The controversial Professor Raoult published a second study on the effect of chloroquine in the treatment of Covid-19, confirming the conclusions of the first. However, some criticisms and questions remain.
[Mise à jour le 30 mars 2020 à 11h54] Didier Raoult, the now famous professor from Marseille, champion of the use of chloroquine against the coronavirus, persists and signs. This infectious disease specialist published, Friday, March 27, 2020, a second study on the effects of this widespread antimalarial in the treatment of Covid-19. The study involved 80 rather young patients who had been treated at the Marseille University Hospital Institute for 6 to 10 days. Patients received a combination of hydroxychloroquine (3 x 200 mg daily) and azithromycin (an antibiotic). At the end of the experiment, 65 patients (ie 81%) experienced “a favorable development”. 13 patients were still in intensive care after 10 days and an 86 year old patient died. After 8 days, the viral load was undetectable in 93%.
The Professor concluded: “We confirm the efficacy of hydroxychloroquine associated with azithromycin in the treatment of Covid-19.” However, some colleagues criticize the absence of a control group (group of patients to whom the treatment studied is not administered). Sure Twitter, Professor François Balloux, from University College London, regretted: this is a study without a control group “which follows 80 patients with fairly mild symptoms. The majority of patients recover from Covid-19, with or without treatment with hydroxychloroquine and azithromycin. ” Didier Raoult defended himself: “Our study concerns 80 patients, without a control group because we offer our protocol to all patients with no contraindication. This is what the Hippocratic oath we have dictates loaned. ” He confirmed in Le Monde: “The doctor can and must think like a doctor, not like a methodologist.”
In France, the government, via the Minister of Health Olivier Véran, said it was in favor of more extensive clinical trials and currently underway on a European scale, in at least 7 countries, since March 22. Meanwhile, a decree had been published Thursday, March 26 in the Official Journal to regulate the prescription of this molecule considered miraculous by some doctors. Only hospital doctors, by way of derogation, may prescribe it to their most seriously ill patients. The decree stated that “hydroxychloroquine and the combination lopinavir / ritonavir may be prescribed, dispensed and administered under the responsibility of a doctor to patients affected by Covid-19, in the health establishments which take them in charge, as well as for the continuation of their treatment if their condition allows it and with the authorization of the initial prescriber, at home “. Finally, on Friday March 27, the government backed down by modifying the decree and authorizing chloroquine only for the most serious cases. “These prescriptions come into play, after a collegial decision, in compliance with the recommendations of the High Council for Public Health and, in particular, the indication for patients suffering from oxygen-demanding pneumonia or organ failure”, may we now read.
For their part, city doctors are prohibited from using it for their patients with coronavirus. French people who usually use the prescribed molecule, especially in the case of malaria, will be able to continue to benefit from it. The High Council of Public Health had issued an opinion on Monday, March 23, indicating that chloroquine could certainly be administered to patients suffering from “serious forms” of coronavirus, but only in a strict medical protocol and on “collegial decision of doctors”. It cannot be marketed and used on a larger scale, for “less severe” forms. On Saturday March 28, the Council of State will have to answer the following question: should we stock up on chloroquine to avoid the shortage?
Little known to the general public until recently, chloroquine is a molecule used in medicine in antimalarial treatments. In other words, it is used as a preventative before going to countries at risk, as in curative once malaria is contracted. Hydroxychloroquine is the most commonly administered substance by mouth. Chloroquine then has a hydroxyl group (the OH entity comprising a bonded oxygen and hydrogen atom). We speak most often of “hydroxychloroquine sulfate”.
Nivaquine and Plaquenil are the other terms often used for a few days about a potential treatment for coronavirus. These are actually the names behind which the molecules of chloroquine and hydroxychloroquine are marketed. Nivaquine is a brand of Sanofi that presents chloroquine in the form of a 100 mg scored tablet. Plaquenil, from the same pharmaceutical group, is composed of hydroxychloroquine sulfate in the form of 200 mg tablets. Chloroquine or hydroxychloroquine are also found under the brands Axemal, Dolquine and Quensyl. All these treatments are also used in the treatment of rheumatoid arthritis and lupus. In France, the only French manufacturer of chloroquine (Sanofi – NDLR) is currently working to supply the establishments carrying out tests.
Taking chloroquine is not without risk for patients. The molecule is considered a “narrow therapeutic margin” drug, which means that the therapeutic effective dose is close to the toxic dose. Among the effects of chloroquine, the main ones concern cardiovascular disorders which can occur suddenly during treatment. A study by the Toulouse University Hospital going back to 2011 also evokes long-term effects on the retina, in other words after 5 to 7 years of treatment at 6.5 mg / kg / day. “The risk then increases further with the continued use of the drug,” wrote the CHU. Risks which explain in particular the very precise dosages used during the tests carried out in Marseille by Professor Raoult.
Monday March 23, we learned that an Arizona resident had died, died after ingesting chloroquine phosphate, a product used in particular … to clean aquariums. This American in his sixties was notably inspired by the words of President Donald Trump, who praised the merits of chloroquine as a remedy against the coronavirus. The American head of state allowed himself to be convinced by Professor Didier Raoult, as much criticized as glorified for his tests considered positive, but also limited. The victim’s wife was also hospitalized.
If you consult the instructions for Plaquenil or Nivaquine, the list of undesirable effects and counter-indications is very long. Chloroquine should be avoided in case of allergy to hydroxychloroquine or its derivatives, of course, but also in case of retinopathy (retinal disease), deficiency in “Glucose-6-Phosphate Dehydrogenase” or porphyria (diseases of the blood), severe liver or kidney disease, or intolerance to certain sugars. It is also not recommended in case of pregnancy or breastfeeding or must at least be the subject of a medical opinion. Chloroquine is also incompatible with other treatments such as anxiety remedies (citalopram, escitalopram, hydroxyzine), depression (tricyclic antidepressants), psychiatric disorders (antipsychotics), vomiting (domperidone), bacterial or other antimalarial infections (for example, halofantrine or piperaquine). A cocktail with other drugs known to affect the heart rate can also be very dangerous.
As with many drugs, side effects are very numerous and sometimes frightening, although some are considered to be uncommon. They range from heart rhythm disturbances in some patients, to a risk of hemolysis (destruction of red blood cells) or a decrease in blood sugar levels, passing by an acute attack of porphyria, visual disturbances (visual acuity, color vision …), worsening of lesions in case of psoriasis, muscle stiffness, abnormal movements, tremors, nausea, stomach pain, diarrhea, vomiting, loss of appetite, itching, hives or sudden swelling in case of allergy, a rash of pimples or a “slate color of the skin or mucous membranes” or even rash of bubbles or detachment of the skin, discoloration or even hair loss, headache, buzzing ears to deafness, dizziness, convulsions, progressive muscle weakness or even muscle atrophy (myopathy), hepatitis in more rare cases … “This medication should only be taken under medical supervision “, still warn the notices that we have consulted. A complete ophthalmological assessment is sometimes recommended before treatment.
Professor Raoult extensively cited experiments carried out in China on the molecule, from which he was inspired: “The fact of ignoring what the Chinese said about chloroquine is delusional. They were the ones who had the patients to experiment , not us, “he said in an interview to Marianne. Several hospitals in China tested the molecule on their patients at the start of the epidemic, with the publication of some studies even going back to the beginning of January. But they did not provide a clear answer on chloroquine.
An article written by a team of pharmacologists from Qingdao University Hospital, published on February 19 and reported in the Japanese online scientific journal J-STAGE, indicates that “a lot of effort has been made to find effective drugs against virus in China “. And the conclusion is clear: “it has been shown that chloroquine phosphate, an old drug for the treatment of malaria, has apparent efficacy and acceptable safety against pneumonia associated with Covid-19”. To establish this observation, the authors rely on in vitro studies, then on the experience of 10 hospitals in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai, Chongqing and Ningbo. “The results of more than 100 patients have shown that chloroquine phosphate is superior to other treatments for inhibiting the exacerbation of pneumonia”, all “without serious adverse effects”. It is also pointed out that the anti-viral and anti-inflammatory potential of chloroquine may explain its “powerful efficacy” in the treatment of patients with Covid-19. A conference organized on February 15, 2020 with government experts approved the use of chloroquine in the treatment of pneumonia and its recommendation by the Chinese National Health Commission, said the text.
But another study, published on March 3 on the website of ZheJiang University, south of Shanghai, gave results more difficult to interpret. This involved (only) 30 patients in a still mild condition, half being treated with chloroquine, the other without the molecule. On arrival, 86.7% of the “chloroquine group” were negative for the coronavirus after 7 days of treatment, ie 13 patients. But in the same period 93.3% of the patients in the other group, or 14 patients, were also negative. All patients were considered to be cured after 14 days. Hydroxychloroquine therefore did not give any significant results, but the sample proved to be too thin to really assess its effects by “randomizing” the doses, the power of the treatment and by evaluating the relevance of choloroquine according to the severity cases.
On February 25 the Marseille IHU will already publish a video entitled “Towards a way out of the crisis?” highlighting Chinese advances. Two Chinese publications are cited there, which emphasize the value of chloroquine, “to accelerate the healing of patients” affected by the coronavirus. But the results of these tests would be unclear: this Monday, March 23, Philippe Klein, French doctor in Wuhan, epicenter of the global epidemic of Covid-19, assured on LCI that the tests conducted in China and having started well before those of Marseille had produced “no significant results” so far. Studies have also been carried out in Iran, South Korea and Saudi Arabia.
To get everyone to agree and to follow a strict protocol, a European clinical trial called “Discovery” was launched on March 22, 2020 in at least seven countries, including France. Four experimental treatments against the coronavirus will be tested on a total sample of 3,200 patients, including 800 in France. These four treatments are the combination of the anti-viral and anti-infectious agents remdesivir, lopinavir and ritonavir, other combinations of these three treatments with or without beta interferon, used against multiple sclerosis, and finally the treatment based on hydroxychloroquine. . Inserm, the organization that oversees medical research in France, indicates that five French hospitals are participating in the trials, but not the IHU Mediterranean. In France, Director General of Health Jérôme Salomon praised this approach, considering it essential to produce “all, all together, urgent scientific knowledge in good conditions so that very quickly solutions appear, whether negative or positive” . The results should be available 15 days after the start of treatment, that is, in the first week of April.
Pending the results of clinical trials, chloroquine is causing debate among scientists, some believing that it should be generalized, others believing that the molecule must continue to follow clinical tests according to the conventional protocol before d be used more massively. Other medical professionals place the cursor in the middle: they are not against tests, but they wait to see to decide whether or not to favor chloroquine as a remedy for coronavirus. This is the case of François Bricaire, infectiologist and former head of department at the Pitié-Salpêtrière hospital in Paris. “The advantage is a known product (…) We don’t take a lot of risk using it,” he reacted on March 23, when asked about the LCI antenna. It is notably on the basis of this argument that the Marseille IHU conducts its tests directly on patients, even before the publication of the results of the European clinical trial.
Among politicians too, the molecule arouses enthusiasm on the one hand, distrust on the other. Among the most convinced, we find the current mayor of Nice Christian Estrosi, himself struck by the coronavirus and who considers himself cured after being treated with chloroquine. “We don’t have time to experiment on mice,” said the former interior minister. The deputy LR Valérie Boyer, also contaminated and treated with the treatment of Didier Raoult, says to “trust this professor and his teams”. “I would like to thank them for the hope they give us in front of the Covid-19,” she said on Twitter. Bruno Retailleau, chairman of the LR group in the Senate, urged the government not to “fall behind” on the issue. Seven LR deputies also wrote to Emmanuel Macron asking him to speed up on chloroquine, according to the letter that Le Figaro obtained. On the left, however, we are cautious.