To clarify the factors associated with delayed reduction of HBV
DNA during combination treatment with
adefovir dipivoxil (ADV) and
lamivudine (
LAM) for patients with
LAM-resistant hepatitis B virus (HBV), factors including patient characteristics, viral mutations, and drug metabolism were investigated during a 5-year observation period. Delayed reduction of HBV
DNA was defined as delayed viral response of detectable HBV
DNA after 3 years of combination
therapy. Of 67 consecutive patients, 47 attained undetectable HBV
DNA after 3 years of combination
therapy, and the mean therapeutic duration was 5 years (range: 3.0-8.4 years). The patients with delayed viral response had high levels of HBV
DNA and HBe
antigen, while those with negative or low levels of HBe
antigen were also negative for HBV
DNA, even if they had high levels of HBV
DNA. In the multivariate analysis with the proportional hazards model, a high baseline level of HBe
antigen was negatively associated with viral decline to an undetectable level (P = 0.013). A higher baseline of HBe
antigen corresponded to a lower annual decline in HBV
DNA (R = -0.38, P = 0.004). No patients showed ADV-resistant mutations in the HBV
reverse transcriptase region. Trough concentrations of
LAM and ADV showed no clear associations with viral response. HBe
antigen levels at the initiation of
therapy, and reductions in these levels during
therapy are predictive of the therapeutic response to combination
therapy with ADV and
LAM for patients with
LAM-resistant HBV.