On March 21st, 2020, Trump tweeted about hydroxychloroquine and azithromycin as treatments for Covid-19. Ever since then, chloroquine is consistently trending on social media, including a lot of incomplete information or falsehoods about the drug. What is the complete story?

In this post, I will try to tell apart facts from fiction methodically, starting with a brief presentation of what chloroquine is in the first place before chronologically going over proposals to use it as treatment of the Covid-19 disease. I will then attempt to fact-check a few widespread claims about the drug, before concluding on its potential to help solve the ongoing pandemic.

While I am not a health professional, critical claims in this article will be sourced with medical textbooks, scientific research papers, or guidelines and citations of health authorities and infectious diseases experts. Please consult a health professional before taking any drug on your own.

Chloroquine — a brief presentation

Chloroquine is a molecule that was first discovered in 1934 and has been used as an anti-malaria drug since the 1940s, both in prevention and treatment. Hydroxychloroquine is derived from chloroquine and very close to it chemically. It is also used as treatment of malaria as well as some forms of arthritis, lupus, or other chronic diseases with common doses in the range of 200–400mg per day.

Chloroquine is a relatively simple organic molecule. Hydroxychloroquine has exactly the same structure, with an added -OH group at one of the ends of the molecule.

Further than that, both molecules have been known for a long time to be effective in preventing in vitro cells infection by some type of viruses (like Zika in vitro) by acting on the acidity of the surrounding medium. More references can be found in scientific papers linked in this article. This is of course not the case for every virus, but it has been suggested that SARS-CoV (the virus responsible for the 2003 outbreak) might be inhibited by concentrations of chloroquine attainable with very well known dosage.

The inhibitory effects observed on SARS-CoV infectivity and cell spread occurred in the presence of 1–10 μM chloroquine, which are plasma concentrations achievable during the prophylaxis and treatment of malaria (varying from 1.6–12.5 μM) [26] and hence are well tolerated by patients.

It is no surprise then that chloroquine / hydroxychloroquine are being considered as candidate treatments for SARS-CoV-2, the virus reponsible for the Covid-19 pandemic.

Chloroquine and Covid-19 — Chronology

Many people first heard about chloroquine about a week ago when Trump presented it during a press conference, but the story starts earlier.

As previously discussed, it was already identified as an inhibitor of some viruses way before the ongoing pandemic started. Doctors and researchers in China naturally investigated as a potential treatment, as the novel coronavirus was rampaging in Wuhan. They discovered that it could effectively inhibit SARS-CoV-2 in vitro :

Our findings reveal that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro. Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, we suggest that they should be assessed in human patients suffering from the novel coronavirus disease.

These results were published on February 4th, 2020 in Nature. A few days later on February 11th, a team of French infectious diseases experts published a short position paper recalling that they had proposed a systematic review of the effect of chloroquine on viruses 20 years ago, emphasizing that it was one of the most prescribed drugs in the world with an established safety profile, and as such that it should be promptly evaluated for the treatment of Covid-19.

One of the co-authors of this last paper, Pr. Didier Raoult, quickly came at the center of media attention in France after a video originally called “Coronavirus : fin de partie ?” (translation: “Coronavirus: end game?”) was uploaded by his institute (IHU Méditerranée-Infection) on February 25th where he can be seen discussing published and unpublished Chinese results and stating his optimism that this treatment could solve the crisis.

Pr. Raoult is not some voodoo pseudo-scientist: he is consistently ranked among top researchers in infectious diseases and was part of the scientific council put together by the French government to address the Covid-19 crisis. The French Health Minister said he was taking notes of chloroquine and following the situation closely. Teams at the IHU Méditerranée-Infection quickly started to treat Covid-19 patients who agreed with known dosage of hydroxychloroquine.

“I am not an outsider, I am ahead of others”. Pr. Raoult was spearheading research into chloroquine as a treatment of the Covid-19 in France before the outcry following Trump’s tweet.

Meanwhile, more results started to come from China pointing in the direction of hydroxychloroquine as a potential treatment and a (not peer-reviewed) manuscript was uploaded by an American researcher, further insisting that:

There is ample evidence of the in vitro and in vivo efficacy of CQ and its derivatives in the prevention and treatment of multiple species of coronavirus, including in vitro experiments with SARS-CoV-2.

On March 17th, 2020, the IHU published preliminary results of their “open-label”, non randomized trial on the treatment of Covid-19 with hydroxychloroquine and a combination of hydroxychloroquine and azithromycin, an antibiotic. While this research is flawed (non randomized, 3 patients dropped out of the study before the end), it showed encouraging results.

Under the pressure of this body of evidence accumulating, the drug is now included in randomized, controlled clinical trials around the world to definitely assess its effectiveness. However, several countries did not wait for trials to include hydroxychloroquine in their official treatment guidelines (source for Belgium — to be verified for China, South Korea and Italy).

It is in this context, 4 days after Raoult’s team publication, that Trump mentioned the drug during his press conference. From this chronology, we can see that his claim of hydroxychloroquine showing potential as treatment is not a random, baseless claim. However, it is still exaggerated and arguably irresponsible: there is still no conclusive evidence of its effectiveness in vivo, and it has only been used so far under doctor supervision.

Results from the preliminary study of Gautret et al. The study is flawed in that it was not randomized and that not all patients who started the trial could be included in the final results, but it is still promising.

But why exactly don’t we call it a day and start using the drug widely? Does it have side-effects? Is it dangerous? Soon after Trump’s mention, cases of chloroquine overdose were reported in Nigeria and an Arizona man died of poisoning. Surely, this proves this molecule is a dead-end, a highly dangerous poison that inhibits the virus only at the cost of violent side effects, right? Let’s do some debunking.

Fact-checking chloroquine claims

Chloroquine (CQ) and hydroxychloroquine (HCQ) have many side-effects

This is true. There are many known side effects of these two molecules. According to the American College of Rheumatology:

The most common side effects are nausea and diarrhea, which often improve with time. Less common side effects include rash, changes in skin pigment (such as darkening or dark spots), hair changes, and muscle weakness. Rarely, hydroxychloroquine can lead to anemia in some individuals. (…) In rare cases, hydroxychloroquine can cause visual changes or loss of vision.

However, it is also noted that it is “typically is very well tolerated. Serious side effects are rare.” Furthermore, it is noted that some of these side effects only happen over long term use.

CQ and HCQ can easily lead to overdose

Rigorously speaking, it is true that one can overdose on CQ and HCQ. However, this claim is false at recommended doses. As we have previously seen, there are many patients in the world who are treated with HCQ for conditions such as arthritis or lupus with 200–400 mg per day (sometimes a bit more) over several months. This is a very similar dosage to that recommended in Belgian guidelines for treatment of Covid-19 patients, or the one used by the Pr. Raoult team. Remember though that there is a risk zone: more than 2g in one take can lead to acute poisoning. This corresponds to 10 pills of PLAQUENIL, one of the commercial versions of HCQ. Fortunately, this is well above the dosage discussed in the context of Covid-19 treatment. The claim that it is easy to overdose on CQ/HCQ is only true to the extent that it is easy to overdose on any medication if one takes 10 pills at a time.

There are dangerous contra-indications for CQ and HCQ

As noted in the Belgium guidelines from health authorities, there are indeed some contra-indications for CQ and HCQ. This includes some drug interactions, QT interval over 500 ms, epilepsy and others. However, these don’t appear to be common occurrences. With that being said, this means that the treatment should be administered under doctor advice and supervision.

Pregnant women can’t take HCQ

There is a suspicion that CQ/HCQ might present some risk for pregnant women. However, several health authorities still say it can be used at any stage during the pregnancy within recommended dose (see for example this French institute or the aforementioned Belgium guidelines).

Taking both HCQ and azithromycin will kill you

This is blatantly false at recommended dosage, as attested by the trial conducted by the team of Pr. Raoult and his team of other infectious disease experts in France where they administered the two drugs at the same time to patients.

Towards a potential chloroquine based treatment

Yes, there is an accumulating body of evidence pointing towards CQ/HCQ being an effective treatment against SARS-CoV-2 infections.

No, it is not proven yet beyond reasonable doubt.

No, CQ/HCQ are not highly dangerous drugs that will kill you or lead to dangerous side effects if you take the recommended dose, they are in fact extremely well known drugs with extremely well understood safety profile.

Yes, it is highly recommended to take any drug under doctor supervision only.

What are we to make of all this? Several clinical trials are underway and should bear fruit within the next few weeks. There is hope based on scientific understanding that CQ/HCQ could prove to be an effective treatment to cure the Covid-19 disease or prevent severe forms. In the meantime, several health authorities worldwide issued recommendations to use it with patient agreement, and some doctors are already doing it.

But isn’t it highly unethical to administer an untested treatment to patients? Here we should recall that it is not just any unknown treatment. These drugs have been on the market for several decades and are well understood. They are also the only drugs on the market that have shown promise in treating the Covid-19 disease which has already killed thousands of people and will continue to do so if things continue this way. In this context, it would appear that not attempting to save patients’ with a known substance (administered with proper care) is the unethical thing to do, not the other way around.

In France, it was decided on March 23rd to restrict the use of hydroxychloroquine to patients in critical conditions, pending clinical trial results. This is directly at odds with ongoing investigations, which suggest that the treatment is most effective in preventing the disease evolution into a severe form in the first place, and that it is only marginally effective (if at all) once patients are already in critical care. Is this ethical? Pr. Perrone, Medical Chief of the Infectious Disease Department of a Parisian hospital has an opinion on this:

Preliminary studies have shown that hydroxychloroquine works, as long as it is administered to patients who are not already in critical conditions. I was flabbergasted to hear about the decision of my colleagues which is opposite to the recommendations of preliminary research work: if we give the drug to people who are already suffocating, it is too late. Furthermore, we are preparing a clinical trial in Europe with randomized groups, including one which will receive no treatment at all. (…)This is a war, and I am shocked that we are asking patients to agree to receive potentially no treatment while at the same time, there is accumulating evidence that hydroxychloroquine might cure them. - Pr. Perrone, approximate translation from an interview on French television

Of course, future decisions should be informed by the to be published results of ongoing clinical trials.

Thank you for reading and be sure to leave a comment if you spot any inaccuracy.