〔Abstract〕 To compare the antiviral efficacy and renal safety of nucleoside analogs (NAs) monotherapy versus combination therapy in hepatitis B e antigen ( HBeAg)-positive chronic hepatitis B ( CHB) patients with high viral load . Methods This study enrolled a total of 353 treatment-nave HBeAg-positive chronic hepatitis B (CHB) patients with high viral load , the treatment regimen was divided into 5 groups , consisting of 4 monotherapy groups and 1 combination therapy group as follows : 88 cases in the Entecavir (ETV) group , 135 cases in the Teno- fovir Disoproxil Fumarate (TDF) group , 34 cases in the Tenofovir Alafenamide Fumarate (TAF) group , 25 cases in the Tenofovir Amibufenamide (TMF) group , and 71 cases in the ETV combined with TDF (ETV + TDF) group . A retrospective cohort study design was adopted to analyze HBV DNA levels , serological indicators ( HBsAg and HBeAg levels) , renal function indicators ( serum Scr levels , eGFR) at 24 and 48 weeks of treatment across various groups , as well as the HBsAg clearance rates , HBeAg seroconversion rates and HBV DNA suppression rates (HBV DNA < 20 IU/ml) at 48 weeks across the groups . Multivariate logistic regression analysis was conducted to identify the influencing factors for HBV DNA suppression . Results At 24 weeks , the HBV DNA level in the ETV + TDF combination group was significantly lower than that in the ETV monotherapy group (P < 0. 05) , and was similar to the HBV DNA levels in the TDF , TAF , and TMF groups (P > 0. 05) . At 48 weeks , the HBV DNA levels in the ETV + TDF combination therapy group was significantly lower than those in all monotherapy groups ( P < 0. 05) . The HBV DNA levels in the TDF , TAF , and TMF monotherapy groups were similar (P > 0. 05) . The HBV DNA level in the ETV group was higher than those in the remaining four groups (P < 0. 05) . The HBV DNA suppression rates of the ETV , TDF , TAF , TMF and ETV + TDF groups were 31 . 82% , 51 . 11% , 52. 94% , 56. 00% , and 78. 87% , respectively , the HBV DNA suppression rate in the ETV + TDF combination therapy group was signifi- cantly better than those in all monotherapy groups (P < 0. 05) , the rates of HBV DNA suppression were similar a- mong the TDF , TAF , and TMF groups , and all were superior to that of the ETV monotherapy group (P < 0. 05) . Multivariate analysis revealed that low baseline HBsAg levels (OR = 0. 430 , P = 0. 004) , high baseline ALT levels (OR = 2. 389 , P < 0. 001) , and the combination therapy regimen ( OR = 6. 239 , P < 0. 001) were independent predictors of HBV DNA suppression at 48 weeks of treatment. The reduction in HBsAg levels in the ETV + TDF group was significantly greater than that in the ETV monotherapy group[ (3 . 65 ±0. 85) vs (3 . 88 ±0. 64) , P < 0. 05 ] . The HBsAg clearance rate in the ETV + TDF group was 1 . 41% (1 /71) , while the HBsAg clearance rates in the other groups were all 0% . There were no statistically significant differences in HBeAg seroconversion rates , blood Scr levels , and eGFR levels among the groups (P > 0. 05) . Conclusion For HBeAg-positive chronic hepa- titis B (CHB) patients with high viral load , the combination therapy of ETV and TDF significantly enhances viral suppression compared to monotherapy , without increasing the risk of renal adverse events . This suggests that the combination therapy can be considered a preferred strategy for this specific patient population .