Pretreatment with Pegylated Interferon Prevents Emergence of Lamivudine Mutants in Lamivudine-Naive Patients: A Pilot Study

BACKGROUND: In patients with advanced fibrosis, primary end points of long-term or possibly indefinite antiviral therapy are sustained inhibition of viral replication and avoidance of emergence of resistance. In lamivudine-treated patients, the strongest predictor of emergence of YMDD mutations is baseline hepatitis B virus (HBV) DNA viral load. We aimed to verify whether abatement of viraemia by a short course of pegylated interferon (PEG-IFN-alpha2a) treatment before lamivudine treatment could prevent the emergence of lamivudine-associated mutations during long-term therapy. METHODS: A total of 14 patients with hepatitis B e antigen (HBeAg)-negative infection (3 lamivudine-experienced and 11 lamivudine-naive), with moderate/high viraemia (>10(6) copies/ml) and with Ishak stage 4-6 at liver biopsy were sequentially treated with 180 microg PEG-IFN-alpha2a for a period long enough to reach HBV DNA levels < or =10(3) copies/ml or have a decrease of 3 log(10) copies/ml from baseline. Lamivudine was then added to PEG-IFN-alpha2a treatment for 1 month and finally continued as monotherapy for 2 years or until viral breakthrough. RESULTS: Baseline HBV DNA (mean +/-se 2.3 x 10(7) +/-7.2 x 10(7) copies/ml) decreased with PEG-IFN-alpha2a treatment to target value in mean +/-se 3.7 +/-1.3 months. None of the 11 lamivudine-naive patients developed genotypic resistance and were still HBV-DNA-negative after a mean +/-se observation period of 23 +/-2 months, whereas the three lamivudine-experienced patients developed YMDD mutations after 6, 9 and 12 months of lamivudine monotherapy (P=0.003, Fisher's exact test). CONCLUSIONS: In lamivudine-naive patients, abatement of HBV DNA<10(3) copies/ml by pretreatment with PEG-IFN-alpha2a completely prevents the emergence of YMDD mutants after 24 months of lamivudine monotherapy. This sequential schedule can optimize the use of a well tolerated, effective and inexpensive drug, such as lamivudine, in highly viraemic HBV patients.