了解基于RNAi的疗法对HBeAg阳性慢性乙型肝炎感染的抗病毒作

StephenW

Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection
Sarah Kadelka  1 , Harel Dahari  2 , Stanca M Ciupe  3
Affiliations
Affiliations

    1
    Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA.
    2
    Program for Experimental and Theoretical Modeling, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA.
    3
    Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA. [email protected].

    PMID: 33420293 DOI: 10.1038/s41598-020-80594-6

Abstract

The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.

StephenW

了解基于RNAi的疗法对HBeAg阳性慢性乙型肝炎感染的抗病毒作用
莎拉·卡德卡（Sarah Kadelka）1，哈雷尔·达哈里（Harel Dahari）2，斯坦卡·M·库皮（Stanca M Ciupe）3
隶属关系
隶属关系

    1个
    美国弗吉尼亚州布莱克斯堡，弗吉尼亚理工大学数学系，24060，美国。
    2
    美国伊利诺伊州梅伍德市洛约拉大学史密斯医学院的实验和理论建模程序，美国伊利诺伊州60153。
    3
    美国弗吉尼亚州布莱克斯堡，弗吉尼亚理工大学数学系，24060，美国。 [email protected]。

    PMID：33420293 DOI：10.1038 / s41598-020-80594-6

抽象

RNA干扰（RNAi）药物ARC-520在单剂治疗的HBeAg阳性患者中可有效降低血清乙型肝炎病毒（HBV）DNA，乙型肝炎e抗原（HBeAg）和乙型肝炎表面抗原（HBsAg）剂量的ARC-520和每日核苷类似物（恩替卡韦）。为了深入了解ARC-520处理下的HBV动态及其在阻断HBV DNA，HBsAg和HBeAg产生中的功效，我们开发了一种多室药代动力学-超声动力学模型，并通过频繁测量的HBV动力学数据对其进行了校准。我们显示，阻断HBsAg和HBeAg的时间依赖性单剂量ARC-520疗效在第1天左右的有效性超过96％，并在1-4个月内逐渐减弱至50％。 ARC-520和恩替卡韦联合单剂量对HBV DNA的作用随时间变化是恒定的，疗效超过99.8％。观察到的连续HBV DNA下降是由恩替卡韦介导的，而强烈但短暂的HBsAg和HBeAg下降是由ARC-520介导的。该建模框架可以帮助评估正在进行的针对乙肝病毒感染的RNAi药物开发。

StephenW

https://www.nature.com/articles/s41598-020-80594-6.pdf