experiments to end doubts

CORONAVIRUS. Professor Raoult defended his protocol, based on chloroquine, in a video while a vast experiment will be carried out on the national territory …

[Mis à jour le 1er avril 2020 à 15h43] In a video, published on March 31, 2020 on YouTube, Didier Raoult, infectiologist and professor of microbiology at the IHU in Marseille, defended his protocol based on chloroquine, a widespread anti-malaria which causes important debates in the scientific community on its presumed effect on the coronavirus and its dangers. The infectious disease specialist recalled his assessment: “Only one death per 1000 patients treated from the start of the disease.” Convinced, he assured: “When we treat people from the start of the disease, we have results that prevent an unfavorable development and we are happy that things go in this direction.”

However, Didier Raoult, who defends the use of the molecule for many weeks, warned those who would like to use chloroquine or its derivative, hydroxychloroquine, without prescription: “Do not self-prescribe [de la chloroquine]. You must first consult a doctor to perform an electrocardiogram and measure the potassium in your blood. Do not improvise, they are all the same drugs. “Often accused of being” alone “, Didier Raoult presented and praised the qualities of his” staff “, his teams.

It is in this context that the Angers University Hospital announced yesterday the holding of a vast experiment on the effects of chloroquine in the treatment of the new coronavirus. This study will involve 1,300 patients over the age of 75. Professor Vincent Dubée, principal instigator of the Hycovid project, said that it was “a study that meets the highest scientific and methodological standards”. “It will be carried out under conditions which will not leave room for doubt in the analysis of the results,” he added. With this program, the medical profession hopes to put an end to the various controversies aroused by this molecule, considered by Professor Didier Raoult as the miracle cure against the coronavirus.

A few days after a disputed first publication, Professor Didier Raoult released the conclusions of a second study on the effect of chloroquine in the treatment of the new coronavirus, this Saturday, March 28. 80 patients have been tested, which is similar to some traditional clinical trials. The median age of the patients was 52 years, 58% had a comorbidity (hypertension, diabetes, chronic respiratory disease, etc.). For 6 to 10 days, patients received a combination of hydroxychloroquine (3 x 200 mg daily) and azithromycin (antibiotic). At the end of the study, 81% experienced a favorable development and were discharged from the hospital quickly (after 4.6 days). 13 patients were still in intensive care after 10 days and one subject died. In 93% of subjects, the viral load was undetectable after eight days.

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 in the study of Pr Raoult (group of patients to whom the treatment studied is not administered but a placebo generally, to clearly observe the difference in the course of the disease) . 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.”

The first part of the microbiologist’s study was presented in mid-March in a video shot at the IHU in Marseille with his staff. The specialist in emerging tropical diseases had administered to 24 patients this time hydroxychloroquine and azithromycin. After the tests, 75% were no longer carrying Covid-19. This study had already been subject to controversy for the small sample of patients tested and already on the absence of a control group.

Professor Raoult’s studies are controversial. In order to “close the debate”, the Angers University Hospital and 33 health establishments announced, on Tuesday, March 31, the launch of a large study “with the highest scientific and methodological standards”. This experiment will involve 1,300 Covid-19 positive subjects over 75 years of age. Alain Mercat, president of the medical commission of the University Hospital Center of Angers, detailed the protocol: the patients “will receive either hydroxychloroquine, or a placebo, without knowing the nature of the tested tablet. Their consent will be asked.” Pr Vincent Dubée, principal investigator of the project, assured: that the study “will be carried out under conditions which will not leave room for doubt in the analysis of the results.”

This study comes completely from the European clinical trial project called “Discovery”. This study, conducted in 7 countries including France since March 22, aims to test on more than 3,000 patients – including 800 French – five types of treatment: either symptomatic, or Remsdesivir (it prevents the virus from adapting its code patient), either Kaletra (used for HIV-positive patients) or Kaletra combined with beta interferon or chloroquine. Results are expected within a few weeks. This study raised some reservations. Pr Christian Perronne, head of the infectious diseases department at the Garches University Hospital, refused to participate: “because this study provides for a group of severely affected patients who will only be treated symptomatically and will serve as control-controls in the face to four other groups who will receive antivirals. “

The conclusions of a Chinese study, carried out at Renmin Hospital in Wuhan, were made public on Wednesday, March 31, 2020. The experiment focused on 62 subjects, Covid + at a moderate degree of seriousness requiring hospitalization in the classic medical service. For five days, the first half of the patients underwent traditional management (unspecified), the other half received a daily dose of 400 mg of hydroxychloroquine. At the end of the experiment, the patients treated with hydroxychloroquine showed a reduction in their symptoms (cough / fever) in two days, compared to three for the control group. On the other hand, on imaging, 81% of subjects on hydroxychloroquine showed a visible improvement in the lungs. In addition, four patients in the control group experienced deterioration in their health. Chinese researchers have agreed that chloroquine has a modest recovery effect, but allows the infection to remain confined to a mild form.

However, these results are to be moderate. According to Heidi.News, a professional journal, “this study has not yet been published in a scientific journal”, so it has not been corrected by experts. The initial protocol was not followed, it provided for a double-blind trial on two groups of one hundred patients. Finally, the short duration, five days, does not rule out a resurgence of the disease. Despite these reservations, on Twitter, Didier Raoult praised: “A Chinese study shows that hydroxychloroquine improves the prognosis in COVID + patients (moderate to severe symptoms, excluding sheaves). Despite the small number of cases, the difference is significant. This shows the effectiveness of this protocol. “

This is not the first study on chloroquine published by Chinese researchers. 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.

In France, the government, through the Minister of Health Olivier Véran, is trying to find the right balance between urgency and rigor in trials. The latter said he was in favor of more extensive clinical trials that are currently underway on a European scale. In the meantime, the government intends to regulate the prescription of this molecule considered to be miraculous by certain doctors. Only hospital doctors, by way of derogation, may prescribe it to their most seriously ill patients.

A decree was published to this effect Thursday, March 26 in the Official Journal. It states that “hydroxychloroquine and the combination of 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 charge of them, 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 tightened the screw a little more by amending the decree and by 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.

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?

For their part, city doctors are prohibited from using chloroquine or hydroxychloroquine for their patients with coronavirus. French people who usually use the prescribed molecule, especially in case of malaria, will be able to continue to benefit from it.

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.

“At very high doses, chloroquine can kill”, said this Monday, March 30, in Le Parisien, Professor François Bricaire, member of the Academy of Medicine. His warnings seem to be justified. In fact, three suspicious deaths, possibly linked to the absorption of chloroquine, have been reported to the ANSM. These hospitalized patients were receiving treatment with hydroxychloroquine and other drugs such as Kaletra (lopinavir / ritonavir). Analyzes are underway to establish the causes of death. The results should be known by the end of the week.

Chloroquine-based treatments require “special attention”, said Dominique Martin, the director general of the ANSM. He explained that their combination with other drugs “potentiates the risk” of heart rhythm disorders “which can lead to an accident”. This risk is increased in Covid + patients.

For several days, prescriptions for chloroquine, outside the hospital setting, have increased. The ANSM recalled: “in no case should these drugs be used either for self-medication, or on the prescription of a city doctor, or on the self-prescription of a doctor for himself, for the treatment of Covid- 19. ”

This call to order comes when a pharmacist from a large French teaching hospital, correspondent for the Center for pharmacovigilance in his region, recently revealed in Le Point that “cases of Covid-19 positive patients present with associated hydroxychloroquine or no to azithromycin, rhythm disturbances or cardiac conduction. ” He added that some of these judgments have turned out to be “fatal”. At the same time, the ARS of New Aquitaine also warned of “cases of cardiac toxicity” which “have been reported in the region following self-medication of Plaquenil in the face of symptoms suggestive of Covid-19, having sometimes required hospitalization in intensive care. “

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.

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.The side effects, as with many drugs, are very numerous and sometimes frightening, even if some are considered infrequent. 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.

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. 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.

Where is the production of chloroquine at?

Faced with the craze for chloroquine, several laboratories are preparing to relaunch production. “It is an old molecule used against malaria for more than fifty years. So there are significant production capacities, because it is a molecule which is in the public domain. There is no patent and any pharmaceutical company can theoretically produce it. It is a simple production, “Frédéric Bizard, health economist and president of the Health Institute, told RFI. Mylan has thus resumed production and hopes to produce up to 50 million tablets and treat more than 1.5 million patients. Pharmaceutical companies, Novartis, Teva and Sanofi, plan to offer several million doses.

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