Evidence of Residual Ongoing Viral Replication in Chronic Hepatitis B Patients Successfully Treated with Nucleos(t)ide Analogues
Evidence of Residual Ongoing Viral Replication in Chronic Hepatitis B Patients Successfully Treated with Nucleos(t)ide Analogues
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核苷（酸）类似物成功治疗的慢性乙型肝炎患者中残留持续病毒复制的证据
DOI：
10.1093/infdis/jiac493
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通讯作者：
Zhefeng Meng
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作者：
Tong Yu;Miaoqu Zhang;Hanyue Zhang;Jianming Zheng;Chuan Shen;Ning Jiang;Lei Zou;Jing Wang;Yiqi Yu;Qiran Zhang;Shuili Yu;Yanfang Huang;Yuxian Huang;Jiming Zhang;Chao Qiu;Wenhong Zhang;Zhefeng Meng
摘要。背景慢性B型肝炎通常用核苷（酸）类似物（NAs）治疗。然而，即使经过多年的治疗，也很少能治愈。在这里，我们研究了病毒复制是否完全停止以及共价闭合环状DNA（cccDNA）在成功治疗的患者中持续多久。方法.从NAs成功治疗的患者中获得了一系列纵向血清样本和横断面肝活检标本。通过深度测序计数血清HBV RNA中的病毒变体。肝细胞中的病毒复制中间体通过原位杂交直接可视化。估计每种cccDNA的表观半衰期。结果六分之三的成功治疗的患者表现出明确的证据表明，一小部分的病毒进化，虽然压倒性的变种是相同的或具有类似程度的分歧，随着时间的推移。变体的表观半衰期估计为约7.42周至无穷大。此外，在7例肝穿刺活检中的4例中，肝细胞胞质核衣壳相关松弛环状DNA（rcDNA）仍呈阳性。结论.因此，我们得出结论，即使在长期治疗后，一小部分cccDNA库也会通过持续的低水平HBV复制不断补充，而最大量的cccDNA库会随着时间的推移而持续存在。
ABSTRACT. Background. Chronic hepatitis B is usually treated with nucleos(t)ide analogues (NAs). However, a cure is rarely achieved even with years of treatment. Here, we investigated whether viral replication is completely halted and how long covalently closed circular DNA (cccDNA) persists in NAs successfully treated patients.. Methods. A series of longitudinal serum samples and a collection of cross-sectional liver biopsies were obtained from NAs successfully treated patients. Viral variants in serum HBV RNA were enumerated by deep sequencing. Viral replication intermediates in hepatocytes were directly visualized by in situ hybridization. The apparent half-life of each cccDNA was estimated.. Results. Three out of six successfully treated patients demonstrated clear evidence of a small proportion of virus evolution, although the overwhelming variants were identical or possessed a similar degree of divergence through time. The apparent half-life of variants was estimated from approximately 7.42 weeks to infinite. Moreover, hepatocytes remained positive for cytoplasmic nucleocapsids-associated relaxed circular DNA (rcDNA) in four out of seven liver needle biopsies.. Conclusions. We therefore conclude that even after prolonged treatment, a small proportion of the cccDNA reservoir is constantly replenished by continued low-level HBV replication, whereas the greatest amount of cccDNA reservoir persists over time.