Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine-resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxil fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg؉), viral breakthrough during lamivudine therapy, and persistent viral replication (>10 4 copies/mL) after 15 months of ADV monotherapy (range 4-28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow-up (median 12 months, range 3-24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti-HBs after 16 months of TDF therapy. Lamivudine-associated mutations (rtV173L, rtL180M, rtM204V/I) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV-resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV-infected patients with altered responsiveness to treatment with lamivudine and ADV. (HEPATOLOGY 2006;44:318-325.) See Editorial on Page 309 C omplete and sustained suppression of viral replication remains the most important goal in the treatment of patients with chronic hepatitis B virus (HBV) infection. 1,2 In this respect, the introduction of the nucleoside analogue lamivudine and the nucleotide analogue adefovir dipivoxil (ADV) largely improved the outcome in these patients, also by preventing hepatitic decompensation or the development of hepatocellular carcinoma. [3][4][5] These compounds also have a place when interferon-alpha based therapy is contraindicated, as in patients with acute liver failure, decompensated cirrhosis, or extrahepatic manifestations.However, a major disadvantage of nucleoside/nucleotide analogues is that resistant hepatitis B virus mutants develop during long-term treatment, limiting the efficacy of these analogues in suppressing viral replication. As demonstrated in recent studies, approximately 70% of patients receiving lamivudine therapy for more than 4 years suffer the emergence of lamivudine-resistant HBV Abbreviations: ADV, adefovir dipivoxil; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate; HBeAg, hepatitis B virus e antigen. From the