Hydroxychloroquine and Azithromycin: New Efficacy Data Against COVID-19

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Hydroxychloroquine and Azithromycin: New Efficacy Data Against COVID-19
Hydroxychloroquine and Azithromycin: New Efficacy Data Against COVID-19
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At the end of March, Donald Trump urged on his Twitter to use a combination of the antimalarial drug hydroxychloroquine and the antibiotic azithromycin to combat the COVID-19 epidemic, noting that this is "one of the most important and turning points in the history of medicine." But the authoritative scientific journal Science called his initiative "sheer madness." Who is right and is there any new evidence of the effectiveness of these drugs against coronavirus?

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Trump's position is believed to have been influenced by the renowned French virologist at the Mediterranean Institute of Infectious Diseases Didier Raoul. At one time, he discovered giant mimiviruses, marselviruses and faustoviruses, and his Hirsch index is 144 (or 148 if you add doubles), but his pilot work to test the effectiveness of a combination of hydroxychloroquine and azithromycin was subjected to devastating criticism from other scientists.

What are hydroxychloroquine and azithromycin?

Hydroxychloroquine is an anti-malaria drug based on a synthetic analogue of quinine (chloroquine). It was adopted by doctors back in 1955. Its active ingredient penetrates into membrane vesicles - endosomes, which are formed inside cells, and changes their pH value. Presumably, the SARS-CoV-2 virus also enters the cell, being enclosed in a membrane vesicle.

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At certain indicators of the acidity of the environment inside the endosome, the membrane proteins of the virus can begin to pump protons, lowering the pH already inside the viral particle and causing its decay, which leads to the release of the virus RNA into the cell. Therefore, an unfavorable pH value in membrane vesicles reliably "turns off" viral activity.

Azithromycin - a broad spectrum antibiotic against most bacteria, including the causative agents of pneumonia in humans. Its main role in treatment is the suppression of concomitant infections, which the immunity busy with the fight against coronavirus can no longer cope with. In addition, it is likely to significantly enhance the antiviral activity of hydroxychloroquine.

Why do the proposed drugs raise doubts about their effectiveness?

It's all about that very first study led by Didier Raoult. There are several complaints about it:

1) A small sample of subjects. There were 20 people in the experimental group, and 16 in the control group.

2) Both groups of participants in the experiment were in different hospitals, which means that they could be affected by different environmental factors. In addition, they differed in age and severity of symptoms.

3) The subjects knew they were receiving drugs or not receiving experimental treatment.

4) Patients were at different stages of the course of the disease.

5) Some of the subjects immediately began to experience side effects from taking medications, and they were excluded from the final statistics.

6) Some patients received a combination of drugs, while others only received hydroxychloroquine.

7) Conclusions about the effect of treatment were made on the basis of PCR tests for the presence of viral RNA in samples from the nasopharynx, without taking into account the complete clinical picture and computed tomography of the lungs.

Most of these claims cannot be considered significant in relation to the scientific work of Didier Raoul.He stated unequivocally, right in the title of his article, that these were preliminary results of an open, non-randomized study. And this is normal practice.

Usually, open research is always conducted as a pilot, before more complex trials using a double-blind method. However, such works cannot be the basis for including hydroxychloroquine, for example, in the official recommendations of the Ministry of Health.

What has become known now?

Following the first study, Didier Raoult's team conducted a second. 80 patients with COVID-19 have already taken part in it, thus the sample has been quadrupled. This time, all patients received combined treatment with hydroxychloroquine and azithromycin, and 77 of them were hospitalized directly at the Mediterranean Institute of Infectious Diseases in Marseille (France).

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In the introduction, Dr. Raoul cites data from a Chinese study, which notes that virus shedding from infected people lasts an average of 20 days. The minimum period is 8 days, and the maximum can reach 37 days, that is, even after the patient has been relieved of severe symptoms.

All this creates the danger of the further spread of the coronavirus and an increase in the scale of the pandemic. Therefore, the most effective way to overcome this situation can be the means that radically suppress the release of the virus, and therefore reduce the infectiousness of its carriers.

Based on this, in the new work, French virologists assessed three indicators:

1) Clinical results;

2) Infectiousness of patients (according to the PCR test of a sample from the nasopharynx);

3) Length of hospital stay.

This time, the participants in the experiment were divided into two groups: one with damage to the upper respiratory tract (rhinitis and pharyngitis), and the second - lower (bronchitis and pneumonia).

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After listening to criticism of the previous study, Raoul's team carefully documented the time between the onset of symptoms and admission to hospital, as well as before treatment began. All risk factors for each patient were also taken into account: old age, cancer, cardiovascular diseases, hypertension, diabetes, chronic obstructive pulmonary disease, obesity and any immunosuppressive treatment. All participants in the experiment underwent regular CT scans of the lungs and took swabs from the nasopharynx for PCR testing.

The treatment regimen included oral administration of 600 mg hydroxychloroquine (three times a day, 200 mg) for 10 days, azithromycin (500 mg on the first day and 250 mg on the following), and for patients with severe pneumonia, the antibiotic ceftriaxone was added. Therapy began from the day the patient was admitted to the hospital or immediately the next day.

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This approach made it possible to achieve negative PCR tests for the content of coronavirus in samples from the nasopharynx in 83% of patients on the seventh day, and in 93% on the eighth. And on day 12 (two days after the course of treatment) there were no potentially infectious patients left. Dr. Raoul insists that this is a marker of a rapid decrease in viral load and evidence of the effectiveness of the proposed therapy.

65 patients (81, 3%) spent only five days in the infectious diseases department from the start of treatment to discharge. However, it is alarming that 15% of patients still required oxygen during treatment, three people were transferred to the intensive care unit, where one of them - 74 years old - was also at the time of publication of the study, and another 86-year-old patient was not was connected to the ventilator on time and died.

Didier Raoul notes that everyone who was admitted to the hospital of the institute at an early stage of the disease, his group managed to prevent the development of severe pneumonia and acute respiratory distress syndrome (ARDS), with the exception of the deceased patient, who had already arrived in serious condition.

And why take azithromycin as well, because they fought with pneumonia with another antibiotic?

French virologists have given an answer to this question in experiments with cell cultures in Petri dishes. They infected the epithelial cells of the kidney of the African green monkey in test tubes supplemented with a nutrient medium from fetal bovine serum and glutamine. Then added there hydroxychloroquine in a concentration equal to 1, 2 or 5 micromolar or azithromycin in a concentration of 2, 5 and 10 micromolar, or a combination of these drugs.

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The key point in the study was the indicator multiplicity of infection… It reflects the ratio of the number of viruses to target cells. The higher this indicator, the greater the percentage of cells infected with at least one viral particle. Raoul and his team examined two groups of samples: with a high multiplicity of infection equal to 2.5 (about 90% of infected cells) and a low multiplicity of 0.25 (slightly over 20%).

As it turned out, at a low multiplicity of infection, both drugs separately had no pronounced effect, with the exception of a moderate result of hydroxychloroquine at a concentration of 5 micromoles. At the same time, a combination of drugs at a concentration of 5 micromoles of hydroxychloroquine and 5/10 micromoles of azithromycin showed a significant reduction in the multiplication of coronavirus in cell culture.

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For high multiplicity of infection, the combination of 2 micromoles of hydroxychloroquine and 10 of azithromycin gave a moderate effect. Thus, it is likely that both drugs somehow enhance the action of each other, although the mechanism of this phenomenon has not yet been established.

It should be noted that in this work, Raoul managed to use such concentrations of active substances that can be observed in some cases in the tissues of the lungs of patients, which means that they are achievable in a living organism without reckoning in the form of severe side effects.

Another important point is that taking a combination of hydroxychloroquine and azithromycin should be started as early as possible, until the disease has gained momentum. In this case, there is a chance to suspend its flow. But if the viral load rises dramatically, there will be little benefit from treatment.

And what will happen next?

Didier Raoul, as a headliner and top scientist with a worldwide reputation, as well as the entire team of the Mediterranean Institute of Infectious Diseases, are actively promoting their treatment protocol in social networks and the media.

So, more recently, Raul published a tweet in which he stated that 16,506 patients with suspected COVID-19 were admitted to the institute. They were all tested and 1,988 people tested positive for SARS-CoV-2. Of these, 13 died during their stay at the institute clinic, and another 1003 received (or continue to receive) treatment according to the hydroxychloroquine plus azithromycin scheme. In this experimental group, only one patient died, probably the same 86-year-old admitted in serious condition.

But this is not the end, almost for the first time in the world scientific practice, Raoul … published a teaser of his new scientific article! And in pursuit of it, and a table with data based on the results of the study, which traced the effect of treatment depending on age, the presence of chronic diseases, taking other drugs and other factors.

In this work, a sample is already from 1061 patients (it is separately noted that data on them have not been published before). It is not yet possible to carry out a detailed analysis of the article due to its absence. Three indicators are said to have been tracked: patient death, deterioration, and virus shedding. At the same time, good results after 10 days of therapy were observed in 973 patients (91, 7%). What exactly they are is not completely clear, apparently in the fact that the patient survived, he felt better, the viral load decreased, or in the pharyngonasal test the coronavirus was no longer detected using a PCR test.

For 46 patients, no significant results were achieved. Ten of them were sent to the intensive care unit, five died, and another 31 required prolonged hospitalization (10 days or more).Nevertheless, at the time of publication, 25 of them were cured and only 16 are still under observation.

Poor results Raoul associates with old age - all the dead were from 74 to 95 years old - and admission in a serious condition to the clinic of the institute, as well as the use of selective beta-blockers and blockers of angiotensin II receptors by patients for the treatment of hypertension.

Now there remains one key question for all the work of Raoul's group: does the use of a combination of hydroxychloroquine and azithromycin really prevent the further development of the disease and its course in a relatively mild form, or does it present as evidence of effectiveness the results on patients who were already sick in a moderate form, and therefore would have recovered in any case and without any special complications?

So far, it is impossible to clearly answer this question, but nevertheless, hydroxychloroquine and azithromycin remain one of the few potential treatment options in the absence of other, at least somehow tested not only in vitro means. Therefore, it is definitely not worth neglecting them during clinical trials of new drugs. By the way, similar tests are already underway in a number of countries around the world (under the auspices of the WHO).

In conclusion, we would like to draw the attention of readers to an important point: do not self-medicate and do not take the drugs described in the article without a doctor's recommendation! Everything described above is only the results of scientific research at the forefront in the fight against coronavirus. Any uncontrolled use of potent drugs can lead to serious consequences. This is especially true for the drug hydroxychloroquine, which has extremely unpleasant side effects.

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