Clinics in Dermatology
Elsevier
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Remdesivir: A giant step, or a tiptoe?
Volume: 38, Issue: 6
DOI 10.1016/j.clindermatol.2020.05.015
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Dickinson: Remdesivir: A giant step, or a tiptoe?

To the Editor,

The abrupt emergence and spread of SARS-COV-2 has taken the world by surprise. There is a global search for treatment. One of the most promising is remdesivir, a drug developed to treat Ebola virus (of which it did not) that has not yet been fully studied. The preliminary reports indicate activity versus COVID-19 and some efficacy.

Remdesivir reminds one of other viruses and another drug. The AIDS epidemic also took the world by storm, first recognized in 1981 and without any “proven” treatment for several years. A drug, 3′-deoxy-3′-aido-thymidine, sitting on the shelves of the National Cancer Institute since the 1960s when it failed as a chemotherapeutic agent against cancer, was tested and shown to have beneficial effects at shutting down HIV replication in the laboratory and in a limited trial. In 1986 a randomized clinical trial documented that it did stop HIV. This compound, named “zidovudine,” rapidly entered clinical use, although there were skeptics. Unfortunately, zidovudine was potentially toxic, and its benefit was short-lived, as the HIV would escape control through mutation. But zidovudine did show the way; many other drugs followed; and in 1996, thanks to the benefit of new assays and laboratory tools to guide treatment, we were able to combine drugs and achieve lasting control of HIV. A different virus, a different epidemic, but a similar first step, although, as of this writing, we are unsure if this will end the lethal effects of COVID-19 infection.

Remdesivir is a nucleoside analog of adenosine that was developed by a research team at Gilead searching for a treatment for Ebola virus. The drug did not work for Ebola, although the studies indicated that it was a safe drug. Work with the corona viruses suggested activity in vitro and in monkeys, and we now have some anecdotal information and the initial human trials that suggest activity.1

There are three studies now available:

    • 1. A small randomized double-blind study performed in China and published in The Lancet suggests minimal activity, but enough to recommend further studies.2
    • 2. A second study, reported by the company but not yet published, compared 5 to 10 days of remdesivir and showed no difference in outcome.3
    • 3. A third study, the randomized controlled Adaptive COVID-19 Treatment Trial, is reported to have reduced the time to recovery from 15 to 11 days and reduced the mortality rate from 11.6% to 8%. These preliminary data, most not yet published, have been deemed sufficient to allow the FDA approve its use in hospitalized patients.3

There are several reservations:

    • 1. The efficacy as reported thus far is moderate at best.
    • 2. The safety when given for a potentially fatal infection appears good.
    • 3. The optimal time to use the drug is unclear. Our understanding of the COVID-19 disease is that its lethality often stems from an aggressive host response with a cytokine storm in which the host response kills the patient. One can reasonably posit that the time to use the drug is early in the infection before the patient is severely ill. But we do not know this.
    • 4. The drug exists only in a form that must be given by intravenous infusion. This is acceptable for the ill hospitalized patient, but not so for the patient with minimal clinical manifestations.
    • 5. Conversely, we presently have only a few other candidate antiviral drugs with potential.

As of May 5, 2020, Remdesivir appears to be a relatively safe drug that currently has been christened the standard or treatment for severe COVID-19 disease4, but whether it remains so is not at all clear. As was the case with zidovudine for HIV, it may be only the initial therapy that will be replaced by more effective regimens in the near future.

References

1 

    Williamson B., Feldmann F., Schwarz B.. Clinical benefits of remdesivir in rhesus macaques infected with SARS-CoV-2. BioRxiv [preprint] 2020. , doi: 10.1101/2020.04.15.043166

2 

    Wang Y., Zhang D., Du G.. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial. Lancet 395: 2020. , pp.1569-1578

3 

Gilead report (on line press release).

4 

Nature, News April 29, 2020.

https://www.researchpad.co/tools/openurl?pubtype=article&doi=10.1016/j.clindermatol.2020.05.015&title=Remdesivir: A giant step, or a tiptoe?&author=Gordon M. Dickinson,&keyword=&subject=COVID-19: Important Updates and Developments,Edited by Franco Rongioletti, MD, and Leonard J. Hoenig, MD,