What is treated with COVID-19: list of drugs and conditions for their use

In the past two weeks, the flow of news about the discovery of drugs for the treatment of coronavirus infection, about the beginning of clinical trials of new substances or even the use of drugs outside the scope of studies (that is, without proven effectiveness) has been growing endlessly, Meduza.

The discussions were largely triggered by statements by US President Donald Trump about the old anti-malarial drug hydroxyquinolone - as a substance that could become "one of the greatest discoveries in the history of medicine." A few days after Trump's statements, the head of the Federal Medical and Biological Agency Veronika Skvortsova announced the start of tests in Russia of another antimalarial substance - mefloquine. And on Wednesday, April 1, the US Food and Drug Administration (FDA) issued permission to use antimalarial drugs outside of clinical trials.

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First of all, read this short chapter. Self-medication can be deadly!

Before discussing how to relate to this news, what is the data on the effectiveness of these drugs, what their mechanism of work and other complex and interesting topics are based on, it is very important to once again say the most commonplace things that are constantly forgotten against the background of a loud information background.

• As of March 31, 2020 there is not a single specific antiviral drug against COVID-19, the effectiveness of which would be proven in clinical trials and which would be recommended for use by the World Health Organization (WHO).
• Evidence-based medicine requires clinical trials of an intervention for safety and efficacy, and this takes time: depending on the phase of the study, several months or even a couple of years. The coronavirus epidemic is actively developing for only three months.
• If any drug, device or therapy is involved in the study, this does not mean that they really work and are safe: the study needs to be established in order to establish whether it is or not.
• Clinical studies sometimes fail. More precisely, clinical trials fail more often than do not fail.
• In a situation where there is no specific medicine for a serious illness, doctors can use drugs that seem appropriate based on general ideas about the mechanism of the disease and the work of drugs. Each such decision may turn out to be a mistake - but it will be possible to find out only after conducting full-scale clinical studies.
• The vast majority of the substances discussed in this text cannot be bought in Russia.
• Therapy (if required) should be prescribed by a doctor.
• Most drugs are poisons.
• Self-medication can be very dangerous. Several people have already died from attempts at "prevention" of COVID-19.

Only if you have all this in mind, you can fully discuss the possible ways of influencing the virus, its life cycle, differences in the mechanism of work of antiviral drugs, and other topics that are of purely academic, but not practical interest to the vast majority of readers.

What is happening with COVID-19 therapy - clinical guidelines

When treating patients with coronavirus, doctors focus primarily not on scientific publications or the results of clinical trials (although this is also taken into account), but on WHO recommendations and national clinical recommendations.

The Ministry of Health of Russia issued its first temporary recommendations on January 29, 2020, among them the following substances were considered among possible antiviral drugs (read more about them below): ribavirin - an antiviral drug used in the treatment of severe acute respiratory syndrome TARS / SARS; HIV protease inhibitors lopinavir and ritonavir; and also an immunomodulator - recombinant IFN-β1b interferon.

The latest (already fourth) version of this document (i.e. the temporary recommendations of the Ministry of Health), updated on March 27, does not mention ribavirin, but in addition to the already mentioned antimalarials, chloroquine and hydroxychloroquine, as well as tolizumab, an antibody-based drug. At the same time, the authors of the document emphasize that now there is no objective evidence of the effectiveness of all these drugs with COVID-19, therefore, the appointment of treatment should "be accompanied by the receipt of voluntary informed consent of the patient."

WHO, in its clinical advice on COVID-19, also acknowledges that "there is no evidence now to recommend any specific treatment." However, employees of the organization constantly monitor experimental methods of therapy and maintain an updated list of drugs that are used by the organization's countries - both within the framework of clinical trials and outside them.

In addition to the substances mentioned above and their combinations, the WHO list also contains corticosteroids, other antiretroviral drugs (retroviral protease inhibitor darunavir and revertase inhibitors emtricitabine and tenofovir), cytostatics (ruxolitinib and baricitinib), immunosuppressants, other types of interferons, antiviral drugs flu treatments (baloxavir, marboxyl, favipilavir, arbidol / umifenovir) and many other substances.

It is unlikely that it will be possible to give an exhaustive description of each of the substances and even all groups by the mechanism of action. If you want to delve deeper into the topic, at the end of the article there are links by which you can study all available public information on all therapeutic options - and a table of the most ambitious clinical trials.

Next, we will talk only about the most high-profile drugs, which, on the one hand, are considered by WHO to be promising enough to be included in international studies, and on the other, have received wide media coverage. These are remdesivir, kaletra (lopinavir + ritonavir) and, of course, anti-malarial drugs - chloroquine and its analogues.

WHO-led Solidarity: four treatments, four drugs

On March 18, at the next meeting of the WHO on the situation with coronavirus, the head of the organization, Tedros Gebreisus, announced the launch of a large-scale international clinical research project called Solidarity, which creates the infrastructure for collecting data on clinical trials of drugs against COVID-19 in different countries .

The idea of ​​the project is to simplify research as much as possible: not even the most advanced medical centers located in emergency loading conditions can participate in the collection of information. Paperwork on registration of patients will be minimized.

According to the description provided by Science magazine, it will be enough to enter information about the patient on the WHO website, inform about the drugs available in the hospital and send an electronic copy of the informed consent. After that, the system randomly allocates the patient to an experimental group or a placebo group (of course, the drugs should be in the hospital - WHO will not bring them), and the doctors will only have to inform about the final results of therapy: discharge time and possible need for an artificial lung ventilation apparatus (mechanical ventilation) )

As early as March 18, it became known that Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland and Thailand had already joined Solidarity. Whether Russian hospitals will participate in the program has not been officially announced. The Russian Ministry of Health at the time of publication of the material did not respond to a request from Medusa.

It is important to note that only four types of therapy are involved in the Solidarity program:

• remdezevir
• chloroquine or hydroxychloroquine
• lopinavir + ritonavir
• lopinavir + ritonavir + β-interferon (IFN-β1b)

They are considered by WHO as the most promising.

Chloroquine, hydroxychloroquine and other anti-malarial drugs

What is this? Chloroquine is a synthetic antimalarial drug similar to the natural substance quinine, discovered in 1934 by the German chemist Hans Andersag. Hydroxychloroquine is a very similar substance, differing from chloroquine in only two atoms (OH hydroxyl group) and approved for medical use by the American FDA in 1955. Mefloquine is a fluorine derivative on the same structural basis as all other quinolines, but significantly different from chloroquine and hydroxychloroquine; developed by the US military in the 1970s, used as an analogue of quinoline - after drug resistance has spread to the latter. As antimalarials, all of these drugs are quite old, but can still be recommended for use.

What is the mechanism of action? All these funds were created to combat malaria, but since about the beginning of the 2000s, scientists began to discuss two side types of their activity: a broad antiviral effect and effects on the immune system. Back in 2003, at the height of the SARS outbreak, Italian scientists led by Roberto Cauda suggested using chloroquine to fight coronaviruses and described a possible mechanism for antiviral activity.

In short: it consists in the fact that chloroquine penetrates the endosomes (membrane vesicles that form inside the cells) and changes their pH (the same thing happens with malaria, but with parasite cells - malarial plasmodium). After this, enzymes that work in endosomes and require a strictly defined level of acidity are inactivated.

Some viruses penetrate the cell in this way - through the formation of endosomes, so chloroquine, theoretically, can block the penetration of a wide range of such viruses, inactivating the necessary enzymes for viral penetration. However, at the molecular level, the mechanism of antiviral activity of all these substances has not been established. In addition, an understanding of this process is complicated by their effect on the immune system, which plays a key role in case of viral infection, and especially with complications such as acute respiratory distress syndrome (when mechanical ventilation is required).

Why might it work? Chloroquine is a simple and cheap substance that can be taken in the form of tablets (unlike, for example, remdesivir). It is not without side effects, but is generally considered quite safe. Chloroquine not bad blocks the entry of SARS-CoV-1, MERS and SARS-CoV-2 viruses into the cell in in vitro experiments, that is, on cell cultures. Previously, the same results were shown for the Chikugunya and Dengue viruses.

Why might not it work? An antiviral effect requires a rather high concentration of the substance. In addition, in vitro experiments on model animals and randomized clinical trials of Chikugunya and Dengue did not produce any positive effect. In experiments with SARS-CoV on special lines of mice that are sick with an analogue of the Middle East respiratory syndrome MERS, the use of chloroquine showed small positive results, but the concentration of the virus in the blood did not decrease. In the human studies that are currently being discussed, the situation was the opposite: the concentration of the virus fell, while no significant clinical differences between the groups were found in a short time of the study.

What else is important to know? After Trump's speeches about the use of antimalarial drugs for the treatment of COVID-19, there was a heated debate among experts about how justified the statements about effectiveness are now. According to Science magazine, the position of the American president was primarily influenced by a small French study by a group of the famous virologist Didier Raul (he is known for the discovery of giant mimiviruses and original anti-Darwinism).

The work, which was preceded by several very small Chinese studies, provides observations of 42 patients, half of whom were given hydroxychloroquine in combination with azithromycin and the concentration of the virus in nasal swabs was measured for six days. Researchers concluded that the drug inhibits the reproduction of the virus and has shown its effectiveness, however, many scientists have questions about this study.

First, they noticed that this is not a blind study in which both doctors and patients knew what they were getting. Moreover, the study participants themselves chose whether to get into the experimental group or the control group - and this severity is known to influence this decision. Secondly, the size of the control and experimental groups was very small. Thirdly, the collection of material using a smear cannot be quantitative and the concentration of the virus in it may be the result of random factors. And finally, a decrease in virus concentration alone is not a guarantee of cure; the more so of a disease whose mortality is associated with a malfunction of the immune system in acute respiratory syndrome. You can read more about the claims to this work. here, here, here и here.

WHO dedicated a special meeting of experts to the arguments for and against the use of hydroxychloroquine, which resulted in a document summarizing the current state of research on the substance. The decision, as mentioned above, was made in favor of including the substance in the Solidarity study.

Short and clear: There is no proven effectiveness of the drug against COVID-19, you will have to wait for the results of large-scale clinical studies.

Kaletra (lopinavir + ritonavir), with optional interferon

What is this? Two protease inhibitors that are used as part of antiretroviral therapy for HIV. Approved for this purpose in the USA in 2000.

What is the mechanism of action? Lopinavir inhibits one of the proteases (3CLpro), which is necessary for the virus to cut a large propeptide, from which other viral proteins are already formed, including those necessary for the multiplication (replication) of the virus. Lopinavir itself is rapidly destroyed by human proteases in the liver, so it is used in combination with another inhibitor, ritonavir.

Why might it work? Lopinavir inhibits the replication of SARS and MERS coronaviruses in vitro and in animal models. Lopinavir alone or in combination with interferon improved clinical results in monkey experiments and in some patients with MERS.

Why might not it work? Lopinavir has already failed in a relatively large clinical study in China. It involved 199 patients with COVID-19; members of the experimental group were given 400 mg of lopinavir and 100 mg of ritonavir for two weeks, but no improvement was found compared with the control group. In addition, many people have reported side effects.

Short and clear: There is no proven effectiveness of the drug against COVID-19, you will have to wait for the results of large-scale clinical studies.

Remdesivir

What is this? An analogue of one of the “letters” of RNA synthesized by chemists from the pharmaceutical company Gilead in 2012.

What is the mechanism of action? The substance belongs to an extensive class of nucleotide analogues, among which specific antiviral substances are often searched for. The substance can be activated by viral enzymes during the synthesis of new RNA, however, due to the fact that it is not a “real” nucleotide, chain breakage occurs after its incorporation into RNA - and the virus, therefore, cannot multiply.

Why might it work? Remdesivir works in vitro against many very wide range of RNA viruses, including the new coronavirus and Ebola virus. A group of Ralph Barik, one of the most famous coronavirus specialists in the world, has already demonstrated the effectiveness of remdesivir in MERS animal models before the current pandemic.

Why might not it work? Remdesivir is Gilead's patented drug, and its use outside the United States seems difficult - especially now that the substance is in high demand and the company is under pressure from the public. Gilead has already had to abandon its monopoly on the production of remdesivir.

The second difficulty with remdesivir is that it is given by injection and cannot be tabletted. This creates difficulties with prophylactic use, although remdesivir is most effective in the very early stages of the disease.

There are other difficulties: coronaviruses, unlike the influenza virus and many other viruses, are equipped with RNA polymerases that can correct their mistakes. Under such conditions, the use of nucleotide analogues alone, without additional suppression of this ability, can lead to the rapid formation of resistance.

Short and clear: There is no proven effectiveness of the drug against COVID-19, you will have to wait for the results of large-scale clinical studies.

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Alternative Therapies

At the end of March, 260 clinical trials of drugs or other therapy against COVID-19 were registered in the international ClinicalTrials.gov database. Approximately the same number of studies are registered in China, on the corresponding national website. Among all these experimental interventions, there are cell therapy, the well-known colchicine poison, and arbidol popular in Russia, and the transfusion of patients who have been ill, and, of course, all the antiviral drugs listed above that were included in the WHO study.

An adequate description of each of these potential drugs is not possible.

As reported by ForumDaily:

• A new virus was discovered in the Chinese city of Wuhan in December 2019. In 2020, it covered all continents except Antarctica. On March 11, US President Donald Trump imposed a ban on entering the United States from EU countries. The ban came into force on Friday, March 13, and will last at least 30 days. In particular, it will concern people who have visited the Schengen area over the past 14 days.
• March 13 Trump due to coronavirus introduced a nationwide emergency regime in the US.
• On March 11, WHO recognized the situation with the coronavirus pandemic, which covered more than 110 countries. Symptoms of Coronavirus COVID-19 Disease Available here.
• Virologist's tips on how to protect yourself from infection - here to register:.
• Taking advantage of the panic in the society because of the epidemic, fraudsters came up with several schemes to deceive victims of personal data and money. The most common ones can be found here.
• Having succumbed to panic due to a state of emergency, Americans are massively buying toilet paperbut they cannot explain why they need it during the epidemic.
• Trump has signed into law on paid leave due to coronavirus. Who can count on paid leave, read here.
• Read all news about coronavirus in our special project.

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