, χ²=5.682, P = 0.017) compared with the TMF group. The combination group showed significantly lower ALT (24.85 ± 6.94 vs. 29.36 ± 8.17 U/L, t = 3.254, P = 0.001), AST (22.67 ± 5.83 vs. 27.41 ± 7.26 U/L, t = 3.917, P < 0.001), and LSM (6.58 ± 1.46 vs. 7.48 ± 1.72 kPa, t = 3.081, P = 0.003) levels post-treatment. However, the TMF group exhibited better renal preservation with higher eGFR (101.35 ± 10.84 vs. 96.28 ± 11.53 ml/min/1.73m², t = 2.489, P = 0.014). Both groups experienced mild elevations in TC from baseline (TMF group: 5.21 ± 0.94 vs. 4.82 ± 0.89 mmol/L, P = 0.018; combination group: 5.16 ± 0.91 vs. 4.78 ± 0.86 mmol/L, P = 0.022), with no significant between-group differences. Adverse event rates were comparable (TMF group: 20.00%; combination group: 18.33%; χ²=0.055, P = 0.815). Conclusions In ETV-treated CHB patients with LLV, adding TMF to ongoing ETV therapy achieves superior virological response and greater improvements in liver fibrosis compared with switching to TMF monotherapy, whereas sequential TMF monotherapy offers better renal protection. Both regimens are associated with modest TC elevation, warranting regular lipid monitoring during long-term follow-up.