According to teams from the CHRU in Tours, chloroquine “appears ineffective” for patients in serious condition. Update on the controversial molecule …
[Mis à jour le 12 mai 2020 à 11h05] The first conclusions of the Hycovid study, launched in 36 French establishments, are not encouraging as for a possible effectiveness of chloroquine on Covid-19. The New Republic reported that at the CHRU in Tours, doctors and laboratory workers were not convinced of the benefits of hydroxychloroquine (HCQ) in the treatment of coronavirus and its most serious forms. If the HCQ “can sometimes be useful in prevention”, it “appears ineffective when the patient is very sick, placed in intensive care or when the need for oxygen is important”, explained Professor Louis Bernard, head of the service infectious diseases at the CHRU in Tours. In addition, medical teams have noted many side effects already mentioned (chest pain, arrhythmias or myocardial infarction).
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 about 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.
The media and public opinion began to take an interest in chloroquine when, in mid-March, Professor Didier Raoult presented the results of a study, considered to be encouraging. This specialist in emerging tropical diseases, known to take certain liberties with protocols for use in scientific demonstration, had tested on 24 patients a treatment consisting of hydroxychloroquine and azithromycin (an antibiotic). After the tests, 75% were no longer carrying Covid-19. This study was immediately subject to controversy for the small sample of patients tested and for the absence of a control group (group of patients to whom the treatment studied is not administered but a placebo generally, to clearly observe the difference in the evolution of the disease): two parameters considered essential to judge the scientific validation of a result.
The conclusions of a second study on the effect of chloroquine were revealed by Didier Raoult on Saturday March 28. 80 patients were tested this time, which was close to some traditional clinical trials. The median age of the patients was 52 years, 58% presented a comorbidity (hypertension, diabetes, chronic respiratory disease…). For 6-10 days, the patients were again given a combination of hydroxychloroquine (3 x 200 mg daily) and azithromycin. 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 microbiologist delivered this conclusion: “We confirm the efficacy of hydroxychloroquine associated with azithromycin in the treatment of Covid-19.” Again, this study was highly criticized for the absence of control groups: it should indeed be remembered that a large majority of people who contracted the coronavirus recover without any specific treatment, which makes it difficult to analyze the figures of Pr Raoult.
Pr Raoult’s third experiment, in early April, involved 1,061 Covid + patients. The median age was 43.8 years, 46.4% were men and no cardiac toxicity was observed. All received treatment with hydroxychloroquine and azithromycin. Within ten days, virological healing was observed in 91.7% of patients. Five elderly patients died, ten were placed in intensive care and 31 were hospitalized for ten days or more. According to the IHU, the study has shown that when treatment is administered early, it is “safe and effective against Covid-19, with a mortality rate of 0.5% in older patients. aggravation and eliminates the persistence and contagiousness of the virus in most cases. “
Once again, the absence of a control group poses considerable limits, summarized by the epidemiologist Arnaud Fontanet, member of the scientific council Covid-19, on BFMTV: Does hydroxychloroquine work better, less well or the same as other treatments, or even no treatments at all? “.
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 concerns 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 “receive either hydroxychloroquine or a placebo, without knowing the nature of the tablet tested”. Pr Vincent Dubée, principal investigator of the project, assured that the study is “carried out under conditions which will not leave room for doubt in the analysis of the results.”
The combination of hydroxychloroquine and azithromycin is also being tested by a department of Paris hospitals (AH-HP): a study involves 900 caregivers to assess the preventive effectiveness of this treatment. Each third is either hydroxychloroquine, antibiotic, or placebo. Named PrEP COVID, the first results of this clinical trial should be known within 70 days.
These studies come entirely 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. The results are expected in late April. However, this study raises some reservations. Professor Christian Perronne, head of the infectious diseases department at the Garches University Hospital, notably refused to participate. The program “does not take into account Professor Raoult’s protocol, but only hydroxychloroquine, and this in cases in aggravated pathologies. For this, this test shows an absence of ethics”, he said. stormy in Marianne.
Pending the conclusions, Olivier Véran acknowledged that no experiment had demonstrated significant results. “I have elements which come back to me from hospitals which do not show, at this stage – I am extremely careful – a statistically significant effect of one or the other of the molecules [NDLR: chloroquine et hydroxychloroquine]”said the minister on BFMTV.
A study carried out in four hospitals in Île-de-France questions the effectiveness of chloroquine and hydroxychloroquine in the treatment of the new coronavirus. The experiment, reported on the Medrxiv site, involved 181 Covid + patients suffering from pneumonia and requiring respiratory assistance. “84 [malades] received hydroxychloroquine within 48 hours of hospital admission (HCQ group) while the other 97 (non-HCQ group) did not take it, “the article wrote. 20.2% of patients treated with hydroxychloroquine were transferred to intensive care or died, compared to 22.1% in the control group. Doctors described significant side effects: 27.4% of patients on hydroxychloroquine developed acute respiratory distress syndromes seven days after starting treatment (24.1% in the control group) and eight individuals had to discontinue it due to cardiac abnormalities. “interpret with caution” these data, they concluded that “these results are of major importance and do not encourage the use of hydroxychloroquine in patients with pneumonia due to Sars-Cov-2”.
Chloroquine has been the subject of a new clinical trial. The study, pre-published on the MedRxiv site, admits that “hydroxychloroquine must be prescribed for the treatment of seriously ill Covid-19 patients in order to save lives”. The experiment was carried out by three Chinese practitioners from Tongji Hospital in Wuhan. This study involved 568 Covid + patients who presented with severe acute respiratory distress syndromes, despite antiviral therapy. 48 patients received, in addition to antivirals and antibiotics, 200 mg of hydroxychloroquine (HCQ) for 7 to 10 days. The research team admitted that the mortality in the HCQ group was 18.8% compared to 45.8% in the “control group”. “Treatment with hydroxychloroquine is significantly associated with a decrease in mortality in critically ill patients with COVID-19,” concluded the authors.
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 conventional 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, against 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 a 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, according to Heidi.news, a specialist journal, this study was not corrected by experts and the initial protocol was not respected, it provided for a double-blind trial on two groups of one hundred patients.
Another study, published on March 3 on the website of ZheJiang University, south of Shanghai, gave results that are 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 evaluate its effects by “randomizing” the doses, the power of the treatment and by evaluating the relevance of choloroquine according to severity cases.
What tests have been done on chloroquine in the United States?
The only American study on chloroquine is not encouraging. This randomized experiment, published in the New England Journal of Medicine, studied the effect of HCQ on 811 patients (at a rate of 1200 mg the first day, then 400 mg for 4 days). 565 patients did not receive the drug. Ultimately, the research team observed that “the risk of intubation or death was not significantly greater or less among patients who received hydroxychloroquine than among those who received nothing”.
“At very high doses, chloroquine can kill”, bluntly alerted on March 30 in Le Parisien, Professor François Bricaire, member of the Academy of Medicine. Le Monde reported that since March 27, 54 cases of cardiac disorders – including seven fatal – have been identified at the regional pharmacovigilance center (CRPV) in Nice, responsible for the national surveillance of cardiac adverse effects of drugs evaluated in the infection to the new coronavirus. Taking hydroxychloroquine alone or in combination with azithromycin is believed to be involved in nine of the deaths.
Dominique Martin, the director general of the National Agency for the Safety of Medicines (ANSM), called for caution: “Pending the results of the numerous clinical trials in progress, it is legitimate to reserve the prescriptions of these products for the hospital environment “.
Overdosage of chloroquine can be very dangerous. The molecule is considered to be a drug with a narrow therapeutic margin, i.e. the difference between the effective dose and the toxic dose is small. The main symptoms of poisoning are: cardiovascular disorders, digestive disorders (nausea and vomiting) and neurosensory signs. According to the French Network of Regional Pharmacovigilance Centers, whatever the dose supposed to be ingested, any chloroquine poisoning requires prehospital care by a mobile emergency service.
Performing an ECG before and during treatment is strongly recommended. It can lead to cardiomyopathy, conduction and heart rhythm disorders (atrioventricular block, prolongation of the QTc interval, torsades de pointes, ventricular tachycardia, ventricular fibrillation). Other side effects may occur: gastrointestinal complaints, mucocutaneous effects (especially pruritus and rashes), hematological disorders, psychiatric disorders, nervous system disorders (headache, dizziness and convulsions), metabolic disorders, eye effects (exceptional cases of retinopathies linked to the accumulation of the molecule and which can lead to irreversible damage to the macula) and hepatobiliary disorders.
In addition, certain contraindications should be noted: in the event of allergy to chloroquine or hydroxychloroquine, retinopathy or certain drug interactions (in particular with citalopram or escitalopram, domperidone, hydroxyzine or piperaquine). Finally, the treatment requires precautions for use in diabetic, epileptic, cardiac subjects, suffering from Parkinson’s disease, suffering from porphyria or having disorders of serum potassium or magnesemia. The Network recommends that chloroquine and hydroxychloroquine be avoided during pregnancy “unless the clinical situation justifies the use of the treatment in view of the potential risks incurred for the mother and the fetus.”
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