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AIM: To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA (ca: DNA) in HBeAg-positive chronic hepatitis 8 patients. METHODS: Seventy-one patients received lamivudine (n=35), or sequential therapy with lamivudine-interferon alpha 2b (IFN-α 2b,n=24) for 48 wk,or IFN-α 2b (n= 12) for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc: DNA was measured quantitatively by PCR.HBV genotypes were analyzed by PCR-RFLP. RESULTS: Sequential lamivudine-INF-α therapy, lamivudine and INF-α monotherapy reduced ccc DNA of 1.7 log,1.4 log and 0.8 log, respectively (P<0.05=.Seventeen out of the 71 patients developed HBeAg seroconversion, the reduction of ccc: DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients (3.0 log vs 1.6 log,P=0.0407).Twenty-four weeks after antiviral therapy withdrawal,16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound (4.6 log vs 5.4 log, P=0.0472). HBV genotype C accounted for 85.9% (n=61), and genotype B for 14.1% (n=10), respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B (2.1 log vs 1.9 log). CONCLUSION: Forty-eight week sequential lamivudine INF-α therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-α monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load.