Paris (AFP)
More than four months after the emergence of the new coronavirus, no treatment has yet proven its effectiveness, but some encouraging data are starting to emerge, among the hundreds of clinical trials already launched.
Block the entry of the virus into cells, prevent its replication, control the body's immune response ... All avenues are being explored to enable patients to better fight this multifaceted disease, which has killed more than 260,000 people in the world.
- A "research epidemic"
More than 800 clinical trials seek to assess dozens of potential treatments, according to the medical journal The Lancet (https://covid-trials.org/), including more than 300 in China, 125 in the United States and 45 in France.
Professor Florence Ader, who is piloting the European Discovery trial, moderates the enthusiasm generated by this "research epidemic", with many "aborted" trials, including very few patients or with insufficient methodologies " robust ". And advises to concentrate efforts on some "big studies". Many researchers also call for not sacrificing scientific rigor, so as not to "raise false hopes".
But at the same time, researchers and labs all dream of announcing the first "the" solution to Covid, and some leaders do not hesitate to promote leads with unproven effectiveness.
In the United States and France, large institutes have created controversy by announcing "positive" results before their work is fully published.
However, we are still awaiting the results of Discovery, which relates to four existing treatments. French President Emmanuel Macron announced a "milestone" next week, but the most likely is that no "signal of effectiveness" will emerge for several more weeks, according to researchers participating in the study, due to '' longer than expected patient recruitment.
- Remdesivir: contradictory data
This experimental antiviral was developed by the American laboratory Gilead to counter Ebola, a goal for which it proved to be ineffective. But it has blocked the replication of other viruses in the laboratory.
It exploits a weakness of RNA viruses, which include coronaviruses: during replication, they can mistakenly incorporate parts of this molecule into their genetic heritage, which makes them non-functional.
But the data on its effectiveness against the Covid-19 remain contradictory and fragmented.
In the United States, which relies heavily on this drug, the FDA urgently authorized its use outside of clinical trials on hospitals on May 1, based on a large public trial which concluded that it shortened by four days ( median duration) recovery from severely ill patients, increased from 15 to 11 days.
A result described as "modest" by many researchers, even if others see it as a way to reduce the saturation of hospitals. And the full results of the study have not been released, drawing criticism in the scientific community.
In addition, the study does not make it possible to say whether remdesivir reduces mortality, because the difference obtained (8% of the treated patients, against 11.6% in the control group) is below the threshold of statistical reliability.
"If there were 15% or even 10% decrease in mortality, we would not even ask the question. There, there is really debate" on the interest of expanding the use of this molecule, said AFP Yazdan Yazdanpanah, infectious disease specialist at the head of the REACTing research consortium.
Especially since another smaller trial in China, published in The Lancet, concluded that there was no clinical benefit.
Some also believe that this drug is more likely to act on the early stage of the disease, before the virus has done too much damage.
- Tocilizumab: hope for severe forms
For the second phase of the severe forms of Covid-19, less marked by the action of the virus than by an uncontrolled inflammatory reaction of the organism, called "cytokine storm", another family of drugs is tested: immunomodulators, including tocilizumab, sarilumab or even anakinra.
These are monoclonal antibodies, created from mice whose immune systems have been "humanized". When exposed to live or attenuated viruses, they produce human antibodies, which are then multiplied in the laboratory.
At the end of April, the Parisian hospital group AP-HP announced that tocilizumab reduced "significantly" the risk of dying or going to resuscitation in Covid-19 patients in serious condition, but without precise figures or publication of the study.
Premature communication according to the experts of the study's monitoring committee, who resigned en bloc.
Other clinical trials are underway. A Dutch study published in Nature on Monday also showed that monoclonal antibodies specifically targeting a protein on the surface of Sars-CoV-2 were able to neutralize it in vitro.
But even if they are effective, the high cost of these biomedicines and their intravenous administration are obstacles to their generalization.
- Hydroxychloroquine: praised but not proven
The antimalarial chloroquine and its derivative hydroxychloroquine, used in particular in the treatment of lupus, have an in vitro action on many viruses, including Sars-CoV-2: they create a hostile environment for the virus by increasing the pH of the cell it seeks to infect.
But they have never shown effectiveness in real conditions, or even worsened the condition of patients in certain diseases.
Some researchers and leaders tout this molecule, sometimes combined with an antibiotic, as a possible solution to the Covid-19 pandemic, but the studies published so far do not allow to conclude.
The Didier Raoult IHU Mediterranean Infection in Marseille published a study on Tuesday concluding with a low mortality rate, with eight deaths in a thousand patients (compared to only five in a summary of the study in early April). But this level is comparable to that observed in the case of a natural course of the disease.
A study carried out in New York hospitals and published Thursday in the American journal NEJM shows that hydroxychloroquine has neither improved nor significantly deteriorated the condition of patients in serious condition. Other studies are underway in several countries.
And pharmacology specialists believe that for it to work, it should be administered in extremely high doses, which would be toxic or even fatal.
Health officials have also warned of serious side effects on the heart, which may be more common in people with coronavirus.
- False leads?
The combination of two anti-HIV drugs, lopinavir and ritonavir, has yet to deliver.
A Chinese study published in the NEJM on March 19 concluded that this treatment did not reduce either the mortality or the recovery time. However, there is some evidence to suggest efficacy if administered early.
A small Hong Kong study published in The Lancet on Saturday finds improved efficacy in combination with two other antivirals (ribavirin and interferon beta), reducing the time from 12 days (dual therapy) to 7 (triple therapy) presence of the virus in patients with a moderate form of Covid-19.
Other larger trials are underway.
Also evaluated at the beginning of the epidemic, the treatment of inflammation with corticosteroids presents a risk of promoting other infections and delaying the elimination of the virus.
- Cured blood plasma
The idea is to transfuse the blood plasma of healed people to the sick, to eliminate the virus faster and reduce its damage.
Trials were launched in April and this treatment was authorized in hospitals, notably in France, the United States, China and Austria, which announced convincing results on three patients on Thursday.
But the French Academy of Medicine has drawn limits: the number and effectiveness of antibodies are "very variable from one donor to another" and there is a risk of side effects or transmission of other agents infectious.
Rather, it relies on "hyperimmune immunoglobulins", produced from the plasma of patients with many antibodies. They could be used "not only for the treatment of severe forms", but also "for prevention in relatives" of patients and "from the start of infection in fragile subjects".
- New tracks to clear
Dozens of other less publicized avenues are explored, in particular through "repositioning" programs (review of already existing molecules). Like chlorpromazine, an antipsychotic, which will be the subject of a first clinical trial in France.
This strategy saves time: it is either drugs already on the market, or molecules still in development but whose non-toxicity for humans is already established.
The downside: we will probably not find in this category a miracle molecule, "warns Florence Ader. These drugs are not" initially designed to target the virus ", their possible effectiveness" will not be complete, but partial " .
To have "second generation molecules", created specifically to attack Sars-CoV-2, you will have to be patient, she recalls: researchers are still working to "dismember" the genome and structure of the virus, to analyze it "compound by compound" and identify "relevant targets" for future treatments.
© 2020 AFP