Objective: This study aims to systematically compare the efficacy differences of different antiviral regimens in preventing and treating low-level viremia in patients with chronic hepatitis B. Methods: (1) This study retrospectively included 734 CHB patients diagnosed and treated in the infectious diseases Department of our hospital from January 2023 to June 2024. They were divided into non first-line NAs group of 48 cases, first-line NAs group of 585 cases, and combined treatment group of 101 cases. The first-line NAs group was divided into ETV subgroup (347 cases), TDF subgroup (140 cases), and TAF subgroup (98 cases). (2) Analysis of independent influencing factors on LLV and HBsAg clearance.Compare the differences in therapeutic efficacy among different groups and observe and analyze the dynamic evolution of virological and serological markers during Peg-IFN α-2b treatment. Result: High baseline HBV DNA, high HBsAg, HBeAg positivity, liver cirrhosis, and hepatocellular carcinoma are independent risk factors for LLV.There was a significant difference in the incidence of LLV among the three groups (χ ²=72.34, P<0.001): the non first-line NAs group had the highest incidence of LLV, reaching 47.92%; The first-line NAs group is second, accounting for 32.65%; The combination therapy group had the lowest rate, only 3.96%. The CVR rate of the combination therapy group showed a continuous upward trend with prolonged treatment time, with outstanding performance in the dynamic decline of HBsAg. Conclusion: There are significant differences in the prevention and treatment efficacy of different antiviral regimens for LLV, and TAF can be the preferred choice among first-line NAs;Combined interferon therapy is an independent protective factor. Interferon has made "functional cure" an accessible target in advantageous populations. Clinical doctors should have a correct understanding of the transient HBV DNA elevation during interferon treatment and adhere to full course treatment.