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MARCH 2020 -- Could the old generic malaria drug hydroxychloroquine (Plaquenil, Sanofi-Aventis, among others), which is also used for the treatment of rheumatic disease, be an essential treatment for COVID-19?
This hypothesis, put forward by some, including Professor Didier Raoult of the IHU Méditerranée Infection in Marseille, was dismissed by other eminent infectious disease specialists and dismissed as fake news recently by the Ministry of Health.
Yet it resurfaced yesterday with the presentation on YouTube by Prof Raoult of positive results in a non-randomised, unblinded trial of 24 patients.
This follows encouraging in vitro results obtained by a Chinese team led by Xueting Yao, from Peking University Third Hospital, Beijing, China, which were published online by the journal Clinical Infectious Diseases on March 9th. However, the data were deemed insufficient by the infection community to recommend the compound as a treatment.
Moreover, chloroquine is not listed among the four treatments studied as part of the recently launched European clinical trial piloted by Inserm, which includes 3200 severe hospitalised patients, including 800 French patients.
Chloroquine was ruled out due to the risk of interactions with other medications for common comorbidities in infected patients, and because of possible adverse effects in patients undergoing resuscitation.
The Marseille Study
The European Union Clinical Trials Register shows that the Marseille study was accepted on 5th March by the National Medicines Safety Agency (ANSM). It could include up to 25 COVID-19 positive patients, comprising five aged 12–17 years, 10 aged 18–64 years, and 10 more aged 65 years or over.
While the data have not yet been published, and should therefore be interpreted with caution, this non-randomised, unblinded study showed a strong reduction in viral load with hydroxychloroquine.
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 Prof 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.
"Everyone who died from COVID-19 were still carriers of coronavirus. To no longer have the virus changes the prognosis," Prof Raoult said.
More detailed results of the study have been submitted for publication in the International Journal of Antimicrobial Agents.
Study Splits Infectious Disease Community
The announcement of positive results from this small study split medical opinion.
Professor Gilles Pialoux, an infectious disease specialist at Tenon Hospital, was cautious in his response. He told Medscape's French Edition: "The idea is interesting but we need large, randomised, controlled trials. We should not communicate this kind of information on YouTube, it is not meaningful.
"Don't forget, this compound has not been included in Inserm's trial because there are more interesting avenues, such as remdesivir or Kaletra [lopinavir/ritonavir]. We must be careful not to repeat the story with cyclosporin in HIV."
Christian Perronne, head of infectious diseases, University Hospital Raymond Poincaré, Garches, Paris, was more enthusiastic.
"I really believe in hydroxychloroquine. It is a drug I find rather fascinating, that has been used for decades. There have been positive results in an in vitro study and a preliminary Chinese study in 100 patients which showed that hydroxychloroquine reduced the viral load, the symptoms lasted for less time, and they are not as severe. This could reduce the number of carriers, which I find interesting from an epidemiological perspective.
"I think from an ethical point of view, we should suggest it to all patients with severe disease who are hospitalised, under surveillance and on short treatment, paying attention to drug interactions, especially with drugs that prolong the QT interval. Afterwards, in terms of adverse effects, at increased doses, it is possible that patients will have pain or fever, but it seems that the treatment is effective at lower doses, according to the Chinese data. In any case, the adverse effects of this compound are not dangerous."
On the adverse effects, Professor Thomas Papo, from Bichat Hospital, the University of Paris, confirmed via email: "Hydroxychloroquine (Plaquenil, which is not chloroquine), vaunted by Didier Raoult as an anti-viral, has been used for decades in tens of thousands of patients, for several decades, so we have a huge follow-up and lots of data. This drug is remarkably well tolerated and we give it to all patients with lupus (for example), including in pregnant women. The main complication (retinal toxicity) is rare and does not last beyond 5 years of continuous use."
Hydroxychloroquine Tested in Other Hospitals
At the end of Tuesday's Council of Ministers, Sibeth Ndiaye, a government spokesperson, discussed the results published by Prof Raoult. "The clinical trial in Marseille is a promising start; we are extending it because science requires the experience to be validated and repeated several times to be able to say whether or not it works," she warned. Other tests will be carried out at Lille Hospital to confirm, or not, Prof Raoult's results.
Chloroquine is currently being examined in a number of clinical studies in China and elsewhere, and some in France have also decided to suggest it following Prof Raoult's findings.
This is the case for Dr Alexandre Bleibtreu, an internal medicine specialist at Pitié Salpêtrière Hospital, Paris, who was initially not persuaded by the in vitro data but has changed his opinion after having seen the results of the study carried out by Didier Raoult.
Contacted by CheckNews, the on-demand journalism service from Liberation, he explained that the compound was now used in almost all (approximately 50) hospitalised patients in their service, except those who refuse it or who have contraindications.
"I heard about the results, which changed my mind. We followed the Marseille protocol, and there are surely others who will use it. It is not the most obvious treatment; it works in vitro but we didn't have data in vivo.
"The aim is not to be right but that our patients get better. No treatment is magic and the publication of the results raises questions but between doing nothing and repositioning drugs based on their adverse effects, interactions, etc, we try things as we go."
In the UK, Robin May, Professor of Infectious Disease at the University of Birmingham, explained that there is a scientific rationale for the use of hydroxychloroquine in the treatment of COVID-19, based on its mode of action in malaria.
In a statement through the Science Media Centre, he explained that, as chloroquine is a "weak base" and so helps to neutralise acids, it makes the environment "less suitable" for the malaria parasite to live in when it diffuses into red blood cells.
While the mode of action against COVID-19 is not established, Prof May said, he pointed out that many viruses enter host cells via endocytosis, as a result of which they are initially taken up into an intracellular 'compartment that is "typically fairly acidic".
"Chloroquine would alter the acidity of this compartment, which can interfere with the ability of viruses to escape into the host cell and start replicating."
He continued: "Another possibility is that chloroquine may alter the ability of the virus to bind to the outside of a host cell in the first place," adding that the drug "has subtle effects on a wide variety of immune cells…and it may be that one of these effects helps stimulate the body's ability to fight off COVID-19."
Crucially, the drug is also "cheap and relatively easy to manufacture" and so could easily be put into clinical trials and, eventually, treatment, May underlined.
The study by Yao et al was supported by the "13th Five-Year" National Major New Drug Projects of China, Ministry of Science and Technology of the People's Republic of China, and Bill & Melinda Gates Foundation.
Two of its authors have patents pending for an anti-microbial infection pharmaceutical composition and its application.
Professor Pialoux has been a board member or attended meetings for Gilead, MSD, Bristol-Myers Squibb, Janssen, Abbvie, AstraZeneca.
Clin Infect Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237
Translated and adapted from Medscape's French edition.
Editor's note, 18th March 2020: This article was updated to include Prof May's comments. On 19th March the US FDA issued a statement on chloroquine: "The FDA has been working closely with other government agencies and academic centers that are investigating the use of the drug chloroquine, which is already approved for treating malaria, lupus and rheumatoid arthritis, to determine whether it can be used to treat patients with mild-to-moderate COVID-19 to potentially reduce the duration of symptoms, as well as viral shedding, which can help prevent the spread of disease. Studies are underway to determine the efficacy in using chloroquine to treat COVID-19."
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