Université de Paris, INSERM, IAME, Paris, France.
Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Basel, Switzerland.
J Viral Hepat. 2021 Feb;28(2):383-392. doi: 10.1111/jvh.13425. Epub 2020 Nov 2.
Hepatitis B virus RNA (HBV RNA)-containing particles 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 analyse 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 analog 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 min. In contrast, HBV DNA decline was predicted to be less rapid, due to the continuous secretion of already formed viral capsids (t = 17 ± 6 h). After few days, both markers declined at the same rate, which was attributed to the loss of infected cells (t ≅ 6 ± 0.8 days). By blocking efficiently RNA reverse transcription but not its encapsidation, nucleotide analog in contrast was 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.
乙型肝炎病毒 RNA（HBV RNA）含有颗粒，除了已被建议作为治疗效果标志物的病毒粒子（HBV DNA）外，还可在慢性感染患者中检测到包含前基因组 RNA（pgRNA）。这使得核心蛋白变构调节剂（如 RG7907）的使用具有前景，RG7907 可破坏核衣壳组装并显著降低 HBV RNA。在这里，我们开发了一种 HBV 的多尺度模型，将标准病毒动力学模型扩展到分析 35 名接受 RG7907 治疗 28 天的患者的 HBV DNA 和 HBV RNA 的动力学。我们将预测结果与接受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 封装（范围：92.1%-99.9%），导致 HBV DNA 和 HBV RNA 均下降。由于其作用模式，HBV RNA 的第一阶段下降迅速，揭示了半衰期为 45 分钟的病毒颗粒的清除。相比之下，由于已经形成的病毒衣壳的连续分泌（t = 17 ± 6 h），HBV DNA 的下降预计不会那么迅速。几天后，两种标志物以相同的速率下降，这归因于受感染细胞的丧失（t ≅ 6 ± 0.8 天）。通过有效地阻断 RNA 逆转录但不阻断其封装，核苷酸类似物相反地预计会导致 HBV RNA 在细胞内和细胞外都短暂积累。该模型为理解 HBV DNA 和 HBV RNA 动力学之间的差异提供了一个概念框架。将 HBV RNA 整合到病毒动力学模型中可能有助于更好地量化治疗效果，特别是在 HBV DNA 不再可检测的病毒抑制患者中。
