Brazil: Chloroquine's silent revenge

By Dr. Olavo Amaral

Revisiting the unlikely saga of the most hated drug of the last decade is an exercise in humility for the scientific establishment.

No one expected this to happen in 2024. But on September 12, the largest study ever conducted on pharmacological prophylaxis for COVID-19 was published. Led by the Center for Tropical Medicine and Global Health at the University of Oxford, COPCOV brought together more than 70 authors and 26 medical centers in 11 countries and three continents to test the effect of hydroxychloroquine and chloroquine – yes, those same ones – in preventing the disease in unvaccinated individuals at risk of infection.

The randomized, double-blind study, which began in April 2020 and continued in fits and starts amid a minefield of controversy until March 2022, enrolled 4,652 unvaccinated participants—far fewer than initially planned—before being shut down. Still, it was not published in the journal PLoS Medicine until more than two years later, after a full year of peer review. 

The results? The group treated with hydroxychloroquine (in Europe and Africa) or chloroquine (in Asia) had a 15% lower prevalence of confirmed infections than the placebo group after three months of follow-up—a result that met the commonly used thresholds for statistical significance. Among secondary outcomes, prophylaxis was associated with more robust reductions of 39% in PCR-confirmed infections and 13% in workdays lost due to illness, but not in the prevalence of asymptomatic infections or in symptom severity. Nor did it lead to an increase in serious adverse events, the incidence of which was even higher in the placebo group.

Although the results are modest, they are quite consistent with the aggregate evidence from previous studies – which, as a meta-analysis published in 2022 and analyzed by this column at the time indicated – pointed to a benefit of this magnitude. An updated analysis including COPCOV carried out by the authors of the study themselves estimates a 20% reduction in the chance of infections with prophylaxis, with remarkable agreement between the included studies and a 95% confidence interval of the effect – the popular “margin of error” in electoral polls in which you expect to find the true value 95% of the time – between 9 and 29%. 

Until a few years ago, the announcement would have caused shock, outrage, euphoria and controversy. In 2024, however, no one seems to care anymore. Apart from the websites of the institutions involved and the irreducible chloroquiners of Médicos pela Vida, basically no one has commented on the study, which went unnoticed in the media – as had already happened with PRINCIPLE, a late clinical trial on ivermectin that also suggested some benefit. And the authors themselves admit that, with vaccines, treatments and reduced virulence of Covid-19, there is little or no reason to take prophylaxis for the disease in 2024. 

Still, they also argue that if the results had been available in 2020 or 2021, when there were no vaccines and the virus had a higher lethality, the prophylactic use of the drug could have played a relevant role. And that the polarization associated with chloroquine – a side effect of the drug that has been taken up as a political banner by far-right politicians around the world – compromised the objective assessment of the issue by the scientific community.

It is already too late to take the opposite path and give hydroxychloroquine a chance at the height of the pandemic. As a result, it is likely that we will never be able to measure the impact of the politicization of the drug, and its consequent demonization by an academic environment that is not very sympathetic to its defenders , on the number of lives lost by COVID-19. On the one hand, the evidence of the drug's benefits as a prophylactic has become increasingly convincing. On the other hand, large clinical trials in hospitalized patients have consensually indicated the lack of benefit and potential risks with the use of the drug.

In between one thing and another, there is the use of the drug in outpatients – the much talked about “early treatment” that mobilized love and hate in the popular imagination during the pandemic. In this scenario, the issue is more nebulous, and existing meta-analyses oscillate between a modest benefit in preventing hospitalizations (although with a much greater degree of uncertainty than that observed in prophylaxis, due to the low statistical power of the studies that evaluated the issue) and the absence of effect – results that justify the non-inclusion of the drug in official treatment recommendations, but not the statement that it is “ provenly ineffective ”.     

I’m not bringing this up to take sides on the issue – that would require reading the literature with a level of time and attention that I no longer have. But I don’t really care who was right at this point in the game – especially since the existing evidence was built in a world of more lethal SARS-Cov2 variants and non-immunized patients that no longer exists. I’m just writing to point out the fact that there is a legitimate margin of uncertainty on the subject – and that it probably always has been. Even though you probably don’t know it, because both sides of the political spectrum have spent the last few years dedicated to wiping any doubt about the subject off the map .

If for drug enthusiasts there was never any doubt , on the part of the scientific establishment, chloroquine soon gained the status of flat-earther after a few negative clinical trials – even though these were not large enough to rule out a modest benefit from outpatient use. I cannot tell you the number of times I have heard in academia that “we have to defend scientific training so that people do not take chloroquine”, or seen images of Bolsonaro offering the drug as a kind of stock image to talk about denialism – including in my own articles. Likewise, the idea that the drug was responsible for thousands of deaths during the pandemic has become commonplace, even though the evidence to support this is indirect, unreliable or simply fraudulent. 

The mainstream media, by the way, is still very prolific in using the fact that someone defended chloroquine to label doctors, scientists, politicians, journalists and personas non grata in general as “anti-science”. Not that many of these people do not deserve it for countless other reasons. But it is ironic that the pathognomonic sign of their rejection of science is a cause that, from a scientific point of view, is quite defensible.

And what really worries me is that the vast majority of activists who speak “in defense of science” – whether in the press, at scientific conferences or on social media – have no idea about all this, and do not seem to have spent more than five minutes delving into the evidence on the subject. Which seems to indicate that the passionate and antagonistic positions on the drug can be explained almost entirely by the sources of information used by different individuals .

Ultimately, this is simply inevitable: any of us only have time to delve into a handful of topics, or not even that, and getting information from other people's opinions is completely norma . What bothers me is the difficulty self-proclaimed defenders of science have in admitting this fact – that we are in the dark about almost everything, and that finding our way in the world is less a question of knowledge or scientific training than of being able to choose sources of information that are less likely to be wrong.

And after a few years studying the debate surrounding hydroxychloroquine, based on an essay that will be published in a book in 2025, the main lesson I have learned is about epistemic humility. Seeing that almost everyone has strong opinions on a topic that dozens of hours of study were not enough to give me certainty about makes me realize how much my own convictions on other subjects, from global warming to interest rates, were determined by other people. This has made me much more thoughtful when expressing my opinion on them in classes, on social media or in bars.

But my personal silence will not save the world from the risks of hasty consensus – which has occurred not only with hydroxychloroquine but with several other issues related to the pandemic . This will only happen if academic science and the institutions that use it – such as health authorities, media outlets or legal courts – can incorporate a similar spirit into their daily practice.

And if there is an obvious first change in behavior to be made, it is to let go of the idea that “fighting misinformation” is a panacea for science to win the battle against darkness and spread its benefits to all of us. Of course, there are consensus topics on which it is easy to point out falsehoods: the earth is more spherical than flat, smoking is associated with lung cancer beyond any reasonable doubt, and so on. For these topics, ignoring dissenters is healthy, and sometimes necessary to avoid creating false controversies .

But for many subjects, the scientific evidence is far less solid than we would like, and it is not usually easy to navigate. As a result, differing convictions about the best way to interpret data can easily lead experts to take opposing positions for absolutely defensible reasons. In this scenario, the equivalence of chloroquine with flat-eartherism in the minds of most people – including the scientific community – is living proof of our collective difficulty in separating the topics on which consensus is obvious from those on which it is not.

And until we create better ways to do this, there seems to be no option but to let the public debate happen – which we hesitate to do even within academia. The very fact that a clinical trial takes a whole year to be peer-reviewed before being published is the result of the expectation – apparently unrealistic – that a handful of guardians of the truth will be able to separate the wheat from the chaff. Solutions to speed up the process have existed for a long time – preprints have been around for more than three decades – and the fact that we care so much about what two or three reviewers think attests to the overconfidence in our control mechanisms.

And as we face a flood of content of heterogeneous quality – which the somewhat Manichean dichotomy between “information” and “disinformation” does not always describe – I worry that the world has been contaminated by our arrogance and bought into the idea that “ science does not have two sides” and is capable of perfectly self-regulating. And in the process, it has built the belief that defining what constitutes scientific truth will be a task easily carried out by fact-checkers, social media algorithms or courts of law.

By the way, my delay in talking about COPCOV is due to the fact that the social network through which I used to find out about these things was blocked for a while – coincidentally or not, with the same motto of “fighting fake news”. And it is at least curious that I found out about the study through the website of Médicos pela Vida – or more precisely through its editor Filipe Rafaeli, four-time Brazilian champion in aerial acrobatics, anti-vaccine activist and fact-checker – with whom I happened to establish a communication channel during the pandemic to talk about these things.  

This kind of contact has helped me realize that this whole “science advocates” vs. “deniers” thing is kind of a load of crap. At the end of the day, we’re all human beings, misinformed about almost everything, trying to navigate a landscape of insufficient and complex evidence amidst the noise of the world and a myriad of personal biases. And if I disagree with Rafaeli on almost everything regarding COVID-19, it has less to do with misinformation and more to do with our varying degrees of familiarity with the scientific process and trust in the institutions responsible for it.

Because despite all of the above, I still trust that science—not the idealized process of textbooks, but the human enterprise with a small “c” that tries to put it into practice—tends to get it right more often than it gets it wrong. A conviction that has a lot to do with being busy trying to change it from the inside. But when scientific institutions throw defensible ideas into the flat-earther bucket, leading journalists to ridicule them and algorithms to censor them despite the available evidence, it’s hard to blame anyone looking in from the outside for losing that trust.

And I hope that the belated redemption of chloroquine serves as a lesson in humility that makes us reflect on what we can do to maintain trust in science. When you start to depend on anti-vaccine activists to inform you about a topic, because they follow the evidence better than an establishment too busy controlling the discourse on it, the conspiracy theory wormhole is just around the corner. I don't think I've gone down it yet. But if so many people are getting on board, it's worth wondering if it's our fault.

Olavo Amaral is a physician, writer, and professor at UFRJ. He was a neuroscientist for two decades and today he is dedicated to promoting a more open and reproducible science. He coordinates the Brazilian Reproducibility Initiative, a multicenter replication of experiments in Brazilian biomedical science, and No-Budget Science, a collective to catalyze projects dedicated to building better science. As a writer, he is the author of Dicionário de Línguas Imaginárias and Correnteza e Escombros

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