Coronavirus. Credit: https://www.scientificanimations.com / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)

Testing Treatments for COVID-19

Multiple clinical trials for COVID-19 treatments are in progress.

With a vaccine more than a year away from being ready for mass use, companies and researchers are looking for ways to treat the disease caused by the new coronavirus SARS-CoV-2. COVID-19 is a respiratory system illness that can cause pneumonia in some patients and organ failure in some patients, possibly through an out of control immune response called a cytokine storm. Either pneumonia or organ failure can cause death. Although most lethal in older people or people with underlying health conditions, many adult patients across the age spectrum require respiratory assistance to survive the disease.

Current trials aim to reduce replication of the virus, reduce entry of the virus into the cells, boost the antiviral immune response, or prevent lung tissue damage. The drugs most likely to be rapidly approved are ones that are already approved to treat other diseases. This is called drug repurposing and has an advantage over newly developed drugs, because previously approved drugs have already been safety tested in healthy people.

Some of the trials testing drugs that block viral replication or viral entry into cells build on data showing inhibition of the virus in cultured cells or animal models. Some of these antiviral drugs are approved for use against other viruses in various countries. None are yet approved as of 21 March 2020 for COVID-19 (2019-nCOV, SARS-CoV-2).

  • Umifenovir (Arbidol): approved antiviral in Russia and China, blocks viral entry, Phase IV, COVID-19 trial NCT04255017
  • Favipiravir (T-705, Avigan, favilavir): approved antiviral in Japan, inhibits viral RNA polymerase, Phase II, COVID-19 trials ChiCTR2000029544, ChiCTR2000029600, ChiCTR200030254
  • Lopinavir (Kaletra): approved antiviral in US, inhibits HIV protease, Phase IV, COVID-19 trial NCT04255017
  • Oseltamivir (Tamiflu): approved antiviral in US, inhibits viral neuraminidase, Phase IV, COVID-19 trial NCT04255017
  • Ritonavir (Norvir): approved antiviral in US, inhibits HIV protease, Phase III, COVID-19 trial NCT04255017
  • Remdesivir (GS-5734): investigational antiviral, inhibits viral RNA polymerase, Phase III, COVID-19 trials NCT04252664, NCT04280705, EudraCT 2020–000842–32, EudraCT Number 2020–000841–15
  • Ribavirin: approved antiviral, inhibits viral RNA polymerase, not in trials for COVID-19, PMID: 32020029

The trial ChiCTR200030254 testing favipiravir versus umifenovir indicated that favipiravir may be superior in reducing the duration of disease.

The mechanism of action of some other drugs with antiviral properties is less understood. These include the antimalarial drugs chloroquine and hydroxychloroquine. These drugs increase the pH in intracellular compartments involved in viral entry. When the pH in these compartments is increased, the enzymes in those compartments are inhibited, blocking viral release into the cytoplasm for replication. This could be a mechanism for their action.

Trials testing the natural antiviral cytokine IFNβ-1a (SNG001, EudraCT number 2020–001023–14 ) are also ongoing.

Some trials have already shown negative data. A Chinese trial (ChiCTR2000029308) of the combination of lopinavir and ritonavir did not provide any benefit in terms of mortality in hospitalized patients with severe COVID-19 symptoms.

Undoubtedly more results will become available soon. Any treatment should be tested through appropriate clinical trials to ensure that they do not do more harm than good.

References

Andersen PI, Ianevski A, Lysvand H, et al. Discovery and development of safe-in-man broad-spectrum antiviral agents [published online ahead of print, 2020 Feb 17]. Int. J. Infect. Dis. S1201–9712(20)30076-X (2020). DOI:10.1016/j.ijid.2020.02.018

Belhadi D, Peiffer-Smadja N, Yazdanpanah Y, Mentré F, Laouénan C, A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19. medRxiv 2020.03.18.20038190 (2020) DOI: https://doi.org/10.1101/2020.03.18.20038190 [preprint, not peer-reviewed]

Burkard C, Verheije MH, Wicht O, et al. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog. 10, e1004502 (2014). DOI:10.1371/journal.ppat.1004502 [published correction appears in PLoS Pathog. 2015 Feb;11(2):e1004709]

Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 [published online ahead of print, 2020 Mar 18]. N. Engl. J. Med. 0.1056/NEJMoa2001282 (2020). DOI:10.1056/NEJMoa2001282

Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Zhang J, Yin P, Wang X, Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv 2020.03.17.20037432 (2020). DOI: https://doi.org/10.1101/2020.03.17.20037432 [preprint, not peer-reviewed]

Gough NR, A Combination Therapy that Eliminates the COVID-19 Virus. Medium (19 March 2020).

NIH clinical trial of remdesivir to treat COVID-19 begins. National Institutes of Health (25 February 2020) https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins.

DrugVirus.info https://drugvirus.info/ (accessed 21 March 2020)

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