Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B
Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B
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DOI：
10.1016/j.jhep.2016.08.022
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发表时间：
2017-02-01
影响因子：
25.7
通讯作者：
Yuen, Man-Fung
中科院分区：
文献类型：
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作者：
Lai, Ching-Lung;Wong, Danny;Yuen, Man-Fung
背景和目的：乙型肝炎病毒（HBV）共价闭合环状DNA （cccDNA）是HBV复制所必需的一条小染色体，被认为对核苷(t)类似物治疗具有抗性。我们研究了长期核苷类似物处理对cccDNA的影响。方法：在之前参加国际核苷类似物临床试验并在基线和治疗后1年进行肝活检的129例患者中，我们招募了43例长期连续治疗72至145个月的患者进行第三次肝活检。检测血清HBV DNA、乙型肝炎表面抗原（HBsAg）水平、肝内总HBV DNA （ihHBV DNA）、cccDNA、HBV基因组前RNA （pgRNA）及组织学变化。结果：在第三次活检时，除1例患者外，所有患者血清HBV DNA水平均未检测到。HBsAg、ihHBV DNA和cccDNA的中位水平分别为2.88 log IU/ml、0.03拷贝/细胞和0.01拷贝/细胞。与基线水平相比，HBsAg水平降低了0.54 log (71.46%)， ihHBV DNA水平降低了2.81 log (99.84%)， cccDNA水平降低了2.94 log(99.89%)，其中49%的cccDNA水平低于检测限。1例患者HBsAg检测不出。仅在第三次活检中测量的中位pgRNA水平为0.021拷贝/细胞，40%的患者未检测到pgRNA。结论：在大多数患者中，长期的核苷类似物治疗导致cccDNA明显减少，而血清HBsAg水平虽然降低，但在除1例患者外的所有患者中均可检测到。cccDNA缺失是否持续并与更好的患者预后相关还需要进一步研究。摘要：一般认为，乙肝病毒DNA的一种形式，称为共价闭合环状DNA (cccDNA)，它隐藏在慢性乙肝患者的肝细胞核内，不能通过抗病毒治疗来减少。目前的研究表明，随着治疗时间的延长（中位期126个月），cccDNA可以显著减少，49%的肝活检未检测到cccDNA。这表明在长期抗病毒治疗后，病毒复制能力将非常低。(C) 2016欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background and Aims: Hepatitis 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.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 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.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. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.