This derivative of chloroquine, an antimalarial molecule, has been at the heart of debates since an infectiologist, Didier Raoult, claimed that it is effective against the coronavirus. The Dr Gilles Pialoux, an infectious disease specialist and head of the infectious and tropical diseases department at Tenon Hospital in Paris, answered your questions about hydroxychloroquine.
Pierre_Dog: What is the risk of trying large-scale chloroquine treatment? Is the test protocol suitable for this exceptional situation?
Research should determine the best evaluation criteria and take full account of the feasibility of experiments, such as the sample size. Which was not the case in the small Marseille study. At least four trials have started with hydroxychloroquine.
Recall that the High Council of Public Health (HCSP) recommended not to use hydroxychloroquine, “With the exception of severe hospital forms, on the collective decision of the doctors and under strict medical supervision” !
Vivien: In the discovery trial, why is hydroxychloroquine not associated with azythromicin, when it is this combination that seems to produce the best results, according to Dr Raoult?
Discovery is a European trial coordinated by the National Institute for Health and Medical Research (Inserm) which started on March 22. Eight hundred French patients with severe forms of Covid-19 will be included in this trial (3,200 in Europe). More than twenty French hospitals are expected to participate.
This research is a “randomized” trial (draw) which provides five treatment methods, called arms mixing the antiviral approach and the immunological approach:
- standard care;
- standard care plus Remdesivir (an antiviral developed against Ebola, not marketed);
- standard care plus Lopinavir and Ritonavir (an old anti-HIV molecule);
- standard care plus Lopinavir, Ritonavir and interferon beta (a medicine used to fight lung inflammation);
- standard care plus hydroxycholoroquine.
Hydroxychloroquine will be compared like the other molecules. No more no less. This research trial is done in real time and is scalable. It has a scientific committee and an independent committee. The investigators will be reactive to epidemic outbreaks and develop research as they go, to select the best molecules as quickly as possible. In the presence of too little efficiency, they will stop an arm to switch to other candidate molecules.
Nono: The Discovery study has started. When can we expect results that would lead to the implementation of possible treatments for the population? What is your current perception of the effectiveness of the four treatments currently being tested?
As of March 25, on NIH website, there are more than 130 trials in the world in progress or in preparation, including Discovery, a European trial with eight hundred patients in France. Also including seven with hydroxychloroquine in Norway, the United States, France and China. And this concerns the treatment of severe forms of pneumonia caused by Covid-19 up to post-exposure prophylaxis in a person in close contact with a patient, especially caregivers.
Loisach21: Can you explain to us what are the biases and weaknesses found in the studies carried out by Dr Raoult? If I understand correctly, it was based on Chinese studies, what do they tell us?
The main criticisms of the study published in a journal – whose editor is also a signatory to the study -, beyond the communication, are the following as argued by the Pr Dominique Costagliola, member of the Academy of Sciences:
out of the twenty-six patients treated, we are told that six patients were lost to follow-up – including three for resuscitation on D2, D3 and D4 – one for death on D2, one who was discharged from the hospital (decision of the patient) on D3 and a discontinuation of treatment for an adverse event (nausea) on D3. These six patients are excluded from the analysis and their characteristics are not described, which is contrary to the basic rules of this type of study. A rigorous analysis should have considered these cases as failures. This is for example how we analyze trials in the HIV field where the primary criterion is also a viral load rate below the detection threshold, any missing data, whatever the cause being analyzed as a failure;
there is no clinical data except death and resuscitation;
The article relates only to thirty-six people including twenty of the twenty-six included in the test (out of an expected number of twenty-five according to the European test register) and only these people are described;
The results presented by the authors do not conform to what has been achieved according to the suplementary Table 1. If we exclude the patients not sampled then we compare the effectiveness of 2/11 versus 13/19 (p = 0.021), and in the worst case scenario, the reverse of that chosen by the authors (missing = negative in the untreated and missing = positive in the treated) this becomes 7/16 versus 13/20 p = 0.313, illustrating the low robustness of this study and the statistical effect of the treatment;
The results relating to the addition of azitrhomycin, mainly on patients with pneumonia (four of the six receiving this treatment), are even more difficult to interpret, all the more so since few untreated people have pneumonia and qu ‘none received azitrhomycin;
The analysis appears to have been conducted to favor the “treated” arm.
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