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了解 RNAi 为基础的治疗在 HBeAg 阳性慢性乙型肝炎感染中的抗病毒作用。

Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection.

机构信息

Department of Mathematics, Virginia Tech, Blacksburg, VA, 24060, USA.

Program for Experimental and Theoretical Modeling, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA.

出版信息

Sci Rep. 2021 Jan 8;11(1):200. doi: 10.1038/s41598-020-80594-6.

DOI:10.1038/s41598-020-80594-6
PMID:33420293
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7794570/
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.

摘要

RNA 干扰 (RNAi) 药物 ARC-520 显示在接受单次 ARC-520 治疗和每日核苷类似物 (恩替卡韦) 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)。为了深入了解 ARC-520 治疗下的 HBV 动力学及其阻断 HBV DNA、HBsAg 和 HBeAg 产生的疗效，我们开发了一个多隔室药代动力学-药效学模型，并使用频繁测量的 HBV 动力学数据对其进行了校准。我们表明，在第 1 天左右，时间依赖性单次剂量 ARC-520 阻断 HBsAg 和 HBeAg 的疗效超过 96%，并在 1-4 个月内缓慢降至 50%。ARC-520 联合单剂量恩替卡韦对 HBV DNA 的作用随时间保持恒定，疗效超过 99.8%。观察到的持续 HBV DNA 下降是恩替卡韦介导的，强烈但短暂的 HBsAg 和 HBeAg 衰减是 ARC-520 介导的。该建模框架可能有助于评估正在进行的乙型肝炎病毒感染的 RNAi 药物开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/8c4509f55751/41598_2020_80594_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/52752b157714/41598_2020_80594_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/548ad0a05b29/41598_2020_80594_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/e538a02e509a/41598_2020_80594_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/e34c1404d360/41598_2020_80594_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/e1225309b294/41598_2020_80594_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/711cab36ccb2/41598_2020_80594_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/3fa27da54ba8/41598_2020_80594_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/04434e3c295c/41598_2020_80594_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/6f6aa745df6c/41598_2020_80594_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/8c4509f55751/41598_2020_80594_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/52752b157714/41598_2020_80594_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/548ad0a05b29/41598_2020_80594_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/e538a02e509a/41598_2020_80594_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/e34c1404d360/41598_2020_80594_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/e1225309b294/41598_2020_80594_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/711cab36ccb2/41598_2020_80594_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/3fa27da54ba8/41598_2020_80594_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/04434e3c295c/41598_2020_80594_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/6f6aa745df6c/41598_2020_80594_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e94/7794570/8c4509f55751/41598_2020_80594_Fig10_HTML.jpg

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