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Remdesivir slows COVID-19 disease progression in macaques — US National Institutes of Health

Early treatment with the antiviral drug remdesivir is shown to reduce viral load and prevent lung disease in macaques infected with SARS-CoV-2, reports a study. The findings support the early use of remdesivir treatment in patients with COVID-19 to prevent progression to pneumonia.

Remdesivir has broad antiviral activity and has been shown to be effective against infections with SARS-CoV and MERS-CoV in animal models. The drug is being tested in human clinical trials for the treatment of COVID-19.

Emmie de Wit and colleagues at the National Institute of Allergy and Infectious Diseases, National Institutes of Health investigated the effects of remdesivir treatment in rhesus macaques, a recently established model of SARS-CoV-2 infection. Two sets of six macaques were inoculated with SARS-CoV-2; one group was treated with remdesivir 12 hours later (close to the peak of virus replication in the lungs) and these macaques received treatment every 24 hours until six days after inoculation. In contrast to the control group, macaques that received remdesivir did not show signs of respiratory disease and had reduced damage to the lungs. Viral loads in the lower respiratory tract were also reduced in the treated animals; viral levels were around 100 times lower in the lower-respiratory tract of remdesivir-treated macaques 12 hours after the first dose.

Infectious virus could no longer be detected in the treatment group three days after initial infection, but was still detectable in four out of six control animals. Despite this virus reduction in the lower respiratory tract, no reduction in virus shedding was observed, which indicates that clinical improvement may not equate to a lack of infectiousness.

Dosing of remdesivir in the rhesus macaques is equivalent to that used in humans, the authors note. They caution that it is difficult to directly translate the timing of treatment used in corresponding disease stages in humans, because rhesus macaques normally develop only mild disease. However, their results indicate that remdesivir treatment of COVID-19 should be initiated as early as possible to achieve the maximum treatment effect.

Abstract
Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1,2, that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection.2,5,6 In vitro, remdesivir inhibited replication of SARS-CoV-2.7,8 Here, we investigated the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection9. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.

Authors
Brandi N Williamson, Friederike Feldmann, Benjamin Schwarz, Kimberly Meade-White, Danielle P Porter, Jonathan Schulz, Neeltje van Doremalen, Ian Leighton, Claude Kwe Yinda, Lizzette Pérez-Pérez, Atsushi Okumura, Jamie Lovaglio, Patrick W Hanley, Greg Saturday, Catharine M Bosio, Sarah Anzick, Kent Barbian, Tomas Cihlar, Craig Martens, Dana P Scott, Vincent J. Munster, Emmie de Wit

[link url="https://www.nature.com/articles/s41586-020-2423-5"]Nature abstract[/link]

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