是什么驱动治疗过程中HBV RNA的动力学？

StephenW

What drives the dynamics of HBV RNA during treatment?
Antonio Gonçalves  1 , Annabelle Lemenuel-Diot  2 , Valérie Cosson  2 , Yuyan Jin  3 , Sheng Feng  3 , Qingyan Bo  4 , Jérémie Guedj  1
Affiliations
Affiliations

    1
    Université de Paris, IAME, INSERM, F-75018, Paris, France.
    2
    Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
    3
    Clinical Pharmacology, Pharmaceutical Sciences, Roche Pharma Research & Early Development, Roche Innovation Center Shanghai, China.
    4
    I2O DTA, Roche Pharma Research & Early Development, Roche Innovation Center Shanghai, China.

    PMID: 33074571 DOI: 10.1111/jvh.13425

Abstract

Hepatitis B RNA-containing particles (HBV RNA) are encapsidated pre-genomic RNA (pgRNA) detectable in chronically infected patients in addition to virions (HBV DNA), that have been suggested as a marker of the treatment efficacy. This makes promising the use of core protein allosteric modulators, such as RG7907, which disrupt the nucleocapsid assembly, and profoundly reduce HBV RNA. Here we developed a multiscale model of HBV extending the standard viral dynamic models to analyze the kinetics of HBV DNA and HBV RNA in 35 patients treated with RG7907 for 28 days. We compare the predictions with those obtained in patients treated with the nucleotide analogue tenofovir. RG7907 blocked 99.3% of pgRNA encapsidation (range: 92.1% - 99.9%) which led to a decline of both HBV DNA and HBV RNA. As a consequence of its mode of action the first phase of decline of HBV RNA was rapid, uncovering the clearance of viral particles with half-life of 45 minutes. In contrast, HBV DNA decline was predicted to be less rapid, due to the continuous secretion of already formed viral capsids (t1/2 = 17±6 hours). After few days, both markers declined at the same rate, which was attributed to the loss of infected cells (t1/2 ≅ 6±0.8 days). By blocking efficiently RNA reverse transcription but not its encapsidation, nucleotide analogue in contrast were predicted to lead to a transient accumulation of HBV RNA both intracellularly and extracellularly. The model brings a conceptual framework for understanding the differences between HBV DNA and HBV RNA dynamics. Integration of HBV RNA in viral dynamic models may be helpful to better quantify the treatment effect, especially in viral suppressed patients where HBV DNA is no longer detectable.

Keywords: HBV RNA; Hepatitis B; Viral kinetics; core protein allosteric modulators.

This article is protected by copyright. All rights reserved.

StephenW

是什么驱动治疗过程中HBV RNA的动力学？
AntonioGonçalves1，Annabelle Lemenuel-Diot 2，ValérieCosson 2，Jin Yuyan 3，Sheng Feng 3，Qingyan Bo 4，JérémieGuedj 1
隶属关系
隶属关系

    1个
    巴黎大学，IAME，INSERM，F-75018，法国巴黎。
    2
    罗氏制药研究和早期开发，药物科学，瑞士巴塞尔罗氏创新中心。
    3
    罗氏制药研究与早期开发部临床药理学，药物科学，上海罗氏创新中心。
    4
    I2O DTA，罗氏制药研究与早期开发，罗氏创新中心，中国上海。

    PMID：33074571 DOI：10.1111 / jvh.13425

抽象

除病毒体（HBV DNA）外，在慢性感染患者中还可以检测到含乙肝RNA的颗粒（HBV RNA）衣壳化前基因组RNA（pgRNA），已提出将其作为治疗功效的标志。这使使用有前景的核心蛋白变构调节剂（如RG7907）成为可能，它会破坏核衣壳装配并显着降低HBV RNA。在这里，我们开发了扩展标准病毒动力学模型的HBV多尺度模型，以分析RG7907治疗28天的35例患者的HBV DNA和HBV RNA动力学。我们将预测结果与核苷酸类似物替诺福韦治疗的患者的预测结果进行比较。 RG7907阻断了99.3％的pgRNA衣壳化（范围：92.1％-99.9％），这导致HBV DNA和HBV RNA均下降。由于其作用方式，HBV RNA下降的第一阶段很快，发现了半衰期为45分钟的病毒颗粒清除率。相反，由于已经形成的病毒衣壳的连续分泌（t1 / 2 = 17±6小时），预计HBV DNA下降的速度较慢。几天后，两种标记物以相同的速度下降，这归因于感染细胞的丢失（t1 / 2×6±0.8天）。相反，通过有效地阻断RNA逆转录而不是其衣壳化，预计核苷酸类似物会导致HBV RNA在细胞内和细胞外的短暂积累。该模型为理解HBV DNA和HBV RNA动态之间的差异提供了概念框架。在病毒动力学模型中整合HBV RNA可能有助于更好地量化治疗效果，尤其是在无法再检测到HBV DNA的病毒抑制患者中。

关键字：HBV RNA；乙型肝炎；病毒动力学；核心蛋白变构调节剂。

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