用慢性乙型肝炎中的长期核苷（t）类似物治疗减少共价闭合

StephenW

Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B [url=]Ching-Lung Lai[/url][url=]Press enter key for correspondence information[/url]†,Press enter key to Email the author
,  [url=]Danny Wong[/url][url=]Press enter key for correspondence information[/url]†,Press enter key to Email the author
,  [url=]Philip Ip[/url]
,  [url=]Malgorzata Kopaniszen[/url]
,  [url=]Wai-Kay Seto[/url]
,  [url=]James Fung[/url]
,  [url=]Fung-Yu Huang[/url]
,  [url=]Brian Lee[/url]
,  [url=]Giuseppe Cullaro[/url]
,  [url=]Chun Kong Chong[/url]
,  [url=]Ringo Wu[/url]
,  [url=]Charles Cheng[/url]
,  [url=]John Yuen[/url]
,  [url=]Vincent Ngai[/url]
,  [url=]Man-Fung Yuen[/url]
†These authors contributed equally to this work.


DOI:            http://dx.doi.org/10.1016/j.jhep.2016.08.022 |

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Background and AimsHepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a mini-chromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA.
MethodsAmong 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145 months for a third liver biopsy. Serum HBV DNA, hepatitis B surface antigen (HBsAg) levels, total intrahepatic HBV DNA (ihHBV DNA), cccDNA, HBV pregenomic RNA (pgRNA) as well as histologic changes were examined.
ResultsAt the time of the third biopsy, serum HBV DNA levels were undetectable in all but one patient. The median levels of HBsAg, ihHBV DNA, and cccDNA were 2.88 log IU/ml, 0.03 copies/cell, and 0.01 copies/cell, respectively. Compared to baseline levels, there was reduction of HBsAg levels by 0.54 log (71.46%), ihHBV DNA levels by 2.81 log (99.84%), and cccDNA levels by 2.94 log (99.89%), with 49% having cccDNA levels below the detection limit. One patient had undetectable HBsAg. The median pgRNA level, measured only in the third biopsy, was 0.021 copies/cell, with 40% of patients having undetectable pgRNA.
ConclusionsLong-term nucleos(t)ide analogue treatment induced marked depletion of cccDNA in the majority of patients while serum HBsAg levels, though reduced, were detectable in all but one patient. Whether cccDNA depletion is sustained and associated with better patient outcome requires further study.
Lay summaryIt is generally presumed that a form of hepatitis B virus DNA, called covalently closed circular DNA (cccDNA), which hides inside the nuclei of liver cells of patients with chronic hepatitis B, cannot be reduced by antiviral treatment. The present study showed that with prolonged treatment (median period 126 months), cccDNA can be markedly reduced, with 49% of liver biopsies having undetectable cccDNA. This suggests that viral replication capacity would be very low after prolonged antiviral treatment.

Keywords:                Hepatitis B virus, Liver biopsy, Antiviral therapy, Virus replication, Circular DNA

StephenW

用慢性乙型肝炎中的长期核苷（t）类似物治疗减少共价闭合的环状DNA
青龙莱信
，Danny Wong作者
，Philip Ip
，Malgorzata Kopaniszen
，Wai-Kay Seto
，詹姆斯·冯
，Fung-Yu Huang
，Brian Lee
，Giuseppe Cullaro
，Chun Kong Chong
，Ringo Wu
，Charles Cheng
，约翰
，Vincent Ngai
，Man-Fung Yuen
†这些作者同样为这项工作贡献。
文章的评分为14分
DOI：http://dx.doi.org/10.1016/j.jhep.2016.08.022 |


图缩略图fx1
背景和目的

乙型肝炎病毒（HBV）共价闭合环状DNA（cccDNA），HBV复制所必需的微型染色体，被认为对核苷酸类似物治疗有抗性。我们调查长期nucleos（t）ide类似物治疗对cccDNA的影响。
方法

在129名曾参加过国际核苷类似物临床试验并在基线和治疗后1年接受肝活检的患者中，我们招募了43名长期连续治疗的患者72至145个月进行第三次肝活检。检查血清HBV DNA，乙型肝炎表面抗原（HBsAg）水平，总肝内HBV DNA（ihHBV DNA），cccDNA，HBV前基因组RNA（pgRNA）以及组织学变化。
结果

在第三次活检时，在除一名患者外的所有患者中血清HBV DNA水平检测不到。 HBsAg，ihHBV DNA和cccDNA的中值水平分别为2.88log IU / ml，0.03拷贝/细胞和0.01拷贝/细胞。与基线水平相比，HBsAg水平降低0.54log（71.46％），ihHBV DNA水平降低2.81log（99.84％），cccDNA水平降低2.94log（99.89％），其中49％具有低于检测的cccDNA水平限制。 1例患者检测不到HBsAg。仅在第三次活检中测量的中值pgRNA水平为0.021拷贝/细胞，其中40％的患者具有不可检测的pgRNA。
结论

长期核苷（t）类似物治疗诱导大多数患者的cccDNA的显着消耗，而血清HBsAg水平虽然降低，但在除一个患者外的所有患者中都可检测。是否cccDNA耗尽是持续和与更好的患者结果相关需要进一步研究。
放置摘要

通常认为，被称为共价闭合环状DNA（cccDNA）的乙型肝炎病毒DNA的形式隐藏在慢性乙型肝炎患者的肝细胞核内部，不能通过抗病毒治疗来减少。本研究表明，长期治疗（中位数126个月），cccDNA可以显着减少，49％的肝活检具有不可检测的cccDNA。这表明在长期抗病毒治疗后病毒复制能力将非常低。
关键词：
乙型肝炎病毒，肝活检，抗病毒治疗，病毒复制，圆形DNA

newchinabok

感谢分享，祝sw新春快乐，希望2017新药有进展

StephenW

回复 newchinabok 的帖子

非常感谢你, 同感.

shirlenna007

回复 StephenW 的帖子

中位数126个月啊，相当于10年多。我们才吃了三年不到，看来路漫漫其修远兮啊
现在就是担心，有没有数据统计在服用替诺福韦的过程中，癌变的几率。病毒DNA虽然长期检测不到，但毕竟cccDNA的消耗还是很缓慢的
感谢您一直以来的分享，thanks!

neilhbver

楼主辛苦了。加入这里以来从你的帖子获得不少新知识。

StephenW

回复 shirlenna007 的帖子

HbsAg变阴性, 需要"不可检测到"(undetectable)的cccDNA吗？

http://hbvhbv.info/forum/thread-1405662-1-1.html
"previous reports presenting low levels of cccDNA detectability in a high proportion of individuals who achieved HBsAg clearance spontaneously or following antiviral therapy [Yuen et al., 2008]."
以前的报告表明高比例低水平的cccDNA检测率在自发或抗病毒治疗后实现HBsAg清除的的个人[Yuen等人，2008]。

snowxyxy

谢谢，学习了

轻风飞扬

这说明只要抑制住病毒复制，cccDNA可能会被（免疫力）清除或者自己死亡，因为以前的研究估算出cccDNA的生命可达14年。

newchinabok

cccdna耗竭了，还有病人血中有hbsag，说明hbv基因整合人体基因，还在表达hbsag，治愈乙肝，好难好难。