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Objective Patients who have not obtained the effective suppression of hepatitis B virus (HBV) replication cannot have an improvement in liver histology.We aimed to explore the differences of several rescue therapy for patients with resistance to lamivudine plus adefovir.Methods A total of 101 patients (male 87) who had not obtained viral response by lamivudine plusadefovirfor more than two years from January 2005 to January 2011 were included in this study, including virological breakthrough 62 cases and partial response 39 cases.HBV DNAbefore rescue therapy was 3.72±1.24 logl0 IU/ml.Rescue therapy: (A) lamivudine 100mg + adefovir 20mg (27 cases); (B) entecavir 0.5mg + adefovir 10/20mg (50 cases); (C) entecavir 0.5mg + tenofovir 300mg (11 eases); (D) pegylated-interferon or interferon (13 cases).Alanine aminotransferase (ALT), HBV DNA, HBV markers, and creatinine were detected every 3 months.The period of rescue therapy was 12 (9-18) months.Results The proportion of virological response in A, B, C, and D was 81.4%, 86%, 100%, and 30.7%,respectively.The rate of HBeAg seroconversion was 2.9%.In patients with virological response, the rate of biochemistry response was 80.4% (70/87).In 10 cases with entecavir 0.5mg + adefovir20mg who did not obtain virological response by entecavir 0.5mg + adefovir 10mg, seven cases obtained virological response.In 60 patients with adefovir 20 mg, only one patient had occurred evaluation of creatinine at the time point of a follow-up of 24 months.Conc l us ions The combination of entecavir plus tenofovir is the prefer strategy of rescue therapy for HBeAg-positive chronic hepatitis B with resistance to lamivudine plus adefovir.The strategy of adefovir 20 mg is considerable for its safe and effective.The strategy of interferon is not suitable for its poor response.