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标题: 慢性乙型肝炎病毒患者中持续的病毒复制和传染性病毒的产 [打印本页]

作者: StephenW 时间: 2022-4-2 19:13 标题: 慢性乙型肝炎病毒患者中持续的病毒复制和传染性病毒的产

慢性乙型肝炎病毒患者中持续的病毒复制和传染性病毒的产生被抑制在长期核苷（酸）治疗的定量限以下
Dara L Burdette 1、Scott Lazerwith 2、Jenny Yang 3、Henry L Y Chan 4、William E Delaney Iv 1、Simon P Fletcher 1、Tomas Cihlar 1、Becket Feierbach 5
隶属关系
隶属关系

1
Discovery Virology，Gilead Sciences，美国加利福尼亚州福斯特城。
2
药物化学，吉利德科学，福斯特城，CA，美利坚合众国。
3
临床研究，吉利德科学，福斯特城，CA，美利坚合众国。
4
香港中文大学，中国香港特别行政区。
5
临床病毒学，吉利德科学，福斯特城，加利福尼亚，美利坚合众国。

PMID：35363817 DOI：10.1371/journal.pone.0262516

抽象的

核苷（酸）类似物是治疗慢性乙型肝炎的标准疗法，可有效减少乙型肝炎病毒 (HBV) 复制，但很少治愈。核苷（酸）类似物不会直接消除病毒附加体，因此停止治疗通常会导致病毒快速反弹。虽然治疗是有效的，但即使在长期治疗后，大多数核苷（酸）类似物治疗的 HBV 患者的外周仍可检测到 HBV DNA（尽管无法量化）。解决可检测到的 HBV DNA 是否代表传染性病毒是一个关键的未知数，对开发 HBV 的治愈性治疗具有重要意义。在人类肝脏嵌合小鼠中建立感染所需的最小 HBV 基因组当量是通过滴定 HBV 患者血清来确定的，并且来自患者（n = 7）的血清在嵌合小鼠中的感染性被抑制到核苷（酸）类似物的检测限治疗进行了评估。在嵌合小鼠中建立感染至少需要 5 个 HBV 基因组当量，证实该模型具有足够的灵敏度来确定来自病毒抑制患者的血清是否含有传染性病毒。引人注目的是，来自 75%（n = 3 / 4）核苷（酸）ide 治疗的 HBV 患者的血清，其 DNA 可检测到，但低于定量下限，也在嵌合小鼠中建立了感染。这些结果表明，在一些接受核苷（酸）抑制剂治疗的 HBV 患者中仍然存在传染性病毒。这种残留病毒可能通过持续感染支持病毒持续存在，并解释了尽管长期抑制治疗，HBV 相关并发症的持续风险。因此，额外的强化治疗可能有助于 HBV 治愈。

作者: StephenW 时间: 2022-4-2 19:13

Ongoing viral replication and production of infectious virus in patients with chronic hepatitis B virus suppressed below the limit of quantitation on long-term nucleos(t)ide therapy
Dara L Burdette 1 , Scott Lazerwith 2 , Jenny Yang 3 , Henry L Y Chan 4 , William E Delaney Iv 1 , Simon P Fletcher 1 , Tomas Cihlar 1 , Becket Feierbach 5
Affiliations
Affiliations

1
Discovery Virology, Gilead Sciences, Foster City, CA, United States of America.
2
Medicinal Chemistry, Gilead Sciences, Foster City, CA, United States of America.
3
Clinical Research, Gilead Sciences, Foster City, CA, United States of America.
4
The Chinese University of Hong Kong, Hong Kong SAR, China.
5
Clinical Virology, Gilead Sciences, Foster City, CA, United States of America.

PMID: 35363817 DOI: 10.1371/journal.pone.0262516

Abstract

Nucleos(t)ide analogs are standard-of-care for the treatment of chronic hepatitis B and can effectively reduce hepatitis B virus (HBV) replication but rarely leads to cure. Nucleos(t)ide analogs do not directly eliminate the viral episome, therefore treatment cessation typically leads to rapid viral rebound. While treatment is effective, HBV DNA is still detectable (although not quantifiable) in the periphery of the majority of nucleos(t)ide analog treated HBV patients, even after prolonged treatment. Addressing whether the detectable HBV DNA represents infectious virus is a key unknown and has important implications for the development of a curative treatment for HBV. The minimum HBV genome equivalents required to establish infection in human liver chimeric mice was determined by titration of HBV patient sera and the infectivity in chimeric mice of serum from patients (n = 7) suppressed to the limit of detection on nucleos(t)ide analog therapy was evaluated. A minimum of 5 HBV genome equivalents were required to establish infection in the chimeric mice, confirming this model has sufficient sensitivity to determine whether serum from virally suppressed patients contains infectious virus. Strikingly, serum from 75% (n = 3 out of 4) of nucleos(t)ide-treated HBV patients with DNA that was detectable, but below the lower limit of quantitation, also established infection in the chimeric mice. These results demonstrate that infectious virus is still present in some HBV patients on suppressive nucleos(t)ide therapy. This residual virus may support viral persistence via continuous infection and explain the ongoing risk for HBV-related complications despite long-term suppression on therapy. Thus, additional treatment intensification may facilitate HBV cure.

作者: StephenW 时间: 2022-4-2 19:13

https://journals.plos.org/ploson ... &type=printable

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