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Is Hydroxychloroquine a proven treatment for COVID-19?

Is Professor Didier Raoult the man saving the world from Covid-19, or an arrogant, misguided scientist raising false hopes?

Courtesy Techcrunch.com

Introduction

According to the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and the U.S. Food and Drug Administration (FDA), there are currently no medications or vaccines proven to be effective for the treatment or prevention of the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[1] [2] [3].


Recent hypothesis by Professor Didier Raoult[4], a French virologist who heads the Mediterranean infectious and tropical disease institute in Marseille, regarding the benefit of Hydroxychloroquine and Chloroquine[5], a broadly used antimalarial drug, in the treatment of patients infected by the emerged COVID-19, was dismissed by other eminent infectious disease specialists ( as fake news ) mostly because of poor methodology showing positive results in a non-randomised, unblinded trial of 24 patients[6].

Professor Didier Raoult . Photo Olivier Monge. Myop

In February this year, Janet Diaz, the head of clinical care for WHO’s emergency program, issued a statement about whether some drugs could cure patients, saying it needs more trials[7]: “At this moment in time there is no proven effective treatment for COVID-19 so that is clear at this moment in time. However there are ongoing clinical trials being done in China at this moment as well. The two that we’ve already discussed are testing the priority therapeutics that were prioritized by the WHO R&D blueprints and that includes lopinavir and ritonavir as well as remdesivir”. “For chloroquine there is no proof that that is an effective treatment at this time. We recommend that therapeutics be tested under ethically approved clinical trials to show efficacy and safety” Janet Diaz concluded.

What is Hydroxychloroquine and Chloroquine?

Hydroxychloroquine is classified as an anti-malarial drug. It is similar to chloroquine and is useful in treating several forms of malaria as well as lupus erythematosus and rheumatoid arthritis[8]. Both drugs have in-vitro activity against SARS-CoV, SARS-CoV-2, and other coronaviruses, with hydroxychloroquine having relatively higher potency against SARS-CoV-2[9]. According to some experts, If chloroquine is shown to be effective against SARS-CoV-2, it will not be via the same mechanism by which the drug functions as an antimalarial. That’s because malaria is caused not by a virus but by a microparasite of the Plasmodium genus. Chloroquine makes it toxic for the parasite to digest its host’s hemoglobin. Chloroquine might have entirely different effects against a virus, such as, for example, disrupting the virus’s ability to enter a cell[10].


Any published study?

In China, a study reported that chloroquine treatment of COVID-19 patients had clinical and virologic benefit versus a comparison group, and chloroquine was added as a recommended antiviral for treatment of COVID-19 in China[11]. Hydroxychloroquine is currently under investigation in clinical trials for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection, and treatment of patients with mild, moderate, and severe COVID-19.

There are no currently available data from Randomized Clinical Trials (RCTs) to inform clinical guidance on the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection.


What is the Marseille study?

The Marseille study[12] was accepted on 5th March by the French National Medicines Safety Agency (ANSM). An ongoing study coordinated by “The Méditerranée Infection University Hospital Institute in Marseille”[13].

36 Hospitalized patients with confirmed COVID-19 were included in this study if they fulfilled two primary criteria: i) age >12 years; ii) PCR documented SARS-CoV-2 carriage in nasopharyngeal sample at admission whatever their clinical status. After 6 days, the percentage of patients testing positive for COVID-19 who received hydroxychloroquine fell to 25% versus 90% for those who did not receive the treatment (a group of untreated COVID-19 patients from Nice and Avignon). In addition, comparing untreated patients, those receiving hydroxychloroquine and those given hydroxychloroquine plus the antibiotic azithromycin, the results showed there was "a spectacular reduction in the number of positive cases" with the combination therapy, said Professor Raoult.

At 6 days, among patients given combination therapy, the percentage of cases still carrying SRAS-CoV-2 was no more than 5%. Azithromycin was added because it is known to be effective against complications from bacterial lung disease but also because it has been shown to be effective in the laboratory against a large number of viruses, the infectious disease specialist explained.


Any Bigger study?

On the 22 March 2020, a clinical trial called “Discovery”, coordinated by Inserm as part of the Reacting consortium, starts in France to test four experimental treatments against COVID-19. This European project is led by Florence Ader, infectiologist in the Infectious and Tropical Diseases Department of the Croix-Rousse Hospital of Lyon University Hospital and researcher at the “CIRI ” International Research Centre in Infectiology (Inserm/CNRS / Claude Bernard University Lyon 1). It will include 3200 European patients from Germany, France, Spain, Belgium, Luxembourg, Netherlands, Sweden, and the United Kingdom. [14]

The objective is to evaluate the efficacy and safety of four experimental therapeutic strategies which, in light of latest scientific information, might be effective against COVID-19 including the Hydroxychloroquine.


Courtesy-Clinical trial arena


What are the other drugs?

Remdesivir

Remdesivir was first developed to treat Ebola, but research later showed that it could also block MERS and SARS in cells. It is an investigational intravenous drug with broad antiviral activity that inhibits viral replication through premature termination of RNA transcription and has in-vitro activity against SARS-CoV-2 and in-vitro and in-vivo activity against related betacoronaviruses[15].

There’s also anecdotal evidence that remdesivir helps treat COVID-19 patients, but that’s also no guarantee that a clinical trial will show that it works better than placebo.

Ritonavir/lopinavir and interferon-beta

A study had combined the two antivirals with interferon-beta, a molecule involved in regulating inflammation in the body that has also shown an effect in marmosets infected with MERS. A combination of the three drugs is now being tested in MERS patients in Saudi Arabia in the first randomized controlled trial for that disease[16].

The use of interferon-beta on patients with severe COVID-19 might be risky, if it is given late in the disease it could easily lead to worse tissue damage instead of helping patients.

Lopinavir-ritonavir did not show promise for treatment of hospitalized COVID-19 patients with pneumonia in a recent clinical trial in China[17]. This trial was underpowered, and lopinavir-ritonavir is under investigation in a World Health Organization study.



Conclusion

On this 24 March 2020, no drugs have been proven to be effective for the prevention or treatment of COVID-19. There is still no conclusive evidence that chloroquine will treat COVID-19. Numerous antiviral agents, immunotherapies, and vaccines are being investigated and developed as potential therapies.

It is important to note that recent reports suggesting that chloroquine may have some benefit in treating patients with severe manifestations of COVID-19 are based on small studies that need to be verified with formal clinical trials assessing both efficacy and safety.   

Unfortunately, based upon limited in-vitro and anecdotal data, chloroquine or hydroxychloroquine are currently used for treatment of hospitalized COVID-19 patients in several countries on an uncontrolled basis.


Both chloroquine and hydroxychloroquine have known safety profiles with the main concerns including:

  • QT prolongation and Torsade de pointes,

  • Mental Status Changes and Psychosis.

  • Drug interactions.

  • Retinopathy

  • Hypoglycemia

  • Hemolysis (rare).

  • Overdose.


Anticipatory prescriptions could lead to direct consequences in terms of limiting access to potentially life-saving medicines when they are actually needed.

Amid hydroxychloroquine hopes, lupus patients may face shortages.


Is Professor Didier Raoult the man saving the world from Covid-19, or an arrogant, misguided scientist raising false hopes?


References

[1] World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected https://www.who.int/publicationsdetail/clinical-management-of-severe-acute-respiratory-infection-when-novelcoronavirus-(ncov)-infection-is-suspected





[6] https://www.youtube.com/watch?v=n4J8kydOvbc



[9] https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html#r1



[11]https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html#r6

[12] Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949

[15]https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html#r1

[16]https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3846-x

[17]https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html#r8




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