抗病毒药物对肝组织乙型肝炎病毒共价闭合环状DNA的影响

Effects of antiviral agents on intrahepatic ccc DNA in HBeAg-positive chronic hepatitis B patients

目的 探讨抗病毒药物对肝组织HBV共价闭合环状DNA（cccDNA）的影响。方法71例HBeAg阳性的慢性乙型肝炎患者分别接受48周的拉米夫定-干扰素序贯治疗、单用拉米夫定治疗和24周的干扰素治疗，随访24周。检测治疗前、后肝组织HBVDNA和cccDNA水平；检测治疗前、后及停药24周时的血清HBVDNA和ALT水平。比较C、B基因型HBV感染患者肝组织HBVDNA和cccDNA水平。结果治疗结束时，序贯治疗、拉米夫定治疗和干扰素治疗组患者肝组织HBVDNA分别为（4．7±1．1）log10、（4．6±1．5）log10和（5．6±1．5）log10，均低于治疗前水平（P〈0．05）；cccDNA分别为（3．4±1．3）log10、（3．8±1．1）log10和（5．0±1．5）log10，均低于治疗前水平（P〈0．05）。17例患者出现了HBeAg血清学转换，其肝组织cccDNA下降幅度明显大于HBeAg阳性患者（3．0log10比1．6log10，P〈0．05）。停药24周，18例患者获得持续病毒学应答，其cccDNA基线值明显低于停药后出现病毒反跳患者（P〈0．05）。肝组织cccDNA的变化与肝组织HBVDNA的改变正相关（P〈0．05）；治疗结束时，肝组织cccDNA水平与血清HBeAg滴度正相关（P〈0．01）。C基因型与B基因型HBV感染患者治疗前、后肝组织HBVDNA和cccDNA的变化无统计学意义（P〉0．05）。结论48周的拉米夫定-干扰素序贯治疗和拉米夫定治疗对肝组织cccDNA抑制作用强于24周的干扰素治疗。肝组织cccDNA低水平患者易获得较好的抗病毒疗效。HBV基因型对肝组织cccDNA含量无明显影响。

Objective To evaluate the effects of antiviral agents on intrahepatic HBV covalently closed circular DNA （cccDNA） in HBeAg-positive chronic hepatitis B patients. Methods Seventy-one HBeAg positive chronic hepatitis B patients were enrolled in this study. Lamivudine was administered to 35 patients for 48 weeks, sequential therapy with lamivudine-IFNα-2b to 24 of the 71 patients for 48 weeks, and interferon alpha （IFNα-2b） was administered to 12 for 24 weeks. All subjects were followed-up for 24 weeks. Serum HBV DNA, intrahepatic HBV DNA and cccDNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. Results Forty-eight weeks of sequential lamivudine-IFN α - therapy and lamivudine monotherapy and 24 weeks of IFN cc monotherapy reduced the intrahepatic HBV DNA to （4.7± 1.1） log10, （4.6 ＋ 1.5） log10 and （5.6 ＋ 1.5） log10, and cccDNA to （3.4± 1.3） log10, （3.8 ± 1.1） log10 and （5.0 ±1.5） log10, significantly lower than therapy （P 〈 0.05）. Seventeen of the 71 patients developed HBeAg seroconversion, and the reduction of cccDNA in the HBeAg seroconverted patients was significantly more than that of the HBeAg positive patients （P 〈 0.05）. After 24 weeks of antiviral therapy withdrawal, 18 patients achieved sustained virological response, and the baseline intrahepatic cccDNA in the patients with sustained virological response was significantly lower than that of patients with virological rebound （P 〈 0.05）. The change in intrahepatic cccDNA correlated positively with the reduction in intrahepatic HBV DNA （P 〈 0.05）. The cccDNA levels correlated with the serum HBeAg titers at the end of the treatment （P 〈 0.01）. Of the total 71 cases, HBV genotype C accounted for 85.9% （n = 61）, and genotype B for 14.1% （n = 10）. There was no significant difference in the changes of intrahepatic HBV DNA and cccDNA levels between HBV genotypes C and B （P 〉 0.05）. Conclusions Both 48 weeks of sequential lamivudine- IFNα and lamivudine monotherapy strongly reduced intrahepatic HBV DNA and cccDNA more than 24 weeks of IFN α monotherapy. Low baseline intrahepatic cccDNA levels might predict a good long-term efficacy of antiviral treatment. The reduction of intrahepatic cccDNA correlated positively with the changes of intrahepalic HBV DNA, and intrahepatic cccDNA levels correlated with serum HBeAg liters. HBV genotypes had no obvious influence on intrahepatic HBV DNA load or cccDNA load.