2020-02-02 Lopinavir/ritonavir VS Redemsivir 治疗2019-nCoV

这个说的就是哪种抗病毒药物治疗效果更好

• 抗艾滋病药物洛匹那韦/利托那韦片（Lopinavir/ritonavir，LPV/r，商品名：克力芝），原理：靶向HIV和冠状病毒在复制时用来切割蛋白质的酶(protease)。

Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology

other studies report complete inactivity similar to that of RTV

In contrast, studies evaluating the antiviral activity of type I and type II interferons have reported IFNb as the most potent interferon in reducing MERS-CoV replication in vitro

MIRACLE Trial: LPV/RTV-IFNb improves clinical outcomes in MERS-CoV patients was initiated in 2016 and has thus far enrolled 76 patients in KSA.

沙特临床试验：克立芝联合IFN β-1b

• 抗Ebola病毒，临床试验期药物

Redemsivir(RDV, GS-5734) is a broad-spectrum antiviral nucleotide prodrug with potent in vitro antiviral activity against a diverse panel of RNA viruses such as Ebola virus (EBOV), Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus (RSV), Nipah virus (NiV), and Hendra virus

抗病毒机制：病毒RNA转录提前终止
The mechanism of RDV’s anti-MERS-CoV activity is likely through premature termination of viral RNA transcription as shown in biochemical assays using recombinant EBOV, NiV, and RSV polymerase

研究基础：
In primary human lung epithelial cell cultures, RDV is potently antiviral against circulating contemporary human CoVs, SARS-CoV (EC50 = 0.07 µM), MERS-CoV (EC50 = 0.07 µM), and related zoonotic bat CoVs

RDV showed potent inhibition of MERS-CoV replication with a EC50 of 0.09 µM, no observable cytotoxicity up to 10 μM and a selectivity index 【】

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The antiviral activity of LPV/RTV (EC50 = 8.5 µM) was similar to LPV alone 【rtv似乎无效果】IFNb activity is not improved when combined with LPV/RTV

目前没有头对头临床试验，但是有细胞试验，主要是比较二者对MERS病毒的效果，北卡罗来纳大学Ralph Baric在Nature Communications上发表了名为“Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV”

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结果表明：与克力芝联合IFN-β相比，remdesivir在体外细胞培养以及动物实验中的表现都要更优，并且是实验中唯一能够改善肺组织病理损伤的治疗药物。

remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro.

In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology.

Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology

• 动物实验表明，预防性和早期使用redemsivir能够明显降低SARS-CoV、MERS-CoV感染小鼠的肺组织病毒载量水平，同时改善肺功能、缓解症状。
• 细胞学实验也证明remdesivir比克立芝效果更好。

• 动物实验更证明可以remdesivir可以显著抑制MERS冠状病毒复制和肺部损伤。

  
  
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• Prophylactic LPV/RTV + IFNb does not improve disease outcomes.

  
  
  

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安全性：

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临床试验设计：

• 单克隆抗体ZMapp(对照组)(a triple monoclonal antibody agent)
• Redemsivir组(a nucleotide analogue RNA polymerase inhibitor6)
• 单克隆抗体MAb114 (a single human monoclonal antibody derived from an Ebola sur- vivor7,8)
• the triple monoclonal antibody REGN-EB3(a coformulated mixture of three human IgG1 monoclonal antibodies
• The primary end point was death at 28 days.

结论：

• MAb114和REGN-EB3组死亡率低于ZMapp；

  
  
  

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• 鉴于该试验中97％的死亡发生在入选后10天内，因此MAb114和REGN-EB3与ZMapp和remdesivir的疗效相比可能部分归因于MAb114和REGN-EB3的完整治疗过程单次给药，而ZMapp和remdesivir多次输注。【尽早治疗比较好】
  METHODS
  All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3.

  
  
  

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Redemsivir 有血清和激酶水平增加的现象

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CT值约22，可以区分风险人群，中国的CT37有点太高。

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