He Was a Science Star. Then He Promoted a Questionable Cure for Covid-19. - The New Yor... - 0 views
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In the 1990s, in an early repurposing experiment, he tested the effect of hydroxychloroquine on a frequently fatal condition known as Q fever, which is caused by an intracellular bacterium. Like viruses, intracellular bacteria multiply within the cells of their hosts; Raoult found that hydroxychloroquine, by reducing acidity within the host cells, slowed bacterial growth
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He began treating Q fever with a combination of hydroxychloroquine and doxycycline and later used the same drugs for Whipple’s disease, another fatal condition caused by an intracellular bacterium. The combination is now considered to be a standard treatment for both diseases.
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Chinese reports, however, appeared to confirm Raoult’s longstanding hopes for chloroquine. A deadly virus for which no treatment existed could evidently be stopped by an inexpensive, widely studied, pre-existing molecule, and one that Raoult knew well. A more heedful scientist might have surveyed the Chinese data and begun preparations for tests of his own. Raoult did this, but he also posted a brief, jubilant video on YouTube, under the title “Coronavirus: Game Over!”
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Chloroquine had produced what he called “spectacular improvements” in the Chinese patients. “It’s excellent news — this is probably the easiest respiratory infection to treat of all,” Raoult said. “The only thing I’ll tell you is, be careful: Soon the pharmacies won’t have any chloroquine left!”
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Raoult wrote his first research paper, in 1979, on a tick-borne infection sometimes known as Marseille fever. The disease was also called “benign summer fever,” and more than 50 years of science said it was nonlethal. And yet one of the 41 patients in his data set had died.
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Before submitting the paper, Raoult, who was then a young resident, gave it to a supervising professor for review. “And he takes it,” Raoult told me, “he doesn’t show it to me again, and he publishes it — and he’d taken out the death. Because he didn’t know how to make sense of the death.”
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Raoult was disgusted, and the incident shaped his philosophy of scientific inquiry. “I learned that the people who wanted to follow the familiar path were prepared to cheat in order to do it,” he said.
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In Raoult’s view, French science was a duchy of appearances, connections and self-reverence. “It was people saying” — he mimed the drone of an aristocrat — “ ‘Oh, him, yes, he’s very good.’ And this reputation, you don’t know what it’s based on, but it’s not the truth.”
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“He was a ‘follower,’” Raoult said of the professor. “And these ‘followers’ are all cheaters. That’s what I thought. And it’s still what I think.”
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He is, fundamentally, a contrarian. In Raoult’s view, little of consequence has been accomplished by researchers who endorse the habitual tools and theories of their age.
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“I’ve spent my life being ‘against,’” he told me. “I tell young scientists: ‘You know, you don’t need a brain to agree. All you need is a spinal cord.’” He is thrilled by conflict. It is a matter both of philosophy — the influence, no doubt, of the thinker he refers to admiringly as “master Nietzsche” — and of temperament.
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His peers shake their heads at this behavior but grant him a grudging respect. “You can’t knock him down,” said Mark Pallen, a professor of microbial genomics at the University of East Anglia. “In terms of his place in the canon, the sainthood of science, he’s pretty secure there.”
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In 1985 and 1986, Raoult worked at the Naval Medical Research Institute in Bethesda, Md., where he discovered the Science Citation Index. The index, a tool that can be used to measure a scientist’s influence on the basis of his or her publication history, was relatively unknown in France. Raoult looked up the researchers reputed to be the best in Marseille. “It was really the emperor wears no clothes,” he said. “These people didn’t publish. There was one who hadn’t written a paper in 10 years.”
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In subsequent work, he demonstrated that Marseille fever was indeed fatal in almost precisely one in every 41 cases.
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Raoult’s name sits atop several thousand; in each of the past eight years, he has produced more than 100. In 2020, he has already published at least 54.
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Like many doctors, Molina viewed Raoult’s study with skepticism, but he was also curious to see if his proposed treatment regimen might in fact work. He tested hydroxychloroquine and azithromycin in 11 of his own patients. “We had severe patients, and we wanted to try something,” Molina told me. Within five days, one had died, and two others had been transferred out of his service to intensive care. In another patient, the treatment was suspended after the onset of cardiac issues, a known side effect of the drugs. Eight of the 10 surviving patients still tested positive for SARS-CoV-2 at the conclusion of the study period
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Raoult is reputed to be an indefatigable worker, but he also achieves his extreme rate of publication by attaching his name to nearly every paper that comes out of his institute.
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In recent years, Raoult has amused himself, it seems, by staking out tendentious scientific claims, sometimes in territories that are well beyond the scope of his expertise.
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He is skeptical, for instance, of the utility of mathematical modeling in the realm of epidemiology.
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The same logic has led him to conclude that climate modelers are no more than “soothsayers” for our “scientistic era” and that their dire predictions are mostly just an attempt to expiate our intense but irrational feelings of guilt.
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Raoult’s most recent book, “Epidemics: Real Dangers and False Alerts,” was published in late March, by which time the W.H.O. had reported more than 330,000 confirmed cases of Covid-19 worldwide and more than 14,500 deaths. “This anguish over epidemics,” he writes, “is completely untethered from the reality of deaths from infectious diseases.”
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Testing had been scheduled to run for two weeks per patient, but after only six days, the results were so favorable that Raoult decided to end the trial and publish
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Others might have proceeded with more caution or perhaps waited to confirm these results with a larger, more rigorous trial. Raoult likes to think of himself as a doctor first, however, with a moral obligation to treat his patients that supersedes any desire to produce reliable data.
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For decades, Raoult has boasted of his prodigious rates of publication and citation, which, as objective statistics, he considers to be the best measure of his worth as a researcher.
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This observation has come to be known as the parachute paradigm: We tend to accept the claim that parachutes reduce injury among people who leap from airplanes, but this effect has never been proved in a randomized study that compares an experimental parachute group to an unlucky parachuteless control.
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“If you don’t have something that’s visible in 10 patients, or 30, it’s useless. It’s not of any consequence.” An effective treatment for a potentially lethal infectious disease will be visible to the naked eye.
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There is much about Raoult that might make him, and by extension his proposed treatment, appealing to a man like Trump. He is an iconoclast with funny hair; he thinks almost everyone else is stupid, especially those who are typically regarded as smart; he is beloved by the angry and conspiracy-minded; his self-congratulation is more or less unceasing.
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Raoult classified Trump’s psychology as that of an “entrepreneur,” by way of contrast with that of a “politician.” “Entrepreneurs are people who know how to decide, who know how to take risks,” he said. “And at a certain point, to decide is to take a risk. Every decision is a risk.”
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The French waited far too long, in his estimation, to approve the use of hydroxychloroquine in Covid-19 patients. The authorization came only after Raoult announced in the press that he would continue, “in accordance with the Hippocratic oath” and effectively in defiance of the government, to treat patients with his combination therapy. “I’m convinced that in the end, everyone will be using this treatment,” Raoult told Le Parisien. “It’s just a matter of time before people agree to eat their hats.”
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Raoult had already begun assembling data for a larger study, but he dismissed the need for anything particularly vast or lengthy. Like other critics of the R.C.T., he likes to point out that a number of self-evidently useful developments in the realm of human health have never been validated by such rigorous tests.
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Raoult’s study had measured only viral load. It offered no data on clinical outcomes, and it was not clear if the patients’ actual symptoms had improved or indeed whether the patients lived or died. At the outset, 26 patients were assigned to receive hydroxychloroquine, six more than the 20 who appeared in the final results.
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The six additional patients had been “lost in follow-up,” the authors wrote, “because of early cessation of treatment.” The reasons given were concerning. One patient stopped taking the drug after developing nausea. Three patients had to be transferred out of the institute to intensive care. One patient died. (Another patient elected to leave the hospital before the end of the treatment cycle.)
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“So four of the 26 treated patients were actually not recovering at all,” noted Elisabeth Bik, a scientific consultant who wrote a widely circulated blog post on Raoult’s study. She paraphrased the sarcasm circulating on Twitter: “My results always look amazing if I leave out the patients who died.”
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The report was also riddled with discrepancies and apparent errors.
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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.
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Beyond its apparent errors and omissions, the study’s design — its small size, its flawed control, the unrandomized assignment of patients to the treatment and control groups — was widely viewed to render its results meaningless. Fauci repeatedly called its results “anecdotal”;
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Large, well-controlled randomized trials are by no means the only way to arrive at useful scientific insights. Their utility is that they enhance statistical signals such that, amid the noise of human variability and random chance, even the faint effect of some new treatment can be detected.
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The results of his initial trial have yet to be replicated. “I think what he secretly hopes is that no one will ever be able to show anything,”
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The prime statistical hurdle that any proposed treatment for Covid-19 will have to overcome — one that is delicate for even Raoult’s critics to make note of, amid the sorrow and fear of this pandemic — is that the signal is likely to be very faint, because the disease is, in the end, rarely fatal. Nearly everyone survives; an effective treatment will save the life of the one or so patients in every hundred who would not have lived without it.
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“Alzheimer’s drugs, obesity drugs, cardiovascular drugs, osteoporosis drugs: Over and over, there have been what looked like positive results that evaporated on closer inspection. After you’ve experienced this a few times, you take the lesson to heart that the only way to be sure about these things is to run sufficiently powered controlled trials. No shortcuts, no gut feelings — just data.”
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“I’ve invented 10 or so treatments in my life,” Raoult told me. “Half of them are prescribed all over the world. I’ve never done a double-blind study in my life, never. Never! Never done anything randomized, either.”
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“When you tell the story, it’s extremely straightforward, no? It’s subject, verb, complement: You detect a disease; there’s a drug that’s cheap, whose safety we know all about because there’s two billion people who take it; we prescribe it, and it changes what it changes. It might not be a miracle product, but it’s better than doing nothing, no?”
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Raoult had by then begun to lose his composure. He accused Lacombe of being a shill for the pharmaceutical industry; his fans sent her death threats. On Twitter, he called Bik, the consultant who wrote critically about the first study, a “witch hunter” and called a study that she tweeted — one of several published in April and May that seemed to suggest that Raoult’s treatment regimen was ineffectual or even harmful — “fake news.” The authors of another such study were accused of “scientific fraud.” “My detractors are children!” Raoult told an interviewer.
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It is possible that hydroxychloroquine and azithromycin are an effective treatment for Covid-19. But Raoult’s study showed, at best, that 20 people who would almost certainly have survived without any treatment at all also survived for six days while taking the drugs Raoult prescribed.
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In recent weeks, Raoult has in fact tempered his claims about the virtues of his treatment regimen. The published, peer-reviewed version of the final study noted that another two patients had died, bringing the total to 10. Where the earlier version called the drugs “safe and efficient,” they were now described merely as “safe.”
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He has shown flickers of what appears to be doubt.
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“I don’t trust popularity,” he told the interviewer. “When too many people think you’re wonderful, you should start to wonder.” His initial YouTube video, “Coronavirus: Game Over!” has also been renamed. The new language is more measured, and in place of the exclamation point there now stands a question mark.
