Could the Antimalarial Drug Plaquenil Be a Remedy for Coronavirus Disease (COVID-19)?

What Is Plaquenil (Hydroxychloroquine)?

Could the old antimalarial drug also used to treat rheumatic diseases, hydroxychloroquine (Plaquenil), be a necessary and effective treatment for novel coronavirus disease COVID-19?

Many scientists and doctors around the world are currently debating this; some support it and others oppose it. During his speech on 19 March, Trump even said that Plaquenil had been approved by the US Food and Drug Administration (FDA)—as he announced, but subsequently the FDA stated that it had not approved this use.

However, it reappeared on 18 March with positive results from a nonrandomized, unblinded study of 24 patients, presented on YouTube by Professor Didier Raoult. For some reason, he chose to announce a scientific study on YouTube... (see our articles about Didier Raoult: article 1 and article 2).

This supports the in vitro (laboratory) results obtained by a Chinese team and published on 9 March in Clinical Infectious Diseases (the journal of clinical infectious diseases). However, the infectious diseases community considered the data insufficient to recommend the compound as a treatment.

Furthermore, chloroquine was not included in the recently launched study involving 3200 patients receiving intensive care for COVID-19, including 800 French patients, INSERM, the European clinical trial, as one of the four treatments being investigated.

Chloroquine was excluded because of the risk of adverse interactions with other drugs for comorbid (other) conditions in patients diagnosed with COVID-19, and possible adverse effects in patients undergoing resuscitation.

Note: Hydroxychloroquine is a less toxic derivative of chloroquine.

4 important developments

1. The largest study of Plaquenil use in COVID-19 treatment

Results of a clinical trial were published on 8 October 2020 in the leading medical journal NEJM, with 4716 patients with COVID-19 included, as reported.

This phase-III, randomized, controlled, open-label study enrolled patients hospitalized because of COVID-19.

Patients were randomly assigned to two groups: 1561 to receive hydroxychloroquine and 3155 to receive standard care. The primary outcome the study aimed to measure was the 28-day death rate.

The study found that:

• 27% of those receiving hydroxychloroquine and 25% of those receiving standard care died.
• The discharge rate on day 28 was 59.6% in the hydroxychloroquine group and 62.9% in the standard-treatment group.
• The rate of intubation and mechanical ventilation or death was 30.7% in the hydroxychloroquine group and 26.9% in the standard-treatment group.

In conclusion, hydroxychloroquine use in hospitalized patients with COVID-19 did not result in a lower 28-day death rate.

2. Infectious Diseases Society of America (IDSA) Guideline

IDSA updated its "Guideline on the Treatment and Management of Patients with COVID-19" on 25 September 2020. According to this treatment guideline from a leading infectious diseases organization worldwide:

• For patients hospitalized with COVID-19, hydroxychloroquine is not recommended (a strong recommendation, with moderate-certainty evidence).
• The use of hydroxychloroquine plus azithromycin in patients hospitalized with COVID-19 is also not recommended (a strong recommendation, with low-certainty evidence).

In summary, IDSA does not recommend hydroxychloroquine or chloroquine for COVID-19 treatment because no benefit has been demonstrated and because of serious adverse effects.

3. The FDA revoked emergency use authorization for hydroxychloroquine and chloroquine in COVID-19 treatment!

15 June 2020was the date on which the FDA revoked an authorization it had previously granted. Hydroxychloroquine and chloroquine would no longer be usable for COVID-19 treatment in the USA outside clinical trials. The stated reason was that scientific studies completed up to that point had found these two drugs ineffective in treating COVID-19 and capable of causing serious adverse effects.

4. Hydroxychloroquine does not work as prophylaxis (protection) against COVID-19

In a notable study published in the respected medical journal NEJM on 06 August, hydroxychloroquine started early after exposure to COVID-19 was shown to have no protective effect against COVID-19 infection. This comprehensive randomized, double-blind, placebo-controlled phase-3 clinical trial included 821 participants.

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The Marseille Study

The European Union Clinical Trials Register shows that the Marseille study was accepted by the National Agency for Medicines Safety (ANSM) on 5 March. The study includes up to 25 COVID-19-positive patients: five aged 12-17, 10 aged 18-64, and 10 aged 65 and over.

Although the data have not yet been published and therefore need to be interpreted cautiously, this nonrandomized, unblinded study showed a strong reduction in viral load with hydroxychloroquine.

The results for these 25 patients were compared with a control group that did not receive hydroxychloroquine against COVID-19. At 6 days after hydroxychloroquine was started, test positivity fell to 25% among patients with COVID-19 who received it, while it fell to 90% among those who did not receive treatment.

They also compared untreated patients with those receiving hydroxychloroquine and those given hydroxychloroquine plus azithromycin. The results showed "a dramatic reduction in the number of positive cases" with combination therapy.

On day 6, the proportion of cases still carrying SRAS-CoV-2 among patients given combination therapy (hydroxychloroquine plus azithromycin) was no more than 5%.

The infectious diseases specialist added the antibiotic azithromycin because it is known to be effective against complications from bacterial lung disease.

More detailed results of the study have been submitted for publication in the International Journal of Antimicrobial Agents (the journal of international antimicrobial agents).

The Study Divided Infectious Diseases Specialists

The announcement of positive results from this small study divided the medical world.

Professor Gilles Pialoux, an infectious diseases specialist at Tenon Hospital, was cautious in his response: "The idea is interesting, but we need large, randomized, controlled trials. We should not communicate this type of information on YouTube; it is not meaningful".

"Remember that there are drugs that appear more interesting and effective for COVID-19 treatment, such as ritonavir, lopinavir and remdesivir, and this compound (hydroxychloroquine) was not included in the INSERM study. We must be careful regarding a repeat of the mistake we experienced with cyclosporine in HIV."

By contrast, Christian Perronne, president of the Infectious Diseases Society in France, was more enthusiastic:

"I really believe in hydroxychloroquine. It is a drug used for decades that I find quite fascinating. There have been positive results in an in vitro study and a preliminary Chinese clinical study involving 100 patients showing that hydroxychloroquine reduced viral load; patients’ symptoms lasted for less time and were not severe. This could reduce the number of carriers, which I find interesting from an epidemiological perspective."

"From an ethical perspective, we should offer it to all patients with severe disease who are hospitalized, under observation and receiving a short course of treatment—paying particular attention to interactions with drugs that prolong the QT interval on the ECG. Adverse effects, at increasing doses, may include patients experiencing pain or fever, but according to the Chinese data, treatment appears effective at lower doses. In any case, this compound’s adverse effects are not dangerous."

This drug has been used for decades in patients with lupus, including pregnant women, and a known adverse effect, retinal toxicity (damage to the back of the eye), is rare.

Hydroxychloroquine Tested in Other Hospitals

At the end of the Council of Ministers meeting in France on Tuesday, government spokesperson Sibeth Ndiaye discussed the results published by Prof Raoult. "The clinical trial in Marseille is a promising start; we are expanding it because science requires experience to be measured and repeated several times before we can say whether it works." Further tests will be carried out at Lille Hospital to verify or confirm Prof Raoult’s results.

Chloroquine is currently being investigated in a number of clinical trials in China and elsewhere, and some in France have also decided to recommend it following Prof Raoult’s findings.

Dr. Alexandre Bleibtreu, an internal medicine specialist at Pitié Salpêtrière Hospital in Paris, was initially unconvinced by the in vitro data, but changed his mind after seeing the results of the study conducted by Didier Raoult.

It was announced that hydroxychloroquine was being used in approximately 50 hospitalized patients with COVID-19 in France, except for those who refused it or had contraindications (circumstances in which it could not be used).

"I heard the results that changed my mind. We followed the Marseille protocol, and there are certainly others who will use it. It is not the most obvious treatment; it works in vitro (in the laboratory), but we did not have in vivo (in living organisms or under living conditions) data."

"It is not an approved treatment for this, and the approach may be wrong, but the aim is for our patients to recover. No treatment is magical, but instead of doing nothing, drugs need to be repositioned according to their adverse effects, interactions and so on."

Plaquenil Use in COVID-19 – Scientific Rationale

Professor Robin May, Professor of Infectious Diseases at the University of Birmingham in the UK, explained that there was a scientific rationale for using hydroxychloroquine to treat COVID-19 based on its mode of action in malaria.

In a statement through the Science Media Centre, he explained that chloroquine is a "weak base" and helps neutralize acids, making red blood cells "less suitable" for the malaria parasite to live in.

Against COVID-19, although its mode of action has not been established, Prof May noted that many viruses enter host cells through endocytosis and are initially taken into an intracellular compartment that is "typically quite acidic.""

"By changing the acidity of this compartment, chloroquine may reduce the entry of viruses into the host cell and their ability to begin replicating."

"Another possibility is that chloroquine may change the virus’s ability to attach to the outside of a host cell in the first place". Hydroxychloroquine also has modest suppressive effects on a wide variety of immune cells, some of which are unclear. One of these effects could be to stimulate the immune system’s ability to fight COVID-19.

Importantly, the drug is also "cheap and relatively easy to produce," so it can readily be included in clinical trials and eventually obtain treatment approval.

What Are the Proposed Dose and Duration of Plaquenil Use for COVID-19 Treatment?

In the recently published Handbook of COVID-19 Prevention and Treatment by Chinese clinicians, the section on chloroquine use reads as follows:

"At FAHZU (the First Affiliated Hospital of Zhejiang University School of Medicine), lopinavir/ritonavir (2 capsules orally every 12 hours) combined with arbidol (200 mg orally every 12 hours) was used as the basic treatment regimen. According to our experience with 49 patients treated at our hospital, the earliest time to a negative nucleic acid test was an average of 12 days (95% Cl: 8-15 days). The duration of a negative nucleic acid test result (more than 2 consecutive negative tests at intervals of >24 hours) was 13.5 days (95% Cl:9.5-17.5).

If the basic treatment regimen is ineffective, adults aged 18-65 may receive chloroquine phosphate (500 mg as a single dose for the first two days, followed by 500 mg qd for five days).

The course of chloroquine phosphate treatment should not exceed 7 days. The treatment course for other regimens has not been established and is generally about 2 weeks. Antiviral drugs should be stopped if nucleic acid test results from sputum samples remain negative more than 3 times."

Can Plaquenil Be Used Prophylactically (for Protection) Against COVID-19?

In its guideline entitled Assessment of Healthcare Workers with COVID-19 Contact, published on 26.03.2020, the Ministry of Health recommended hydroxychloroquine prophylaxis for healthcare workers with high-risk contact, in other words, post-exposure prophylaxis.

Mass prophylactic trials of drugs such as Plaquenil before their effectiveness is proven may cause the virus to undergo mutations much faster than its natural course, acquire resistance, and lead us to create a new virus and experience a new outbreak in the near future!

Nearly 100 noncritical mutations have already been identified for this virus. Drugs swallowed like candy on the assumption that they have no adverse effects will put pressure on the virus’s resistance mechanisms.

Believing that taking Plaquenil provides protection is another misconception... As the virus spreads, it may undergo more mutations; this process is random and involves, in particular, what we call genetic drift. This is why allowing the virus to evolve and change by spreading it poses a greater risk that will also negatively affect drug discovery.

Conclusion

Plaquenil, whose active ingredient is hydroxychloroquine and which is an older drug originally used to treat malaria and some rheumatic diseases, has so far shown no effectiveness either in treating COVID-19 or prophylactically (protectively) against COVID-19 disease. Indeed, the scientific study results to date support not using it against COVID-19. Furthermore, because tests of this drug’s safety, dose and interactions with other drugs (such as cancer medicines) in COVID-19 treatment have not been adequately conducted, these factors should be considered when contemplating its use, especially for people with additional illnesses.

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