Lu Hai-ying, Zhuang Li-wei, Yu Yan-yan, Si Chong-wen, Li Jun
Department of Infectious Disease, Peking University First Hospital, Beijing, China.
Zhonghua Gan Zang Bing Za Zhi. 2008 Mar;16(3):198-202.
To evaluate the effects of antiviral agents on intrahepatic HBV covalently closed circular DNA (cccDNA) in HBeAg-positive chronic hepatitis B patients.
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-IFN alpha-2b to 24 of the 71 patients for 48 weeks, and interferon alpha (IFN alpha-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.
Forty-eight weeks of sequential lamivudine-IFN alpha-therapy and lamivudine monotherapy and 24 weeks of IFN alpha 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).
Both 48 weeks of sequential lamivudine-IFN alpha and lamivudine monotherapy strongly reduced intrahepatic HBV DNA and cccDNA more than 24 weeks of IFN alpha 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 intrahepatic HBV DNA, and intrahepatic cccDNA levels correlated with serum HBeAg titers. HBV genotypes had no obvious influence on intrahepatic HBV DNA load or cccDNA load.
评估抗病毒药物对HBeAg阳性慢性乙型肝炎患者肝内乙肝病毒共价闭合环状DNA（cccDNA）的影响。
71例HBeAg阳性慢性乙型肝炎患者纳入本研究。35例患者接受拉米夫定治疗48周，71例中的24例接受拉米夫定-干扰素α-2b序贯治疗48周，12例接受干扰素α（干扰素α-2b）治疗24周。所有受试者随访24周。采用PCR法定量检测血清乙肝病毒DNA、肝内乙肝病毒DNA和cccDNA。采用PCR-RFLP法分析乙肝病毒基因型。
拉米夫定-干扰素α序贯治疗48周、拉米夫定单药治疗48周以及干扰素α单药治疗24周后，肝内乙肝病毒DNA分别降至（4.7±1.1）log10、（4.6±1.5）log10和（5.6±1.5）log10，cccDNA分别降至（3.4±1.3）log10、（3.8±1.1）log10和（5.0±1.5）log10，均显著低于治疗前（P<0.05）。71例患者中有17例发生HBeAg血清学转换，HBeAg血清学转换患者的cccDNA降低幅度显著大于HBeAg阳性患者（P<0.05）。抗病毒治疗停药24周后，18例患者实现持续病毒学应答，持续病毒学应答患者的基线肝内cccDNA显著低于病毒学反弹患者（P<0.05）。肝内cccDNA的变化与肝内乙肝病毒DNA的降低呈正相关（P<0.05）。治疗结束时cccDNA水平与血清HBeAg滴度相关（P<0.01）。71例患者中，乙肝病毒基因型C占85.9%（n=61），基因型B占14.1%（n=10）。乙肝病毒基因型C和B之间肝内乙肝病毒DNA和cccDNA水平变化无显著差异（P>0.05）。
拉米夫定-干扰素α序贯治疗48周和拉米夫定单药治疗均比干扰素α单药治疗24周更能显著降低肝内乙肝病毒DNA和cccDNA。较低的基线肝内cccDNA水平可能预示抗病毒治疗的长期疗效良好。肝内cccDNA的降低与肝内乙肝病毒DNA的变化呈正相关，且肝内cccDNA水平与血清HBeAg滴度相关。乙肝病毒基因型对肝内乙肝病毒DNA载量或cccDNA载量无明显影响。
