Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection.
Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection.
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DOI：
10.1038/s41598-020-80594-6
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发表时间：
2021-01-08
影响因子：
4.6
通讯作者：
Ciupe SM
中科院分区：
文献类型：
--
作者：
Kadelka S;Dahari H;Ciupe SM
RNA干扰（RNAi）药物ARC-520被证明可有效降低单剂量ARC-520和每日核苷类似物（恩替卡韦）治疗的HBeAg阳性患者的血清B病毒（HBV）DNA、B e抗原（HBeAg）和B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，我们开发了一种多房室药代动力学-药效学模型，并用频繁测量的HBV动力学数据对其进行校准。我们发现，ARC-520阻断HBsAg和HBeAg的时间依赖性单次剂量功效在第1天左右超过96%，并在1-4个月内缓慢下降至50%。ARC-520和恩替卡韦联合单次给药对HBV DNA的作用随时间推移而保持恒定，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。该模型框架可能有助于评估正在进行的针对B型肝炎病毒感染的RNAi药物开发。
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.
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影响因子：
13.5
作者：
Dahari, Harel;Shudo, Emi;Ribeiro, Ruy M.;Perelson, Alan S.
通讯作者：
Perelson, Alan S.
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Goyal, Ashish;Chauhan, Ranjit
通讯作者：
Chauhan, Ranjit
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作者：
Ciupe SM;Ribeiro RM;Perelson AS
通讯作者：
Perelson AS
影响因子：
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通讯作者：
Murray JM
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作者：
Ciupe, Stanca M.;Catlla, Anne J.;Schaeffer, David G.
通讯作者：
Schaeffer, David G.