慢乙肝患者长期NAs治疗或能显著降低cccDNA水平

newchinabok

http://www.alabmed.com/content-134-3339-1.html

newchinabok

此文值得仔细一读

tonychant

黎青龙教授的文章，希望是真的。

gx2016

129人
有1人HBSAG检测不到

newchinabok

回复 gx2016 的帖子

43人有一个人hbsag转阴

月圆

乙肝病毒共价闭合环状DNA（cccDNA）是乙肝病毒前基因组RNA复制的原始模板，虽含量较少，每个肝细胞内只有约5～50个拷贝，但对乙肝病毒的复制以及感染状态的建立具有十分重要的意义，目前研究认为其对核苷（酸）类似物治疗具有耐药性。来自香港大学医学院的 Ching-Lung Lai 等研究人员进行了一项旨在评估长期使用核苷（酸）类似物治疗对cccDNA影响的研究。相关研究结果发表在最新的 Journal of Hepatology 杂志上。

在129名已经被纳入正在进行的国际核苷（酸）类似物临床试验研究的慢乙肝患者中，对他们基线状态的肝纤维化程度进行检测，并经过1年的治疗后，研究人员纳入了其中的43例患者进行长期的继续用药研究，延长用药周期为72个月至145个月，并进行第三次的肝组织学活检。另外分别对血清 HBV DNA、HBsAg 水平、总肝内 HBV DNA (ihHBV DNA)、cccDNA、HBV前基因组RNA(pgRNA)以及肝组织学变化分别进行检测。

该项研究结果显示，在进行第三次肝组织学活检之时，除一名患者血清 HBV DNA 处于检测下限之上外，其他所有患者均处于检测下限以下。患者的平均 HBsAg、ihHBV DNA 和 cccDNA 水平分别为 2.88 logIU/mL, 0.03 copies/cell, 0.01 copies/cell。相较于基线水平，患者的HBsAg下降了0.54 log (71.46%)，ihHBV DNA 下降了 2.81 log (99.84%), cccDNA 下降了2.94 log (99.89%), 49% 的患者 cccDNA 水平处于检测下限以下。有1名患者的血清 HBsAg 处于未能检测水平。平均 pgRNA 水平，只在进行第三次肝组织学活检时进行了检测，为0.021 copies/cell，有40%患者的 pgRNA 水平处于检测下限以下。

研究人员在结论中认为，对于多数慢乙肝患者，长期的核苷（酸）类似物治疗能够引起 cccDNA 的明显枯竭，而对于血清 HBsAg 水平，虽然多数患者均出现了不同程度的下降，但除了一名患者处于未能检测水平外，其他所有患者的均还处于可检测水平。另外，对于cccDNA 的枯竭是否能够一直维持下去以及可以使患者获得更好地临床结局仍需要进行更深入的研究以探讨。

该项研究总的来说就是，对于隐匿在慢乙肝患者肝细胞核内的cccDNA，通过一般的抗病毒治疗不能有效减少细胞核内的 cccDNA 含量，而来自香港的研究人员通过延长慢乙肝患者的核苷（酸）类似物用药时间（平均用药时间为126个月）发现，cccDNA 可出现明显的减少，这项研究中有49%患者的肝组织cccDNA 处于未能检测水平。该研究提示通过延长用药时间，病毒的复制能力有可能会非常的低。



英文原文


Reduction of Covalently Closed Circular DNA with Long-term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B


Abstract

Background and aims

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a minichromosome 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.

Methods

Among 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.

Results

At 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 logIU/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.

Conclusions

Long-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 Summary

It 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.

月圆

这样更直观吧

chang7811

我个人理解是cccDNA很难被消灭，但自己寿命也是有限的，我记得说最长寿命能到30年，但平均寿命应该不高。 需要靠复制出来新生病毒形成新的cccNDA. 长期抗病毒的作用消灭了新生病毒，老cccDNA寿命到了挂了之后数量得不到补充所以数量减少了。

StephenW

In a recent paper "Decay of ccc-DNA is slow and marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients", the scientists wrote:

Several interesting interpretations with regards to the persistence of intracellular replication can be inferred from these estimations. First, the slow decay of intrahepatic viral loads underscores that TDF is unable to completely block intracellular viral DNA synthesis, which could in turn account for continuous replenishment of the ccc-DNA pool. Second, total IH-DNA half-lives were
much lower than those of ccc-DNA during both HBeAg-positive and HBeAg-negative infection.
This difference in decline has been observed in other studies with shorter treatment duration [9,26] and highlights the strong stability of the ccc-DNA pool despite effective antiviral therapy.
Third, model comparisons show no evidence for a plateau in ccc-DNA, rather a continual decrease, meaning that the rate of ccc-DNA loss is higher than its formation during long-term treatment.
Certainly with TDF-use, there is a reduction of incoming virus into the hepatocyte with
suppression of circulating viral particles, yet the recent finding of residual viremia during longterm TDF-treatment questions the extent of this reduction [25]. Ccc-DNA levels could be diluted with cell turnover, thus contributing to further reduction of the ccc-DNA pool [23]. The rate of cell turnover, however, substantially declines during potent NA therapy [26], making this an unlikely explanation. Decreases in ccc-DNA could also be due to infected cell clearance from cytolytic immune responses, yet infected cell clearance is highly variable (ranging 10-100 days) between treated patients [27] and a modelling study using inputs from ETV-treated woodchucks implies that other mechanisms besides hepatocyte death contribute to ccc-DNA declines [26].
Taken together, the reasons for continual ccc-DNA decline during TDF-therapy, especially the contribution of cytolytic and noncytolytic cell clearance [28], should be examined in future investigations.
在最近的一篇文章“CCC-DNA的衰变是下HIV-HBV合并感染患者肝内替诺福韦病毒DNA合成的缓慢和持久性标志”，科学家们写道：

至于细胞内复制的持续几个有趣的解释，可以从这些估计中推断出来。首先，肝内病毒载量的缓慢衰减强调，TDF不能完全阻断细胞内病毒DNA的合成，这可能又占了CCC-DNA池连续补货。第二，总IH-DNA的半衰期分别为
既比HBeAg阳性和HBeAg阴性感染在那些CCC-DNA的要低得多。
在下降这种差异在较短的治疗时间[9,26]等研究中观察到，并强调了CCC-DNA库，尽管有效的抗病毒治疗的稳定性强。
第三，模型的比较显示在CCC-DNA，而持续不断降低的高原没有证据，即CCC-DNA丧失速度是长期治疗期间比其形成更高。
当然与TDF使用，有一种减少传入病毒进入肝细胞与
抑制循环病毒颗粒，但残留的病毒血症期间长期TDF处理问题这种减少[25]的程度，最近的发现。 CCC-DNA水平可以与细胞更替被淡化，从而有利于进一步降低了CCC-DNA池[23]。细胞更新的速度，但是，大大强效治疗NA [26]在下降，使之成为一个不可能的解释。降低在CCC-DNA也可能是由于从溶细胞免疫应答感染的细胞间隙，但受感染的细胞间隙治疗的患者[27]及从ETV处理旱獭使用输入的模拟研究暗示之间高度可变（范围10-100天）除了肝细胞死亡，其他机制有助于CCC-DNA下降[26]。
总之，TDF，治疗期间的原因，持续CCC-DNA下降，特别是细胞毒性和noncytolytic细胞清除[28]的贡献，应在今后的调查研究。

newchinabok

免疫激活是关键