Adefovir and lamivudine in combination compared with adefovir monotherapy in HBeAg-negative adults with chronic hepatitis B virus infection and clinical or virologic resistance to lamivudine: a retrospective, multicenter, nonrandomized, open-label study.

Objectives: The aim of this study was to assess the therapeutic effectiveness of adefovir dipivoxil (ADV), administered in combination with lamivudine (LAM) or as monotherapy, and the rate of resistance to ADV, in hepatitis B e antigen (HBeAg)-negative adult patients with chronic hepatitis B virus (HBV) infection and clinical or virologic resistance to LAM. Furthermore, we evaluated in these selected patients the clinical co-variates associated with a sustained virologic response.

Methods: Data from adult outpatients aged >18 years with chronic HBV infection and clinical or virologic resistance to LAM were used in this retrospective, multicenter, nonrandomized, open-label study. Patients were selected if they received ADV 10 mg PO QD + LAM 100 mg QD PO or ADV 10 mg PO QD as monotherapy for 24 to 32 months between June 2003 and July 2006. End points were the proportions of patients who achieved virologic response (undetectable HBV-DNA [<3.3 log(10) copies/mL]) and biochemical response (normalization [<40 IU/L] of alanine aminotransferase [ALT]), and the proportions in whom resistance to ADV (rebound serum HBV-DNA >1 log(10) copies/mL compared with on-treatment nadir, as confirmed on molecular analysis) was found. HBV-DNA and ALT levels were checked every month during the first 3 months of treatment and every 3 months thereafter until 28 months. Data from each center were stored in a centralized database and analyzed by a blinded independent investigator.

Results: Data from 70 patients were included (48 men, 22 women; median age, 51 years; ADV + LAM, 36 patients; ADV monotherapy, 34). The median duration of the pharmacologic treatment in the 2 groups of patients was 28 months (range, 24-32 months). By month 3, virologic response was achieved in 30 patients (83%) in the ADV + LAM group and in 26 patients (76%) in the ADV monotherapy group. At 12 months, virologic response was achieved in 5 additional patients in the ADV + LAM group and 2 additional patients in the ADV monotherapy group. Biochemical response was found to be time dependent: in the 2 groups, the rates of biochemical response were, respectively, 56% and 54% at month 3, 80% and 71% at month 6, and 96% and 79% at month 12, persisting up to the end of the study period. The rates of clinical resistance to ADV were 3% with ADV + LAM and 18% with ADV monotherapy (with a 6% rate of resistance due to rtA181 mutation in the monotherapy group). Logistic regression analysis found that pre-treatment levels of HBV-DNA <5 log(10) copies/mL, ALT levels >150 IU/L, an inflammation score >7, and a fibrosis score <2 were the strongest covariates independently associated with a sustained virologic response in both groups of patients. No adverse events were reported in any of the patients.

Conclusion: ADV, administered in combination with LAM or as monotherapy, appeared to be effective in this small, selected group of HBeAg-negative patients with clinical or virologic resistance to LAM, especially in those with low pretreatment HBV-DNA levels, high ALT levels, and low fibrosis scores.