Are hydroxychloroquine and chloroquine, molecules commonly used against malaria or certain autoimmune diseases, effective in treating covid-19 patients? The question mobilizes the scientific community. Mode of action side effects, contraindications, prescription against coronavirus
What is chloroquine?
Chloroquine, as found in Nivaquine®, is an antimalarial drug. Its marketing authorization dates back to 1949. It is its salt, chloroquine sulfate, which is then used, in prevention and treatment of malaria, but also in the treatment of rheumatoid arthritis, certain forms of lupus, and in prevention of severe forms of sun allergy (lucitis).
Currently, this molecule is very little prescribed in these indications. It is no longer even used for malaria prevention, the parasite causing the infection having become resistant to it.
What is the difference with hydroxychloroquine?
Plaquenil®, the only pharmaceutical specialty containing hydroxychloroquine, is a derivative of chloroquine. It is considered to be two to three times less toxic and better tolerated than chloroquine. Unlike Nivaquine®, marketed in the form of 100 mg chloroquine tablets, Plaquenil® tablets are dosed with 200 mg of hydroxychloroquine.
Its marketing authorization indicates that it can be prescribed to treat rheumatoid arthritis, systemic lupus erythematosus, or to prevent sun allergy. Currently, Plaquenil® is preferred over Nivaquine® in these three indications.
At what doses are hydroxychloroquine and chloroquine used?
- To prevent malaria, chloroquine was used at a dose of 100 mg, one tablet per day during the whole stay in the endemic area, and up to 4 weeks after returning.
- As part of the treatment of rheumatoid arthritis, the French National Authority for Health recommends a dosage of 100 to 300 mg of chloroquine or hydroxychloroquine per day in several doses. The same dosage is recommended for prevention of sun allergy.
- In lupus, the health authorities recommend the dose of 100 to 200 mg per day.
What are the main side effects of hydroxychloroquine and chloroquine?
Both of these drugs can cause digestive upset, such as nausea, vomiting or diarrhea, and cause severe hypoglycaemia (decreased blood glucose levels). Sleep disturbances, headaches or itching are also common. Very important: these drugs can be toxic to the retina and require regular ophthalmological monitoring.
Monitoring is also essential for people suffering or having suffered from heart disease. Indeed, hydroxychloroquine and chloroquine can expose you to a cardiac risk. This cardiac toxicity is dependent on the dose administered and serious cases of arrhythmia have been reported during overdose, but also at usual therapeutic dose.
Hydroxychloroquine and chloroquine are indeed so-called “narrow therapeutic margin” drugs, which means that the effective dose and the toxic dose are relatively close.
This is why, even if these drugs are not formally contraindicated in the event of disease or disorder of the heart, the doctors always carry out an electrocardiogram (ECG) before the initiation of the treatment, a second within 3 to 4 h following the first administration, then twice a week for the duration of treatment and in the event of symptoms which may suggest a disturbance of the heart rhythm such as dizziness or palpitations of recent appearance.
What are their contraindications?
Retinal diseases, or an allergy to the components, are formal contraindications to the use of chloroquine and hydroxychloroquine. These molecules are also incompatible with certain chronic diseases or treatments.
The Medicines Agency (ANSM) thus warns in a notice published on March 30 of a potential risk of interaction with a patient’s usual treatments, which increases their toxicity. Within the framework of its marketing authorization, hydroxychloroquine is for example contraindicated with citalopram (Seropram and generics), escitalopram (Seroplex and generics), hydroxyzine (Atarax and generics ), domperidone (Motilium and generics) and piperaquine (Eurartesim).
Only your attending physician can determine whether this prescription is justified.
Are there any precautions to take for pregnant, breastfeeding women or children?
These two molecules can be prescribed for children, but the dosages will be adjusted by the doctor’s weight. However, it is not possible to take them during pregnancy or breastfeeding. The risk: an abortion, or an ocular malformation.
Chloroquine and hydroxychloroquine cross the placental barrier, are found in breast milk, semen, several months after treatment. If you are a man or woman of childbearing age, you should use effective contraception during treatment and up to 8 months after the end of your treatment.
What studies are being conducted to test the effectiveness of these molecules against Covid-19?
Chinese scientists were the first to take an interest in hydroxychloroquine in the treatment of Covid-19. Several studies, in vitro (on cells) and in vivo (on patients) have been carried out, but only the one of March 6 caught the attention of international researchers for its compliance. Published on March 6 by the Zhejiang University newspaper, this study involved 30 patients with Covid-19. Of these patients, half took hydroxychloroquine, the other half received conventional care.
After seven days, 13 of the 15 patients following this treatment tested negative, meaning that the coronavirus had disappeared from their organism. In the group that did not ingest hydroxychloroquine, 14 of the 15 patients no longer had Covid-19 at the end of the experiment. Patients in both groups therefore took approximately the same time to heal.
Discovery clinical trial
On a European scale, the Discovery clinical trial started on March 22 with the inclusion of the first patients at Bichat Hospital in Paris and at the Lyon University Hospital.
All included patients receive treatment, the trial being said to be “5-armed”, that is to say that it started with 5 treatment modalities. Several molecules are being tested: remdesivir, the combination lopinavir and ritonavir, the combination lopinavir, ritonavir and interferon beta, and finally hydroxychloroquine.
IHU Mediterranean Infection Studies
In France, eyes are on Pr Didier Raoult, whose team is located in Marseille. In a study published on its website on March 28, the University Hospital Institute (IHU) Méditerranée Infection and the Mephi research unit (Microbes Evolution Phylogeny and Infection) of Aix-Marseille University recommend a dual therapy combining hydroxychloroquine and an antibiotic, azithromycin, to treat Covid-19 infection. This study was carried out on 80 French patients hospitalized and tested positive for Covid-19.
Professor Raoult’s team claims to have achieved excellent results: 78 of these patients experienced rapid “clinical improvement” in their health and were able to leave intensive care after five days. Only one, 86, died and another, 74, is still in very serious condition.
However, it is impossible to draw any formal conclusions because no comparison with an equivalent and untreated group of patients has been made. Not to mention that, as the geneticist Axel Kahn points out, “the known data on 600,000 cases (note: of covid-19 disease) are: 85% of mild cases, 15% of severe cases, 5% of cases in intensive care . Figures also found in the 80 people treated at the Marseille IHU. “
Can we say that hydroxychloroquine is effective in the treatment of Covid-19?
Not at the moment. After a first study on only twenty patients, this second study carried out by Pr Raoult’s team is no more conclusive for the scientific community. Its main flaw: no control group has been set up. Composed of patients who receive only standard care but not hydroxychloroquine, this control group is nevertheless essential to measure the effectiveness of the treatment tested. Without a control group, it is difficult, if not impossible, to make a comparison to determine whether the treatment, in this case the hydroxychloroquine / azithromycin combination, is the source of the improvement.
Researchers at the IHU tried to fill this gap by comparing their results to other studies with “control” groups. Among them, a clinical study conducted in Wuhan, the Chinese city in which the epidemic began, in which 28% of patients died. Initially published in the very prestigious journal The Lancet, this study was carried out on 191 patients in China and the criteria for admission of the patients were clearly different, since they all presented severe forms of the disease (cough, respiratory distress and fever ) and almost half of the co-morbidities, such as chronic disease. In Prof. Raoult’s cohort, the profile of the patients was different: if 95% of them had respiratory problems, only 15% were febrile, or 12 of them. 4 patients had no symptoms of Covid-19. Difficult under these conditions to compare mortality rates, and therefore the effectiveness of treatment.
The first results of the Discovery study are expected for the week of April 6, but it will take more time for them to be analyzed and for the data collected to demonstrate the superiority of one treatment over the other. Inserm researchers specify that this clinical trial is “adaptive”, that is to say that the experimental treatments appearing to be ineffective may be abandoned and the patients included will then be able to switch to the most effective treatment if the study reveals it sooner than expected. For the time being, it is this study that the French health authorities have decided to follow to issue their recommendations.
What do we know about their mode of action against the coronavirus?
According to an article published in the journal Cell Research on February 4, chloroquine and hydroxychloroquine would prevent the steps of entry and exit of the virus Sars-CoV-2 in cells cultivated in vitro, thus effectively stopping its replication and its spread. In real life, these treatments would reduce the viral load, and therefore the time it takes to carry the virus, as scientists from the IHU Mediterranean say. In their last study, the viral load in the nasopharyngeal swabs tested daily shows a significant reduction 6 days after inclusion, always in the absence of a control group.
It is important to note that Plaquenil® is anti-inflammatory and immunomodulatory. This is why it is used in the treatment of lupus and rheumatoid arthritis. It would help “re-educate” the immune response.
In summary, although there is a biological plausibility supported by in vitro studies, chloroquine and hydroxychloroquine could influence the regulatory mechanisms of inflammation and the destruction of pathogens, the exact role of these drugs in the pathophysiology of viral coronavirus infection in humans remains unknown to this day.
Why is chloroquine controversial in the scientific community?
The scientific community is concerned about the reliability of the results obtained by the Chinese and French teams on patients with Covid-19. They fear unreasonable runaway and point to the fact that studies have not yet proven the effectiveness of these molecules on covid-19: they have only involved small numbers of patients and have not respected several modalities in force in the publication of scientific articles.
In addition, the median age of the patients included by Dr Raoult’s team is 52 years, and, according to the data relating to all French patients, these people would have, basically, much less risk to be in serious condition or even die from Covid-19. Added to this is the excitement of the population around a so-called “miracle” drug, some of which seem to omit serious adverse effects, formal contraindications, and above all cardiac monitoring at any age, necessary before and during treatment.
Which Covid-19 patients could be treated with hydroxychloroquine?
Scientists at the IHU Méditerranée Infection recommend the use of dual therapy (hydroxychloroquine and azithromycin) in all patients tested positive for Covid-19. According to these researchers, the sooner the better. The objectives: to reduce the viral load, therefore the portage and with, the contagiousness.
If the symptoms are already significant, then it is a question of limiting the vital emergency, and in particular the associated respiratory distress. Thus, even before the publication of the decree framing its prescription, some hospital doctors had decided to administer the hydroxychloroquine / azithromycin combination to patients hospitalized in serious condition and in respiratory distress.
The combination used by Pr Didier Raoult’s team is a combination of hydroxychloroquine (Plaquenil®) 200 mg three times a day for 10 days, and azithromycin 500 mg on the first day, then 250 mg per day for 5 more days. These doses are two to three times higher than those used in the treatment of lupus or rheumatoid arthritis, and are well known to doctors. This is why this dosage and this indication for the use of hydroxychloroquine are called “off-label” (marketing authorization).
What about the current authorized prescription of hydroxychloroquine to Covid patients?
To regulate the prescription of hydroxychloroquine outside the framework of ongoing clinical trials, a decree has been published authorizing its dispensation in an exceptional manner, “for patients suffering from pneumonia requiring respiratory assistance or organ failure”, and in the event of severe pneumonia (oxygen-requiring), after discussion, on a case-by-case basis and failing the association between lopinavir and ritonavir, two antivirals.
This prescription must be a collegial decision shared with the entire medical team that follows the patient to the hospital and complies with current national recommendations. The maximum dosage of hydroxychloroquine in the treatment of SARS-CoV-2 virus infection is 600 mg per day (3 tablets of 200 mg per day). A therapeutic protocol, which defines the modalities of use of Plaquenil, can be consulted on the ansm.sante.fr website. This derogatory prescription only concerns serious cases in a hospital environment.
As for the combination of hydroxychloroquine and azithromycin, the Medicines Agency specifies that it should only be considered in the context of clinical trials.