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The objective of this study was to compare the efficacy and safety of two rescue strategies for hepatitis B e antigen ( HBe Ag)-positive chronic hepatitis B ( CHB) patients with resistance to adefovir dipivoxil ( ADV). This prospective study included 58 HBe Ag-positive CHB patients with resistance to ADV; 30 patients underwent telbivudine ( LdT) plus ADV combination therapy and 28 patients switched to entecavir ( ETV) monotherapy. After 48 weeks of treatment, the rates of hepatitis B virus ( HBV) DNA <3 log10 copies/mL in the LdT plus ADV group and the ETV group were not significantly different (73.3% vs 57.1%, P = 0.195). Six patients receiving LdT plus ADV had HBe Ag seroconversion, while none of the patients receiving ETV alone had HBe Ag seroconversion (20% vs 0%, P = 0.039). During the 48-week treatment period, two patients in the ETV monotherapy group had viral breakthrough and the strains were confirmed to be of a variant associated with ETV resistance (rtM204V+ rtL180M+ rtT184G), while one patient receiving LdT plus ADV had viral breakthrough and an LdT-associated resistance mutation (rtM204I) was detected. For the majority of the patients, both LdT plus ADV combination treatment or ETV monotherapy were generally well tolerated, and no serious side effects were observed. Both LdT plus ADV combination therapy and ETV monotherapy led to significant decreases in serum HBV DNA in HBe Ag-positive CHB patients with resistance to ADV, and LdT plus ADV combination therapy exhibited a significantly higher rate of HBe Ag seroconversion compared with ETV monotherapy. [ABSTRACT FROM AUTHOR]