The drug hydroxychloroquine, touted by President Donald Trump and his allies as a treatment and preventative for the pandemic disease Covid-19, does not keep people from getting sick. A large, randomized study, scheduled to appear today in The New England Journal of Medicine shows that the drug is no better than a placebo at preventing infection in people exposed to the virus under real-world conditions.
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This was a careful, well-planned trial—one of the most rigorous tests of hydroxychloroquine yet completed. Researchers based at the University of Minnesota looked at 821 otherwise healthy individuals in the US and Canada, all of whom had confirmed exposures to people who tested positive for infection with the virus SARS-CoV-2, which causes Covid-19. Half of the subjects got relatively high doses of hydroxychloroquine within four days of exposure, couriered from a pharmacy. The other half, the control group, received placebo pills that looked similar but had no active drug. Since this study was “double-blind,” only the pharmacists knew who got which pills; the researchers only saw the results. The researchers kept in touch over two weeks, at which point they asked: Who had Covid-19?
The answer: 49 people in the hydroxychloroquine group and 58 people in the placebo group. That’s 11.8 percent versus 14.3 percent, respectively. Statistically, there’s no difference. “The results were null. There was no effect. There was no statistical difference between those who got hydroxychloroquine and those who did not,” says David Boulware, an infectious-disease physician and lead researcher for the trial. “That was disappointing, but perhaps not surprising.”
Some folks are going to be more disappointed, or more surprised, than others. Hydroxychloroquine and the related drug chloroquine are human-made versions of the plant compound quinine, used for decades to treat and prevent malaria and more recently as treatments for autoimmune diseases including rheumatoid arthritis and lupus. But in the early days of the pandemic, Silicon Valley influencers picked up on early anecdotal evidence from China and the work of a controversial French researcher named Didier Raoult saying that hydroxychloroquine’s effectiveness against cells infected with SARS-CoV-2 in a petri dish meant that it could work in humans. Nobody had strong evidence, and National Institute of Allergy and Infectious Diseases director Anthony Fauci said hydroxychloroquine wasn’t useful. But the apparent advocacy on social media from people like Elon Musk, combined with a steady flow of hype from Trump and his allies, boosted public interest in the drug; at a press conference in late March, the president said, “I feel good about it. That’s all it is, just a feeling. You know, smart guy. I feel good about it.”
In fact, Trump was so hooked on this feeling that when one of his staff tested positive for Covid-19—potentially exposing the president—Trump told reporters that he himself was taking hydroxychloroquine to stave off infection, as “post-exposure prophylaxis.” (A statement from the White House was more circumspect about whether the president was actually taking the drug.)
The problem with all of this was that the fight over the drug’s possible usefulness (whose sides mostly, but not entirely, overlapped with political affiliation) ended up delaying the kind of gold-standard, randomized, controlled, double-blind trials that Boulware’s group does. (Here’s a good, deep review of what evidence there was from Derek Lowe’s pharma blog.) Ultimately, Boulware had trouble recruiting participants, because people who thought it worked wanted to take it off-label and not risk getting assigned to the placebo group, and people who thought it didn’t worried about the side effects.
In fact, so many people started asking for the drug from willing health care workers that despite drugmakers donating millions of pills to the national stockpile, a shortage and a run on pharmacies resulted. Acting on concerns about the drug’s side effects (especially in the elderly and the very sick), the Food and Drug Administration issued a caution against using it outside hospital settings or supervised drug trials. But since hydroxychloroquine is an old, relatively inexpensive drug, and since no Covid-19 treatment is available, health care workers were prescribing it in massive quantities. A study in the Journal of the American Medical Association found that during the week of March 21, 2020—when the president announced he was taking the drug—prescriptions for 28 pills or fewer of hydroxychloroquine and chloroquine jumped 1,977 percent over the same time a year before. Between February 22 and April 25, there were 483,425 more prescriptions for the drugs than those same weeks in 2019. The drugs became sought after, and hard to get for people with diseases like lupus and arthritis—the ones that the drugs actually help treat.
A recent study in The Lancet made the debate even more heated, and less clear. Researchers working with data put together by a Chicago-based health care information company called Surgisphere analyzed outcomes for nearly 100,000 patients around the world given hydroxychloroquine or chloroquine (either with or without an accompanying antibiotic) for Covid-19, and concluded they were much more likely to die. In response, the World Health Organization and other groups temporarily suspended their trials of hydroxychloroquine, though the WHO announced today that the trials would resume. Meanwhile, researchers running Recovery, a separate large trial in the United Kingdom, analyzed their own in-progress data and found no such risk of death or serious side effects. (They’re continuing as well.)
Other scientists quickly started punching holes in the Surgisphere results, finding errors in the statistical analysis and demanding via an open letter with more than 180 signatories to see the raw data. The critics were concerned, in part, about a problem called “confounding by indication.” Since the trial wasn’t randomized or double-blind, physicians may have preferentially given the drugs to sicker people in a bid to save them. But because sicker people are also more likely to die, that could skew the results. Other reports have since questioned Surgisphere’s reliability. The Lancet has issued an “Expression of Concern” about the paper, and the authors unaffiliated with Surgisphere have said they’re reviewing their results—never a good sign.
In short, nobody could have a real answer until the results came in from a statistically robust, randomized, controlled trial like Boulware’s. Now, they have one. “The absence of any signal that the drug is working is striking,” says Bob Wachter, chair of the department of medicine at UC San Francisco Medical School. “This, coupled with the studies that have demonstrated high rates of some serious adverse effects, I think puts this drug to bed as a potentially useful treatment or prophylactic for Covid.”
It wasn’t a complete surprise. “I don’t know that anyone felt so optimistic that this would have a protective effect. There wasn’t strong evidence for a biological mechanism that was going to work,” says Natalie Dean, a biostatistician at the University of Florida. “Of course we were hopeful that it would work, but it’s not shocking to me that it didn’t.”
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To be sure, the study has some to-be-sures. The “endpoint”—the check to see whether people were sick after 14 days—wasn’t always confirmed with a clinical test. The majority of the people Boulware’s team counted as infected got confirmed by a panel of four physicians who assessed their symptoms. That was out of necessity. The same shortage of tests for Covid-19 that has been a problem in US pandemic response also affected their study. “About two-thirds of the people [in the study] were health care workers,” Boulware says. “We expected health care workers would have access to testing. But they basically did not.”
Diagnostic test kits might have shown that fewer people actually had the disease than the study claimed—what Wachter calls an “overcall,” something that might be more likely in a place like San Francisco, where the overall prevalence of infection was low. Just 4 percent of the people who came to UCSF with Covid-like symptoms in March actually had Covid-19. But in this case, he says, even if that was the case, it wouldn’t have biased the final results. “There’s no good reason to believe that this wouldn’t lead to more cases of Covid being called equally in both groups,” Wachter says, “so it should have no ultimate effect on the study.”
It’s possible, too, that the overall number of people the study looked at wasn’t big enough to pick up a smaller but still positive effect. “The study was designed to be large enough to detect a halving in the risk of infection—and they did not find one. However, their trial could not rule out a more modest difference, which would still be very valuable,” emails Martin Landray, a researcher in the University of Oxford’s Nuffield Department of Population Health and one of the people running the UK’s massive Recovery trial of Covid-19 drugs, including hydroxychloroquine. “So, a small, statistically underpowered randomized trial of an important question. It excludes a large effect (benefit or harm) of HCQ but leaves open the possibility that there may be more modest effects (or none at all).
On a positive note, no matter whether they received the placebo or the drug, only around 10 percent of the study participants exposed to the disease actually got infected—in keeping with overall estimates from the Centers for Disease Control and Prevention. This fact supports the idea that so-called superspreading events have been critical to the disease’s transmission; that whether thanks to some physiological or immunological variation or environmental circumstances, only a small number of people spread the disease to a vastly larger number of people, who account for most new infections. (On the other hand, this could mean that the people in the trial had a lower risk of infection, says Muge Cevik, an infectious disease researcher at the University of St. Andrews. “I think it’s still an open question whether post-exposure prophylaxis would be beneficial if given, for example, to a very high-risk group,” she says.)
Despite the fears of dangerous side effects from earlier studies, Boulware’s trial revealed only mild ones, if any—nausea and diarrhea mostly. That happened to about 40 percent of people taking the drug, but 17 percent of people on the placebo, too.
Does this study spell the end for the idea of prophylaxis? After all, it did not show that the drug prevented infection among people exposed to Covid-19 patients. Boulware allows that the right dose might still prevent the disease if administered before exposure—pre-exposure prophylaxis, for people who haven’t been around anyone who’s infected with Covid-19, but who might be later. And since this trial only looked at prevention, not treatment, it’s still possible to imagine that it would work just well enough as a treatment to make any side effects worth it. Boulware is still working on a paper talking about whether the drug works as a treatment for those who are already ill. But all that is hypothetical if it doesn’t work at all.
So hydroxychloroquine might not be entirely off the table. It’s the nature of science not to be utterly airtight. “No one study is the final word, especially when other trials are ongoing—and it’s not like the percentages with the outcome were exactly the same in the two groups here. The correct interpretation is as the authors wrote, which is that this study does not demonstrate benefit in prophylaxis,” says Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “But it is incorrect to say that this study proves it doesn’t work.”
It’s almost certain that this study will be challenged by the same true believers who have supported hydroxychloroquine all along—it didn’t include antibiotics or zinc, which some people insist are the key ingredients in a perfect combination. But a solid trial like this one does have a certain finality about it. “Everything about this disease and its treatments has become politicized. Everybody has chosen shirts or skins. But it’s ridiculous. Who would not root for the drug to work? I want something to work,” Wachter says. “It just turns out it doesn’t.”
Boulware seems even more convinced. “This should not be rolled out to the general population,” he says. “There’ll be people who’ll be disappointed with our answer, but our goal wasn’t to find the politically correct answer. It was to find the answer.” In dealing with a pandemic about which so much remains uncertain, it’s good to have at least one endpoint.
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