Samedi 16 mai 2020. Décryptage (!) à propos de la chloroquine : mauvaise foi des détracteurs...

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J’ai vu paraître dans je ne sais plus quel journal un article qui faisait état de deux publications démontrant l’inutilité, voire la dangerosité de la chloroquine et de l’hydroxychloroquine. Bien entendu, j’ai cherché. Je n’ai trouvé qu’un article de FERNER et ARONSON, paru dans le British Medical Journal, le 8 avril. Il est intitulé Chloroquine and hydroxychloroquine in Covid-19. Use of this drug is premature et potentially harmful.

Je pensais trouver le résultat d’une étude clinique, exposant les matériels et méthodes utilisés, les résultats virologiques, cliniques, radiologiques. Que nenni. Il s’agit d’un article EDITORIAL de dénigrement systématique qui comprend deux sections : l’une intitulée Laboratories studies, l’autre Poor methods and reporting.

En fait, il n’agit d’une pseudo méta-analyse superficielle, et que je trouve personnellement scandaleuse. Il faut aller à la conclusion pour savoir où les auteurs veulent en venir, et là on comprend tout, notamment la mauvaise foi avec laquelle ils traitent les données. Je vous donne la conclusion en anglais.

We sorely need an effective treatment for Covid-19, but prevention by vaccine or treatment with drug that target specific structures in the virus are more likely to succeed than old drugs that work in the laboratory but lack data supporting clinical use.

Il faut aller ensuite jusqu’au bout et lire ceci, en tout petits caractères. Provenance : Commissioned, not externally peer reviewed. Il s’agit donc d’un article de commande qui n’a pas été analysé par des referees extérieurs au journal.

Allons maintenant lire un autre article, autrement plus sérieux, publié dans European Review for medical and pharmacological sciences, 20, 4539-4547, 2020, par MEO, KLONOFF et AKRAM, trois auteurs exerçant, le premier en Arabie Saoudite, le second en Californie, et le troisième au Pakistan. Il s’agit d’une méta-analyse de neuf publications, de trois essais cliniques et de trois conférences de consensus. Je vous livre, en anglais quelques extraits de cet excellent article, à la fois prudent, factuel, et objectif. La mise en caractères gras est de votre serviteur.

" The present outbreak of COVID-19 infection markedly affected countries which are malaria-free, such as Italy 86498 (15.13% of the total cases in ma- laria non-pandemic countries), United States 85228 (14.90%), China 82230 (14.38%), Spain 64059 (11.20%), Germany 48582 (8.49%), France 32542 (5.69%), Switzerland 12104 (2.11%), and United Kingdom 14547 (2.54%). The findings from WHO incidence data demonstrate that COVID-19 is highly pandemic in countries where malaria is least pandemic, and COVID-19 is least pandemic in nations where malaria is highly pandemic (Figures 1-3). The findings were significantly correlated (Figure 3). Assuming that in malaria-endemic countries a significant fraction of the population uses chloroquine or hydroxychloroquine regularly, this international malaria incidence and COVID-19 incidence data, is consistent with (although not proof of) a beneficial effect of hydroxychloroquine and chloroquine in restraining the replication of SARS-CoV-2 virus causing COVID-19 (Table I)."

Je poursuis en vous donnant aussi la discussion

"In this study, we tested the hypothesis that hydroxychloroquine and chloroquine could be useful for treating COVID-19. From the epidemiologic data we identified, we could not refute this hypothesis. In the current pandemic crisis of COVID-19, there is no proven recommended therapy for COVID-19 other than supportive care.

Chloroquine, a widely used anti-malarial has been reported as a potential broad-spectrum antiviral drug10,11. Chloroquine blocks viral infections by increasing endosomal pH which then interferes with virus/cell fusion. This drug also interferes with the glycosylation of cellular receptors for SARS-CoV and hence decreases virus-cell binding12.

Wang et al13 reported that chloroquine works at entry and post-entry phases of the 2019-nCoV infection in Vero E6 cells. It has an additional immune-modulating activity, which may enhance its antiviral effect in vivo if used collectively. Moreover, the concentration of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achieved, as demonstrated in the plasma of rheumatoid arthritis patients who received administration of 500 mg.

Chen et al14 investigated the effectiveness and safety of hydroxychloroquine in the treatment of COVID-19 patients. The authors enrolled total 30 subjects (15 with a COVID-19 infection and 15 controls). The subjects were randomized 1:1 to a hydroxychloroquine group and a control group. Subjects in the hydroxychloroquine group received hydroxychloroquine 400 mg per day for 5 days while those in the control group received only conventional treatment. The primary endpoint was a negative conversion rate of COVID-19 nucleic acid in a respiratory pharyngeal swab on day 7 after randomization. COVID-19 nucleic acid in throat swabs was negative in 13 (86.7%) cases in the hydroxychloroquine group and 14 (93.3%) cases in the control group. The median duration from hospitalization to virus nucleic acid negative conversion was 4 days in hydroxychloroquine group, which was comparable to that in the control group 1-4 days. The median time for body temperature normalization in the hydroxychloroquine group was 0-2 days after hospitalization, which was also com- parable to that in the control group 0-3 days. Radiological progression was shown on CT images in 5 cases (33.3%) of the hydroxychloroquine group and 7 cases (46.7%) of the control group, and all subjects showed improvement in follow-up examinations. Four cases (26.7%) of the hydroxychloroquine group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function. A problem with interpreting whether hydroxychloroquine was beneficial in this study was the high conversion rate of the control subjects (14 of 15), leaving little room for a statistically significant better outcome to be achieved with any intervention.

Gautret et al15 performed a clinical trial study on subjects with COVID-19 infections who received 600 mg of hydroxychloroquine daily. The authors found that hydroxychloroquine was associated with viral load reduction and viral disappearance in these COVID-19 subjects. Moreover, its impact was magnified by the addition of azithromycin. This latter drug has been shown to block viral internalization into host cells16.

Yao et al17 and Liu et al4 conducted in vitro studies on COVID-19. Cells were infected with nCoV-2019BetaCoV/Wuhan/WIV04/2019. The pharmacological properties of chloroquine and hydroxychloroquine were investigated by using SARS-CoV-2 infected Vero cells. It was found that chloroquine was highly effective in the control of 2019-nCoV infection in vitro. Hydroxychloroquine was more potent than chloroquine in inhibiting SARS-CoV-2 in vitro.

Gao et al18 conducted a clinical trial on 100 COVID-19-infected Chinese patients. The au- thors presented their findings in a scientific session with a team of experts from government and regulatory authorities, along with organizers of clinical trials. They noted that chloroquine had a significant effect both in terms of clinical outcome and viral clearance compared to control groups. Chloroquine was found to be useful in inhibiting the exacerbation of pneumonia, improving lung imaging, and bringing about virus-negative results, therefore shortening the disease’s course. The experts group concluded that chloroquine phosphate has potent activity against COVID-19 and added the drug in the guidelines for the prevention, diagnosis, and treatment of pneumonia caused by COVID-19 under the National Health Commission of the People’s Republic of China.

Zhou et al19 demonstrated that hydroxychloroquine could provide better outcomes than chloroquine for the treatment of SARS-CoV-2 infection. The authors highlighted three likely mechanisms for how these two drugs are beneficial for protecting from the development of and complications from COVID-19 virus infections: (1) inhibition of receptor binding by the virus; (2) inhibition of membrane fusion by the virus; and (3) immune modulation to decrease cytokine release. Hydroxychloroquine appears to decrease the dangerous progression of COVID-19 toward cytokine storm by reducing CD154 expression in T-cells. Moreover, the authors suggested that hydroxychloroquine, compared to chloroquine, has fewer side effects, and is more potent at max- imum tolerated doses.

Finally, consensus reports were published by experts 202020-22 under multicenter collaboration by the Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Consensus and State Council of China. These expert groups recommended chloroquine phosphate tablet, 500 mg twice per day for 10 days, for patients diagnosed as mild, moderate, and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine.

In the present study, besides reviewing evidence supporting the hypothesis that chloroquine and hydroxychloroquine might be useful for COVID-19 infections, we also established a possible correlation between the outbreak of COVID-19 and its spread in malaria pandemic nations. The present outbreak of COVID-19 infection has markedly spread to countries and continents which are Malaria-free such as China, Italy, United States, Spain, Germany, France, Switzerland, United Kingdom and Iran. However, its incidence is very low in south-east Asian and African countries where malaria is pandemic (Table IV, Figures 1-3), despite most of these countries’ health infrastructure being quite fragile. A possible explanation behind this could be that these latter nations frequently suffer from malaria and the population frequently takes anti- malarial drugs including hydroxychloroquine and chloroquine.

These two drugs, which are malaria treatments might be linked to the lower reported incidence of COVID-19 infections in these malaria-endemic countries, compared to many malaria non-endemic countries, because chloroquine appears to have broad-spectrum antiviral properties22. The possible mechanism of antiviral intervention by chloroquine is a multi-targeted mechanism, de- pending on the time point at which the drug is added. When added during and shortly after the infection, chloroquine may raise intracellular pH and then inhibit the endosome-mediated fusion of the virus with human cells. When the drug is given after this first target, it can still act on later stages of the viral life cycle, as reported for other viruses23. We believe it is significant that on March 29, 2020 the United States Food and Drug Administration issued an emergency use authorization for hydroxychloroquine and chloroquine for COVID-19 infections24.

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Comme je ne veux pas trop charger la barque, je vous donnerai demain le résumé de deux articles démontrant l’intérêt et/ou l’efficacité de ces molécules. Les puissances d'argent feront tout pour démolir l'évidence. Mais les faits restent les faits, et les opinions... des opinions ou, pire, des croyances intéressées.