Chloroquine Protocol for Covid-19: what do the studies say?

The new coronavirus has brought a challenge to professionals and specialists around the world. Even after a few months of the first diagnosed case, it is still sought to understand exactly how the virus affects the organism and how clinical management should be carried out, with safety in the lives of patients, as indicated by the Ministry of Health.

Among the treatment possibilities under study is chloroquine, a medication that has been marketed for years for some autoimmune diseases and malaria .

The possibility of the drug having benefits in the treatment against Covid-19 is supported by preliminary analyzes and does not yet have a scientific basis, as the studies and results are quite limited.

Chloroquine and hydroxychloroquine – a less toxic derivative of the drug – have been administered in some cases, but this is still on an experimental basis. In other words, it is up to the medical analysis to decide whether to try the treatment.

Based on some of these researches that point to possible benefits against the coronavirus, the Ministry of Health issued a Protocol for the use of the substance, together with the antibiotic azithromycin in severe, moderate and mild cases.

According to the publication of the agency, the goal is to expand access to treatment for patients, as well as provide guidance on its use – when this is the decision agreed between the doctor and the patient.

However, the document itself points out that there is still no scientific evidence to prove the safety and effectiveness of the drug in Covid-19 cases.


What is Chloroquine?

Chloroquine and hydroxychloroquine have been used for years to treat malaria and some autoimmune diseases, such as rheumatoid arthritis and lupus . According to the package insert, the drug is indicated both for prophylaxis – that is, prevention through the administration of subtherapeutic doses – and for the treatment of malaria, which is a disease caused by Plasmodium vivax, P. ovale and P. malariae .

The drug is also indicated for the treatment of hepatic amebiasis (infection with Entamoeba histolytica type protozoa ).

In conjunction with other medications, it is also used for rheumatoid arthritis, systemic lupus erythematosus and discoid lupus and sarcoidosis (which are autoimmune conditions), as well as photosensitivity diseases, such as porphyria cutanea tarda and severe polymorphic rashes, resulting from exposure to light.

Its use is effective and safe in these cases, as soon as exhaustive studies have been carried out to assess the risks and actions of the drug in patients who suffer from any of these conditions.

But, even so, it should always be done with medical guidance and monitoring, as soon as it can trigger adverse reactions, just like any other medication. In general, they are moderate and pose no risk to the life and health of patients.

As pharmacology doctor Francielle Mathias points out, “Effects on the cardiovascular system, the central nervous system and the blood can occur. It depends on the dose and the clinical condition of the patient, but as they are possible reactions and involve important systems, they are not considered mild. ”

The drug, then, proves to be safe for diseases such as rheumatoid arthritis and malaria because they have been extensively studied in these cases.

The patient is also constantly monitored and, in case of adverse manifestations, the responsible medical team can monitor and change the medication, if necessary – which reduces risks to the health of people undergoing treatment, as pointed out by the biologist and PhD in microbiology Luiz Almeida.

Among the most common possible adverse reactions, with therapeutic dosages guided by the package insert, are headache, irritation of the gastrointestinal tract, visual disturbances and urticaria.

It is the prolonged use of high dosages (above 250mg) that is related to a higher incidence of more intense side effects. In these cases, toxic myopathy, heart disease and peripheral neuropathy, blurred vision, diplopia, confusion, seizures , rashes and other reactions may occur .

How does the medicine work?

Malaria is transmitted through the bite of the female Anopheles mosquito who are infected with the Plasmodium protozoan . After the mosquito bite, the parasites need to invade cells in the organism, replicating themselves and, thus, affecting more cells.

In the cases of malaria, according to Luiz Almeida, biologist and PhD in microbiology, chloroquine “prevents the parasite that causes the disease to infect cells”.

Rheumatoid arthritis and lupus are autoimmune diseases, in which the body ends up attacking the body’s own healthy cells, leading to changes. For these cases, chloroquine acts with an immunomodulation effect. In other words, “it reduces the exaggerated response of the patients’ own immune system”, according to Luiz Almeida.

What is known about the clinical course of coronavirus infection?

According to the Coronavirus Clinical Management protocol (Covid-019), from the Ministry of Health, the transmission of the SARS-CoV-2 virus from human to human occurs mainly through contact with respiratory droplets from infected people.

That is, when speaking, coughing and sneezing, for example, particles of saliva are emitted that contain the virus. They can directly infect another person or be deposited on surfaces and other materials, such as door handles, supermarket products, money, etc.

Thus, when inhaling these droplets, or touching something contaminated and taking your hand to your mouth, the virus invades the healthy organism. On average, the incubation time is 5 to 6 days, and can vary between 0 and 14 days, as indicated by the protocol of the Ministry of Health.

The condition resembles a flu-like syndrome, and can manifest itself in mild or asymptomatic cases, as well as moderate and intense. The most frequent symptoms include fever (above 37.8ºC), cough , difficulty breathing and loss of smell and taste.

The cases with the most severe clinical outcome are those in which the affected person is part of some risk group, such as elderly people and people with chronic diseases (among them, diabetes , heart disease, hypertension).

What is the difference between hydroxychloroquine and chloroquine?

Chloroquine and hydroxychloroquine are well-known medicinal substances in medicine. These drugs have antimalarial and anti-inflammatory action, indicated for rheumatological and autoimmune diseases, such as systemic lupus erythematosus.

Both drugs have an immunomodulatory effect that is known to be safe and effective for several autoimmune conditions, as long as there is a proper prescription. Thus, the treatment helps to improve the immune response against certain agents, that is, they help fight diseases.

Despite the similarities, the remedies have different formulations from the same substance: chloroquine. In general, the expected effects that are observed are similar, but this changes in relation to the adverse effects – hydroxychloroquine has, in general, fewer side effects, being relatively safer.

What are the stages of testing a drug and why use existing medications?

When drugs are being studied to treat a disease, the normal process consists of several steps that can take years to be conclusive.

The purpose of this long process is to ensure the efficacy and safety of the drug. In general, the process starts with in vitro tests – that is, in the laboratory, with isolated cells subjected to interactions with the drug.

The doctor in pharmacology Francielle Mathias points out that “as we are in a pandemic, a totally atypical situation, drugs already used for other diseases were tested in vitro to verify efficacy against Covid-19 and the results were taken into account, to make decisions in relation to therapy ”.

Thus, if the results are positive, the evaluation and studies continue.

Then, in vivo testing begins – that is, done on animals. Studies of the drug are usually carried out in rodents, such as mice, and then in non-rodents, such as dogs and monkeys.

At the end of these tests on animals, more data is obtained on the behavior of the drug in the body. If the data demonstrates effectiveness and safety, then the drug goes for testing in humans.

This also starts in a controlled manner and in small groups previously selected. The studies continue with administration to more patients, until consistent data on the safety of the drug are obtained.

But in situations like the new coronavirus pandemic, the objective is to accelerate this process, but without putting people’s health at risk.

Therefore, an alternative is to resort to drugs that are already available on the market and that demonstrate that they can be indicated for other diseases – in the current case, Covid-19.

As these remedies have already been tested, the knowledge about their actions, side effects and safety is better known, although it still needs tests on how they work for the treatment of other pathologies.

Protocol for use of Chloroquine not to treat Covid-19

With an average mortality rate of 2% to 4%, Covid-19 has been a challenge for professionals at the forefront of research into treatments and vaccines for infection. One of the ways to safely accelerate this process is to study and evaluate the action of existing drugs, but indicated for other conditions, which have liberation and the potential to assist in the researched disease.

This is the case with Covid-19: different antiviral and immunomodulatory drugs are being studied, evaluating the ability to control viral replication and regulate the immune response of patients.

According to Luiz Almeida, PhD in Microbiology, this resource is quite interesting considering especially the context of a pandemic, but still “it is necessary to maintain the seriousness of the studies, taking into account all factors and data”.

Among the substances with evidence to treat Covid-19 is Chloroquine, which in preliminary studies was considered a possible drug with antiviral action.

The drug showed relevant results, but in limited studies, especially in relation to the methodology and the sample size of the groups analyzed. Still, in May, the Ministry of Health published a Protocol of recommendation for the use of the drug, advising on the dosage and how to use chloroquine and hydroxychloroquine for mild, moderate and severe cases of Covid-19.

According to the document, the objective is to guide, in a uniform way, health professionals regarding treatment. Thus, according to the protocol, the aim is to expand the access of patients to Chloroquine, based on indications of potential benefits against the coronavirus, although without a scientific basis.

Thus, the document also highlights that there is no scientific evidence of the substance’s effectiveness in the cases of Covid-19, and that it is up to each professional to analyze the pertinence of the use.

When there is a common agreement between the patient and the medical professional, both must sign the term of responsibility , stating that all risks have been duly explained and that there is knowledge about the lack of scientific evidence about the treatment.

In this sense, it is worth remembering that the use of medication, before this Protocol, was already possible for compassionate cases , that is, severe cases of Covid-19, and it is up to each medical professional to evaluate the risks and benefits of the prescription.

Also in March, the Ministry of Health published a note clarifying that the drugs chloroquine and hydroxychloroquine would be made available to patients with severe forms of Covid-19, as prescribed by a doctor.

Thus, the protocol instructs that patients with mild, moderate or severe cases may receive Chloroquine, or Hydroxychloroquine sulfate, associated with Azithromycin in the first days of the infection – between the 1st and the 14th.

The publication divides opinions and was received with concern by some health entities, which even expressed notes positioning themselves against the use, incentive or release without scientific proof of chloroquine.

It is worth considering, as Luiz Almeida points out, that the protocol refers to a recommendation and not to the release of treatment, since there is, effectively, no scientific proof of the efficacy of the drugs for Covid-19.

Therefore, without scientific proof, the protocol cannot be considered an official document – as soon as this violates the legislation – nor can it receive registration from ANVISA, which is the national regulatory body.

Positioning of health entities

The Brazilian Association of Public Health (Abrasco), in a note , reinforces that there is no scientific proof of the benefits, in any state of Covid-19, for the use of the drugs chloroquine and hydroxychloroquine, as well as they have demonstrated, from tests, increase the risk of lethality.

The note highlights that, in the face of human suffering, doctors must, as a humanized exercise of medicine, prescribe substances, even if with a placebo effect, aiming at better well-being – this includes vitamins , ozone gas and homeopathy, as soon as there are no risks to the health and integrity of the people affected.

However, Abrasco declares that:

“When the substance that is intended to be used for this purpose is strongly associated with serious and known adverse events, especially in the target population of COVID-19, which is older, mostly with heart disease, and therefore more subject to fatal arrhythmias, it is up to the doctor, supported by science, to warn and fight so that we no longer have unnecessary iatrogenic deaths ”.

For the Brazilian Association of Allergy and Immunology (ASBAI) , in light of the scathing studies on the effects and mechanisms of action in the treatment of Covid-19:

“[…] These drugs [chloroquine and hydroxychloroquine] should not be prescribed in a generalized and indiscriminate way in mild and outpatient cases of the disease. On the other hand, they can be prescribed with extreme caution and under specific clinical conditions of COVID-19. ”

The Brazilian Society of Cardiology (SBC) also issued an official note, stating that:

“It does not recommend the use of Chloroquine and Hydroxychloroquine associated, or not, with Azithromycin, until there is definitive scientific evidence about its use.”

However, if this is an option agreed between patient and doctor, the SBC’s recommendation is that precautionary measures be taken by means of electrocardiogram , considering that drugs can trigger serious adverse cardiac reactions.

Likewise, the Federal Council of Medicine (CFM) , in a note, positioned itself as favorable to professional autonomy in the current scenario, leaving the professional judgment to analyze the benefits and risks, in agreement with the affected person, but without encouraging the use.

Thus, it highlights that:

“There is no solid evidence that these drugs have a confirmed effect on the prevention and treatment of this disease. However, in view of the exceptional situation and during the declared period of the COVID-19 pandemic, CFM believes that it is possible to prescribe these drugs in three specific situations. ”

In addition, the National Health Council (CNS) , in response to the publication of the Ministry of Health Protocol, published the recommendation of immediate suspension of the chloroquine recommendation for mild cases of Covid-19:

“[…] Due to non-compliance with SUS legislation and health risks to the Brazilian population, represented by the use of chloroquine and hydroxychloroquine in the context of the new coronavirus pandemic”.

According to the microbiologist PhD Luiz Almeida, the safety of chloroquine is known for the already approved frames, but for Covid-19 it is still very uncertain. “And studies have shown that it is not working or is worsening the condition of some people. It is not because the drug is used successfully for other diseases that it can be indicated to treat Covid-19 ”.

In which coronavirus cases does the Ministry of Health indicate using Chloroquine?

It is worth mentioning that, according to the Ministry of Health, the Protocol dealing with the use of chloroquine and hydroxychloroquine for the treatment of Covid-19 is not a decision for the administration of the drug, with medical autonomy being responsible for assessing the risks and benefits of adopting the medications.

However, the publication gives guidelines regarding dosages for administration, in relation to the condition (mild, moderate and intense), as well as the stage of infection.

For symptoms and mild signs of Covid-19, the advice is to administer chloroquine + azithromycin or Hydroxychloroquine + azithromycin in phases 1 (between the 1st and 5th day) and phase 2 (between the 6th and 14th day).

In phase 3 (after the 14th day), the orientation is to prescribe symptomatic medications (to alleviate the symptoms). For moderate symptoms and symptoms, guidance for phases 1 and 2 is to administer chloroquine + azithromycin or hydroxychloroquine + azithromycin. There is no guidance for phase 3.

In severe symptoms and signs, the guidance for all phases is to administer hydroxychloroquine + azithromycin.

It is worth noting that the protocol indicates the need for consent and common agreement between patient and doctor for treatment with chloroquine. For this, patients must sign the term of responsibility, declaring awareness of the risks of the medication.

Scientific studies and evidence: what is known about chloroquine for the new coronavirus?

A number of possibilities have been raised based on in vitro and in vivo studies . Although some tests demonstrate possible benefits, chloroquine still lacks scientific proof, as soon as the data are not very striking.

Among the possible benefits of using chloroquine – the most likely so far – is the reduction in the length of stay of patients in the ICU, although there are experts who point out that this benefit does not outweigh the risk of the medication.

A few days after the publication of the Ministry of Health Protocol, giving guidelines on the use of Chloroquine for mild cases – in addition to the already possible uses in serious cases -, The Lancet scientific journal published the largest study on the use of the drug for Covid -19, who subsequently suffered a retraction as to the validity of the results .

The survey was carried out with 96,000 patients in 671 hospitals worldwide. The objective was to compare the efficacy of Chloroquine and Hydroxychloroquine administered alone or in conjunction with a macrolide antibiotic (group that includes azithromycin) in relation to patients who did not receive drug treatment.

The study concluded that the use of the substances, in addition to not providing overwhelming benefits to patients, can also increase the risk of serious heart problems and death . In addition, the data indicate that drug treatment also increased the chances of cardiac arrhythmias, which can lead to death.

In view of the publication of the journal, the World Health Organization (WHO) announced the suspension of studies on medication. The organization leads the Solidarity research , carried out in several countries, regarding the safety and efficacy of the drug. However, after rectification, WHO resumed research.

Despite this, other studies and evidence still remain uncertain as to the real efficacy and benefit of chloroquine to treat Covid-19. As the PhD in microbiology Luiz Almeida points out, the first “studies that were completed and showed benefits from the use of chloroquine have serious flaws in the methodology and design of the experiment”.

In Brazil, considering the Protocol published by the Ministry of Health and WHO guidelines, the use remains conditioned to the signing of the term of responsibility, in which the patient’s consent to treatment is declared – the doctor may suffer in the future professional accountability to aggravating factors in the framework.

Does chloroquine have an antiviral effect?

Some preliminary results have shown that chloroquine may have the potential to treat Covid-19, because it works by preventing the entry of viruses into the cell, changing the pH of the endosome – which is a bubble-like structure, responsible for the transport and digestion of captured particles by the cells.

Thus, considering cell infection by means of endosomes, chloroquine would prevent this bubble, containing the genetic material of the coronavirus, from breaking inside the cell and allowing viral replication. That is, as the endosome acts as a vehicle for the viral particle, this change in pH would prevent infection of the cell.

However, other studies point out that, although this means of cell invasion exists, it is not the only one – nor is it preferred by the new coronavirus,

According to Luiz Almeida, “the problem is that the first studies were done with cells that are not similar to those in the respiratory system, because they [those used in in vitro studies ] only have a gateway in which the coronavirus can act – which is through the endosomes ”

Subsequent tests with cells similar to the respiratory system – which have other ways of entering the cell – indicated that chloroquine was not as effective.

According to Luiz Almeida, the results of the tests showed that there was a decrease in the potential for infection of the cells, but that the rate was not considerable. This is because “the virus is able to fuse with the membrane of the target cell, injecting the genetic material, even without the endosome process”.

Thus, points out the microbiologist, chloroquine “does not have the ability to prevent the replication of the virus, it just prevents the genetic material from being released by the endosome”.

In addition, the PhD in microbiology points out that “chloroquine has already been tested for several other viral diseases such as AIDS , dengue , influenza and SARS, with no results – and animal tests ( in vivo ) of the drug for cases of ebola and chikungunya indicated the worsening of the condition, in which there was an increase in viral load.

Are the side effects well known?

Like any other medication, chloroquine can trigger side effects. However, its use is considered safe for the cases in which it was studied – this does not relieve constant medical monitoring.

That’s exactly why chloroquine and hydroxychloroquine are safe for already approved cases – that is, malaria, lupus and rheumatoid arthritis. Because there is a lot of study, following strict scientific protocols, which test the drug in healthy people and in patients with any of these conditions.

Thus, when prescribing this medication, doctors already know what are the possible side effects. As a result, any changes that occur, the patient is monitored by a physician and, if necessary, the medication is changed – which guarantees safety for use.

According to the PhD in microbiology Luiz Almeida, “the side effects of chloroquine and hydroxychloroquine are already very well described, but even in a patient with indication for use they can cause nausea, headache and cardiac arrhythmia . It is especially complicated in people with Covid-19, as there are studies indicating that the disease attacks other organs, such as the heart ”.

That is, the coronavirus infection itself can affect the heart. Along with this, among the groups at risk for Covid-19, there are people with heart problems, such as insufficiency, which aggravates the situation.

With the administration of the drug, there may be one more factor interfering with heart rate and decreasing the interval between beats. Thus, the risk is high when opting for the drug without effectively knowing its safety and action.

Does it have immunomodulatory action?

The mechanism of immunomodulation exists and that is what makes it very useful for treating autoimmune diseases. This is because it works by reducing the action of the immune system, responsible for the improper attack on healthy cells in the body.

For Luiz Almeida, PhD in microbiology, for Covid-19 this effect does not seem to have shown promising results. Considering that the treatment protocol guides the use of chloroquine for 5 days, this period may cause the immunomodulation effect to make no difference to the patient.

In addition, considering the administration in the early treatment, “the use of the drug can still have undesirable effects, as it can lead to depression of the immune system, which can favor the replication of the virus”, according to Luiz Almeida.

Prospects for treatments for Covid-19

Different drugs are in the testing phase and some have shown promise in the treatment of Covid-19. In general, the assistance measures taken for symptomatic patients are the prescription of medications to relieve symptoms, such as antipyretics for fever or antibiotics when patients have bacterial infections, such as pneumonia .

In severe cases, hospitalization and, when necessary, intubation are performed, as a way of controlling pulmonary involvement.

On the possibilities in progress and which prove to be, in fact, promising, Luiz Almeida, PhD in microbiology, points out that some antiviral substances are being tested, some of which operate by mechanisms that prevent the virus from entering the cell and, therefore, consequent viral replication.

In addition, a method called convalescent plasma has been used, also in experimental mode, as a way to assist in viral control and recovery of patients.

The method shows good results and there is enough data to consider it safe – including, it has been tested a few years ago for other cases of coronavirus (remembering that the coronavirus refers to a group of different viruses, and some of them are already known to the community doctor).

The process consists of collecting a blood sample from patients already cured of Covid-19 and separating the plasma from this material, which is a tissue of the blood. As it is estimated that whoever has had the infection produces antibodies to the disease, these may be present in the plasma.

Thus, the material is injected into people undergoing treatment, which can assist in viral control and accelerate the improvement of the condition.

Researchers around the world are looking for drugs to control the disease and develop vaccines for the disease that has affected the world.

In the meantime, studies present promising data and discard previously considered options in search of safe and effective substances against Covid-19.

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