Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy
Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy
复制标题
DOI：
10.1053/j.gastro.2004.03.018
复制
发表时间：
2004-06-01
期刊：
影响因子：
29.4
通讯作者：
Zoulim, F
中科院分区：
文献类型：
--
作者：
Werle-Lapostolle, B;Bowden, S;Zoulim, F
背景和目标：B型肝炎病毒（HBV）共价闭合环状DNA（cccDNA）是一种独特的附加型复制中间体，负责肝细胞的持续感染。技术限制阻碍了对患者中cccDNA维持和清除机制的直接研究。本研究的目的是开发一种灵敏、特异的检测方法，用于定量不同自然病程阶段慢性B型肝炎患者和接受抗病毒治疗患者活检样本中的cccDNA。方法：通过特异性实时PCR测定定量肝内cccDNA水平。对98例慢性B型肝炎自然病程主要阶段患者的肝活检样本和32对接受阿德福韦酯（ADV）治疗患者的样本进行了评估。结果如下：在慢性B型肝炎自然史的不同阶段的患者中检测到cccDNA，其水平范围超过3个数量级。cccDNA水平与总细胞内HBV DNA和血清HBV DNA水平密切相关。48周的ADV治疗导致cccDNA拷贝/细胞显著降低0.8 log。在ADV治疗期间，cccDNA的变化与血清HBsAg滴度的类似降低相关，但与HBV抗原阳性细胞数量的减少无关。结论：cccDNA在慢性肝炎13的整个自然病程中持续存在，即使在有病毒清除血清学证据的患者中也是如此。长期ADV治疗主要通过非细胞溶解机制显著降低cccDNA水平。
Background & Aims: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a unique episomal replicative intermediate responsible for persistent infection of hepatocytes. Technical constraints have hampered the direct study of cccDNA maintenance and clearance mechanisms in patients. The aim of this study was to develop a sensitive and specific assay for quantifying cccDNA in biopsy samples from chronic hepatitis B patients during different natural history phases and in patients undergoing antiviral therapy. Methods: Intrahepatic cccDNA levels were quantified by a specific real-time PCR assay. Ninety-eight liver biopsy samples from patients in the major phases of the natural history of chronic hepatitis B and 32 pairs of samples from patients receiving adefovir dipivoxil (ADV) therapy were assessed. Results: cccDNA was detected, at levels ranging over 3 orders of magnitude, in patients in different phases of the natural history of chronic hepatitis B. cccDNA levels were strongly correlated with levels of total intracellular HBV DNA and serum HBV DNA. Forty-eight weeks of ADV therapy resulted in a significant 0.8 log decrease in cccDNA copies/cell. Changes in cccDNA were correlated with a similar reduction in serum HBsAg titer but not with a decrease in the number of HBV antigen-positive cells during ADV treatment. Conclusions: cccDNA persists throughout the natural history of chronic hepatitis 13, even in patients with serologic evidence of viral clearance. Long-term ADV therapy significantly decreased cccDNA levels by a primarily noncytolytic mechanism.