As hard as it is to believe, it’s been a month since I’ve written about Didier Raoult and his promotion of the combination of the antimalarial drug hydroxychloroquine with azithromycin as a near-miraculous treatment for COVID-19, fueling its rise as the preferred go-to cure that “they” don’t want you to know about among COVID-19 conspiracy theorists and the right wing media based on various Silicon Valley tech bros picking up on his execrable study and singularly uninformative first study, leading President Trump to tout it as a “game changer.” Raoult’s followup studies since then have been no better, including a case series with no control, which he later expanded. The weakness of the science didn’t stop the FDA from issuing an emergency use authorization (EUA) for hydroxychloroquine to treat COVID-19 based on the thinnest of evidence. So, at the end, what we had was an EUA for a drug that had shown almost zero evidence of working, other than studies by a French “brave maverick scientist” and anecdotes, even though the drug could produce substantial cardiac, liver, and retinal toxicity. This was truly a cautionary tale about the dangers of bypassing science- and evidence-based medicine, even during a pandemic, something the FDA also did with remdesivir, issuing an EUA based on a highly questionable study that hadn’t even been published yet (and, two weeks later, still hasn’t).
Didier Raoult back in the news in the US
Interestingly, with the drip-drip-drip of unpromising and negative studies, we’ve been hearing less about hydroxychloroquine over the last few weeks. That’s why earlier this week I was surprised to see a big story about Raoult in the New York Times by Scott Sayare, He Was a Science Star. Then He Promoted a Questionable Cure for Covid-19. I groaned at the headline, complete with an oh-so-artsy photo of Didier Raoult side-lit, the better for the shadows to make him look so very, very serious, and the blurb under the headline:
The man behind Trump’s favorite unproven treatment has made a great career assailing orthodoxy. His claim of a 100 percent cure rate shocked scientists around the world.
I groaned, because this sure looked as though it was going to be a “portrait of a controversial figure” that newspapers love so much. I predicted that, as is so often the case, the controversy will be explored, but many of the warts would be glossed over. Before I discuss that, I will give credit where credit is due. I will give Sayare credit for one bit of irony in the very first paragraph:
When diagnosing the ills afflicting modern science, an entertainment that, along with the disparagement of his critics and fellow researchers, he counts among his great delights, the eminent French microbiologist Didier Raoult will lightly stroke his beard, lean back in his seat and, with a thin but unmistakable smile, declare the poor patient to be stricken with pride. Raoult, who has achieved international fame since his proposed treatment for Covid-19 was touted as a miracle cure by President Trump, believes that his colleagues fail to see that their ideas are the products of mere intellectual fashions — that they are hypnotized by methodology into believing that they understand what they do not and that they lack the discipline of mind that would permit them to comprehend their error. “Hubris,” Raoult told me recently, at his institute in Marseille, “is the most common thing in the world.” It is a particularly dangerous malady in doctors like him, whose opinions are freighted with the responsibility of life and death. “Someone who doesn’t know is less stupid than someone who wrongly thinks he does,” he said. “Because it is a terrible thing to be wrong.”
That is a case of projection so massive that it could be used to show IMAX movies.
What’s left unsaid
If only Sayare had followed through and made this truly a portrait of hubris. Of course, to do that, it would have been helpful not to leave so much out. For example, remember all the findings of bullying, sexual harassment, and intimidation of underlings? Here’s all Sayare had to say about it in a 7,700 word profile of Raoult, and then this paragraph appeared over a third of the way into such a huge article:
With few exceptions, the department heads at the IHU have worked under Raoult for their entire careers, some for more than 30 years. It is an “ancestral system,” “familial” and “clanlike,” said Michel Drancourt, a clinician who is Raoult’s longest-serving collaborator. Raoult is, without question, the patriarch, and he is in some respects reputed to be benevolent. The IHU spends a great deal of money on scholarships and research grants for students from the developing world, for instance, and Raoult is known to be accessible to young researchers in a way that distinguishes him from other high-powered scientists. He is also known for berating his subordinates. While visiting the IHU, I watched a young researcher emerge from Raoult’s office in tears and rush into the arms of her friends, who were evidently accustomed to this. “When he’s not happy about something, he’ll let you know,” one of them told me. A 2017 employee letter of complaint, which was followed by an investigation of the IHU, described the “screaming,” “insults” and “psychological bullying” of a “leadership of another era.” Along the entryway to Raoult’s institute, there’s a line from Horace: Exegi monumentum aere perennius, “I have crafted a monument more lasting than bronze.”
You’ll excuse me if I didn’t take that as bordering on, if not outright, excusing his bullying behavior as a holdover from another generation. It’s also more than that. It’s been widely reported that Raoult revels in publicly humiliating subordinates by dressing them down at meetings. But, hey, he’s accessible to students; so that partially excuses his tendency to reduce them (especially women) to tears with his verbal tirades when they displease him. (That seems to be the implication.) But, hey, he’s crafting a monument more lasting than bronze! So there’s that! What are the feelings of his subordinates compared to that? Maybe Sayare didn’t mean it that way, but it sure came across like that to me (and others).
This culture in Raoult’s lab had (and continues to have) consequences, too.
Then there was this:
In 2017, Raoult’s leadership was challenged by a sexual harassment and assault scandal at his URMITE institute, an affair with at least six victims which the director himself described as “a love story gone wrong“. The perpetrator was eventually sacked, but Raoult did not handle the case exemplary, quite the opposite. This article in MarsActu narrates that Raoult tried to hush up the affair for two years while even trying to have the victim sacked…
This article (in French, but Google Translate works pretty well for French if you don’t read French, by and large) summarizes the issues and the findings of three different reports that paint a very damning picture of Raoult’s labs. These reports predate the pandemic by as much as three years; so none of the problems in Raoult’s Institut Hospitalo-Universitaire Méditerranée Infection, or IHU. First, let’s look at how these reports were described in Sayare’s article:
This apparent sloppiness was unsurprising to many of those who have tracked Raoult’s work in the past. A prominent French microbiologist told me that, in terms of publication, Raoult’s reputation among scientists has been “long gone” for some time. “In private,” the researcher wrote to me, “everybody agrees on the low reliability/reproducibility of most of the papers coming out of his lab.” (He asked to speak anonymously so as not to anger Raoult, whom he knows.) In 2018, after damning evaluations, Raoult’s principal laboratory groups were stripped of their association with two of France’s top public research institutions. Raoult was found to have produced an extraordinary number of publications but few of great quality. “It’s very easy to publish [expletive] when you know how publishing works,” said Karine Lacombe, a professor of medicine in Paris who has recently been among Raoult’s more outspoken critics.
I find it very telling that the person making the criticism above wouldn’t go on the record by name because he’s so intimidated by Raoult. This is a recurring theme again and again in Raoult’s story. For example:
Out of seven written testimonies received, two admit and regret the deliberately biased results of their studies. One engineer thus reports “a falsification of results at the request of a researcher” and another “questions scientific rigor when certain results are obtained”.
Mediapart found other witnesses of such drifts: several engineers or researchers told us of similar facts. Like Mathieu, who prepared his doctoral thesis with Professor Didier Raoult. The problem, according to him, is that “he does not admit discussion”: “We work in reverse. He has an idea and we are working to prove that he is right. With fear of contradicting it, this can lead to biased results. However, it is doubt and discussion that allow science to move forward.”
He remembers the first meeting in the presence of the professor. “It was a Wednesday afternoon, during a“ work in progress ”. This is the time when PhD students present the state of their research. We had five minutes to present sometimes three to four months of work. It’s very short. At the slightest disagreement, Didier Raoult said: “You are not there to think, I am the one who thinks.””
Nowhere in the entire 7,700 word portrait is any mention are the examples of data fabrication by scientists in Raoult’s group. It’s not as though this isn’t public knowledge. After all, in 2006, a reviewre for Infection and Immunity, a journal published by the American Society for Microbiology (ASM) discovered four figures in a revised manuscript were identical to four figures in the original manuscript? So what? The problem is that they were represented as showing a different experiment. One of Raoult’s co-authors was thrown under the bus, claiming an “innocent mistake.” The result:
ASM banned all five authors, including Raoult, from publishing in its journals for a year. “We are not entirely comfortable with the explanation provided,” ASM officials wrote to Mège. “Misrepresentation of data … is an affront to the ethical conduct of scientific inquiry.”
On the plus side, I’ll give Sayare credit for explaining just why Raoult’s first paper was so bad, a description as good as any I’ve seen in a mainstream media outlet. His well-known tendency to value conflict and contrarianism above all else was also well-described. By the end, though, I couldn’t help but get the feeling of a portrait of a brilliant but flawed scientist, rather than the portrait of the crank that Raoult has become.
The drip-drip-drip continues
I thought I’d finish up this post by briefly reviewing some of the data that have come in since the last time I discussed hydroxychloroquine. It’s basically all been negative, except, of course, Raoult’s study published, Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France, a week ago in the same journal whose editor is one of his cronies. This appears to be the study that I mentioned a while back that, at the time, consisted only of data tables published in the IHU website. Does the full manuscript actually illuminate anything? I think you know the answer to that. My discussion of the abstract applies to the full manuscript. One change I noted is that the mortality rate in the abstract was 0.5% but has now risen to 0.75% due to more deaths between the posting of the abstract and publication in the journal. Again, there’s no way of knowing if this mortality rate is any different than it would have been if the patients had not been treated with hydroxychloroquine and azithromycin. Tellingly, even Raoult has changed his conclusion from characterizing the combination as “safe and efficient” to just “safe” and “associated with low mortality.”
Meanwhile, on Monday JAMA published a large cohort study examining 1,438 patients in New York treated with hydroxychloroquine ± azithromycin. Basically, it was a retrospective multicenter cohort study of patients taken from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 area hospitals. The authors compared cohorts who received both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither, with the date of final followup being April 20. The primary outcome was in-hospital mortality, with additional secondary outcomes of cardiac arrest and abnormal electrocardiographic (ECG) findings (defined as arrhythmia or prolonged QT fraction). The authors found no significant differences in the groups in the primary outcome, in-hospital mortality. They also found:
A greater proportion of patients receiving hydroxychloroquine + azithromycin experienced cardiac arrest (15.5%) and abnormal ECG findings (27.1%), as did those in the hydroxychloroquine alone group (13.7% and 27.3, respectively), compared with azithromycin alone (6.2% and 16.1%, respectively) and neither drug (6.8% and 14.0%, respectively). In adjusted models with those receiving neither drug as comparison, cardiac arrest was more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]; E-value = 1.31), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) and azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), and also in patients taking hydroxychloroquine alone vs azithromycin alone (adjusted OR, 2.97 [95% CI, 1.56-5.64]; E-value = 1.81).
Obviously, this is a retrospective study, with all the weaknesses inherent in observational studies. It’s not a randomized, double blind placebo-controlled clinical trial. However, the authors did do a thorough job of controlling for confounders, and they had a relatively large sample size. Not seeing a hint of a benefit in terms of mortality strongly suggests that either Raoult’s combination doesn’t work or its effects are so modest as to be detectable only in a large randomized clinical trial. (Personally, I think it almost certainly doesn’t work.)
Finally, yesterday BMJ published two hydroxychloroquine studies. One is an observational study of 181 COVID-19 patients with pneumonia in four French hospitals who required oxygen but not intensive care comparing hydroxychloroquine at 600 mg/day within 48 hours of admission with standard of care. The primary outcome was survival without transfer to an intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). The 84 patients receiving hydroxychloroquine were compared to 89 patients who did not, and the authors reported that the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). As for the other outcomes, there was no difference in survival at day 21, survival without ARDS at day 21, or weaning from oxygen, but eight patients in the treatment group experienced ECG abnormalities requiring stopping the medication. Yes, again this is an observational study with all the attendant weaknesses of such studies, but again it finds no evidence of a benefit for hydroxychloroquine in COVID-19.
The last study is a Chinese randomized, open-label study of hydroxychloroquine versus standard of care in patients with mild to moderate COVID-19. The primary outcome measure was negative conversion of the virus (eradication) by 28 days. There was no difference in the negative conversion of SARS-CoV-2 at 28 days in the hydroxychloroquine group. True, this was a relatively small study (150 patients) and was open-label, but testing negative for the virus is a “hard” outcome; so the open label design bothers me less than it would for more subjective outcomes. Also, unfortunately, clinical outcomes, other than adverse events, weren’t reported.
So, basically, the evidence for hydroxychloroquine is basically all negative, except for studies from Didier Raoult’s group (and those are singularly uninformative) and a small study long ago. This leads me to ask: Why did the NIH just announce a large randomized clinical trial of hydroxychloroquine:
Given the existing state of the evidence, I would argue that the pretest probability of a positive study is very low. Existing preliminary evidence for hydroxychloroquine, were this any other drug and were we not in a pandemic, would very likely not justify a large randomized clinical trial. Unsurprisingly, Didier Raoult is ecsstatic:
And so it goes. Yet:
187 studies registered on ClinicalTrials.gov? This is madness, particularly for a drug that’s shown so little promise in preliminary studies. That is Didier Raoult’s legacy, shunting research on effective treatments for COVID-19 down what is almost certainly a blind alley that is wasting (and will continue to waste for the foreseeable future) resources before scientists can finally move on to something else.