Chloroquine as Treatment for COVID-19

There has been a lot of speculation in twitter and in news media outlets about whether chloroquine can be used as treatment for COVID.

In this post, I summarize what we know about chloroquine from previous experiments, research reports and tweets.

History

In ancient Peru, indigenous people extracted the bark of the Cinchona tree to fight fevers and chills. This was then introduced in Europe and used to fight malaria. The extracts of this bark were then purified in science laboratories to make quinine and chloroquine. Chloroquine was discovered by Hans Andersag in Bayer labs and then popularized in World War II for its antimalarial purposes.

At present, its most common use is for treatment and prevention of malaria, which is from parasitic infection of red blood cells. Chloroquine also enters red blood cells, binds to heme and becomes highly toxic to the red blood cell, leading to cell lysis. In red blood cells infected by the malarial parasite, this effectively destroys the parasite.

Antiviral Properties

In addition to antimalarial effects, chloroquine has several antiviral effects, more thoroughly described here by Deveaux et al. International Journal of Antimicrobial Agents 2020.

In brief, chloroquine has antiviral activity against RNA viruses such as rabies virus, hepatitis A, Dengue virus, Zika virus, and notably even the 2003 SARS virus, which bears great resemblance to the current COVID pandemic. In vitro, chloroquine inhibits the replication of HCoV-229E in epithelial lung cultures.

Mechanism of Action

Chloroquine’s antiviral properties are through a number of mechanisms.

Fig 1
Red arrows are all the areas in which chloroquine may prevent COVID progression
Source: Deveaux et al. 2020

Chloroquine interferes with viral protein binding to cell receptors, by inhibiting quinone reductase 2, preventing sialic acid production, which is needed for ligand recognition by cells. We know that the current COVID coronavirus infection is mediated through spike protein receptor recognition by angiotensin converting enzyme-2 receptors on lung.

Chloroquine also alters the pH environment which interferes with glycosylation and thus endosomal viral entry.

Finally, chloroquine interferes with post-translational modification of viral proteins which then interfere with proteases and glycosyltransferases. This may be especially relevant to the current COVID virus, which requires serine proteases to enter cells.

Chloroquine in COVID-19

A systematic review for the efficacy of chloroquine in COVID-19 is described here.

In summary, there are six relevant articles regarding its use and there are 23 current clinical trials in process regarding the efficacy of chloroquine.

One research letter from a group of Chinese researchers examined the efficacy of chloroquine to prevent infection multiplicity in vitro with cells infected by COVID, and showed the drug was highly effective in reducing viral replication.

Chloroquine and remdesivir effective in preventing viral replication of COVID-19
Source: Wang et al. Cell Research 2020
Source: https://www.nature.com/articles/s41422-020-0282-0

A few editorials strongly recommended chloroquine. A group of Chinese authors mentioned that Chloroquine had demonstrated marked efficacy and safety in treating COVID-19 from their experience with more than 100 patients. This panel recommended chloroquinine phosphate tablets at a dose of 500 mg twice per day for 10 days for all mild, moderate, and severe COVID pneumonia.

In France, their clinicians recommended chloroquine given its high safety and low expenditure. The Dutch Center of Disease control also recommended chloroquine, but recommended stopping the treatment after 5 days to reduce the risk of side effects. The Italians followed the Chinese recommendations, but extended treatment to even longer depending on the clinical course.

Clinical Trials

A recent open labeled French clinical trial showed that chloroquine was effective in reducing COVID19. The details are in this report here.

Transcribed from the press conference is the following:

On this graph, the Y axis is the percentage of patients with a positive viral load. You can see 90% of those having received no plaquenil still have a positive viral load at day 6. On the other hand, only 25% of people on plaquenil had a positive viral load.

A result that half-surprised us was that the effect of azithromycin. For a long time, we and other people often recommend covering viral respiratory infectious with antibiotics to avoid bacterial complication. So anyone with signs pointing towards developing bacterial complication would get azithromycin – remember that in JAMA there’s an article that azithromycin reduces the risk of people with viral infectious in general. Another reason is azithromycin in the laboratory setting has been shown to be efficacious against a number of virus, even though it’s an antibiotic. So, when it comes to choosing an antibiotic, we choose one with presumed antiviral activity.

Everyone that dies (except those who die of secondary complications) from coronavirus, dies with the virus. So, if you remove the virus, the prognosis by definition changes. This is infectious disease. You remove the pathogen, you save the patient.

The authors strongly support the combination of chloroquine with azithromycin.

Conclusion

The conclusion from most texts is that there is enough theoretical, experimental, and clinical evidence for using chloroquine in treatment of COVID-19. The FDA granted emergency use authorization for chloroquine, assessing that the potential benefits outweigh the risks.

Please see this post for updates about chloroquine.

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