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How do you deal with a new disease? Identifying the infectious agent, understanding the disease and finding an effective treatment... The emergence of Covid-19 represented a "real challenge" for Jacques Reynes*. The infectiologist describes a "totally unprecedented" situation in which "everything was done in a hurry". Interview with the head of the Department of Infectious and Tropical Diseases at Montpellier University Hospital.

Jacques Reynes, infectious diseases physician and head of the infectious and tropical diseases department at Montpellier University Hospital.

How do you develop a treatment for a previously unknown infectious disease?
The first thing to do is to identify the infectious agent. Once we know which family it belongs to, we can draw up a list of potential anti-infectives. To do this, we first look at molecules that have been used to treat similar infections. In the case of Covid-19, an infection linked to the SARS-Cov2 virus, this was the third time we had had to deal with a highly pathogenic coronavirus, so we had data from the SARS-Cov 1 and MERS-Cov epidemics. This first stage enables us to seek an emergency treatment, but Covid-19 is really a new, complex disease, with a highly polymorphic clinical presentation, and we had few known potentially effective products.

What do we do in this case?
If we don't have any known products, we switch to a repositioning strategy. In other words, we consider a drug already used to treat another disease. Therapeutic molecules often have several cellular targets, so a molecule evaluated for a specific disease may also be effective for another. Repositioning a drug saves time: the molecule has already been evaluated in terms of toxicity and tolerance. For Covid-19, there has been an explosion of trials with repositioning products, such as hydroxychloroquine initially used against malaria or to treat certain autoimmune inflammatory diseases such as lupus or rheumatoid arthritis; lopinavir/ritonavir used in HIV infection, or remdesivir, a broad-spectrum antiviral already tested against the Ebola virus. In the first wave of Covid-19, all patients were treated with repositioning products.

How do you identify the right repositioning products?
To be a good candidate, a molecule must meet several conditions. Firstly, it must have in vitro activity against the virus - in this case SARS Cov-2 - i.e. it must inhibit the virus. But it must also be effective at a concentration that can be tolerated by the infected organism. If it's only effective against the virus at a concentration that's toxic to humans, it's not a candidate. It must also have ad hoc pharmacokinetics - the fate of drugs in the body. In the case of Covid-19, for example, the virus is present in the lungs, so we need to find an antiviral that reaches this organ in sufficient quantity to be effective.

And after in vitro testing?
The molecule is evaluated in an animal model. But the choice of model is not always straightforward: the animal must be sensitive to the virus and develop the disease in a form relatively similar to humans. Remdesevir and hydroxychloroquine, for example, have been tested on rhesus macaque monkeys. Clinical trials in humans will then be launched. There are some very promising products, which work very well in vitro, but prove ineffective in clinical trials. This is the case, for example, with hydroxychloroquine, for which the various trials have now shown little or no efficacy, even though it was a logical repositioning product. And even once an effective candidate has been identified, the drug still needs to be rapidly produced at an acceptable cost. So far, 6 or 7 antivirals have been tested.

Is inhibiting the coronavirus the main objective?
It is, but it's not the only one! With Covid-19, we're not just dealing with a virological disease. So we're looking not only for a specific drug against the virus, but also for drugs that are active against the complications of this infection. In this way, we can observe severe lung damage linked to inflammation, the consequence of a cytokine storm. At this stage, patients are given corticosteroid therapy and/or cytokine inhibitors. Patients are also prone to vascular thrombosis with embolic phenomena, justifying prevention or treatment with anticoagulants. So it's not just one drug, but a cocktail of drugs that needs to be administered, with precise timing! For example, corticosteroid therapy should not be started at the beginning of the disease, whereas antivirals are probably useful in the initial phase, when viral multiplication is intense. Not to mention non-drug management: for Covid-19, for example, we've discovered that it's better to put patients in intensive care on their stomachs.

Was the whole process of developing a treatment for Covid-19 unusual?
It's not the journey that was unusual, but the rapid succession of stages - everything accelerated! There was a real change in the time scale compared with other epidemics, which was totally unprecedented. During the first month of the epidemic, we learned more about this disease every day! The studies were carried out in record time: what usually takes 3 to 6 months was achieved in 15 days. It's the first time in my career that I've been involved in a situation like this, and it's a real challenge requiring a high level of responsiveness!


* UMR TransVIHMI (UM, IRD, INSERM U1175, Université Check Anta Diop (Dakar, Senegal), Université Yaoundé 1 (Cameroon))