Why hydroxychloroquine’s appeal endures despite evidence it doesn’t work for Covid-19

“Any study that says hydroxychloroquine doesn’t work is fake science.”

Those were the words of Dr. Stella Immanuel, a physician who claimed to have successfully treated 350 Covid-19 patients with hydroxychloroquine, azithromycin and zinc. Immanuel appeared with a Tea Party-linked group calling itself America’s Frontline Doctors in a July 27 video of a press conference that went viral after President Donald Trump tweeted it. That was before social media companies took it down due to its promotion of medical misinformation related to Covid-19, including claims that hydroxychloroquine is a “cure” for the disease and that masks will not help prevent its spread.

Hydroxychloroquine, a drug normally used to treat malaria and certain autoimmune disorders, entered the public consciousness in March when Trump called it a potential “game-changer” and encouraged its use. That happened after the publication of a French study later found to be deeply flawed. The Food and Drug Administration soon issued an emergency use authorization – many believe it came under heavy pressure from the White House – but the EUA was revoked in June. Randomized, controlled trials – or RCTs, considered the gold standard for medical research – have thereafter produced negative results, along with several large retrospective analyses.

So what explains the endurance of hydroxychloroquine’s appeal in Covid-19? The answer, it turns out, may lie in social science rather than medical science.

First, it’s important to note that science and data are not the main driving force behind hydroxychloroquine’s persistent appeal.

While there is always the possibility of a future RCT surprising observers with a positive result, the published RCT data to date all indicate that hydroxychloroquine is not effective. Studies from the University of Minnesota, Spain and Brazil have all failed to show a benefit. Most retrospective analyses have as well, with exception to one by researchers at the Henry Ford Health System in Detroit, whose results have nevertheless faced skepticism due to multiple confounding factors. Another negative retrospective analysis, published in The Lancet, was retracted over questions about the provenance of data used.

Thus, much of the support springs from ideological tribalism.

“It’s not, ‘Let’s gather research and run the test and collect data,’” said Samuel Perry, a professor of sociology at the University of Oklahoma, in a phone interview. “It’s, ‘Who are the good guys, and who are the bad guys.’”

The politicization of hydroxychloroquine also reflects a broader politicization of science.

“This is pretty unique, and a lot of it is being driven by the way that science has been politicized and the way social media has amplified these political lines, even on topics like hydroxychloroquine and medical research,” said Jevin West, director of the University of Washington’s Center for an Informed Public, in a phone interview. “And that to me is an indication of how far social media has sort of driven this line between the two different parties and has made the partisanship even worse.”

An email sent to this reporter in response to a July 26 story about the Brazilian study is illustrative.

“History will remember two groups of people,” the reader wrote, providing a link to the American Frontline Doctors website. “Those who believed in Hydroxychloroquine and those who didn’t. The month of August will be the month these two groups become wholly identified.”

The sense that those on “Team Hydroxychloroquine” are on the right side of history briefly played out when the Henry Ford Health System study results were announced. Fox News’ Laura Ingraham took to the airwaves to declare the drug vindicated, while various Twitter personalities demanded apologies from those who had expressed skepticism.

The retracted Lancet study had a similar effect.

“If they have to retract a paper, it’s disastrous in that case, but it gave fuel for this movement to say this could be working,” West said, noting that while fraud happens in science, it is very rare, and paper retractions are a fact of life in the field. But that may not assuage a public that is uncomfortable with the ambiguity and nuance inherent in science. “They want answers, and propagandists can sweep right in, in times of uncertainty.”

That shows how membership in Team Hydroxychloroquine has become an emblem for an ideological worldview.

“That’s what happens – hydroxychloroquine has become that brand,” said Timothy Caulfield, a professor of law at the University of Alberta who specializes in public health and science policy, in a phone interview.

Perry refers to the ideology underpinning this anti-science, anti-intellectual attitude as “Christian nationalism,” which is less about religious belief than it is about a tribalistic, us-versus-them worldview based on cultural and ethnic identity.

Such Manichean mindsets have also led to some extreme responses from those who believe the drug to be effective.

“Your lies are helping kill people,” read the subject line of another reader email responding to the July 26 MedCity News story. Caulfield, meanwhile, said his efforts to present available evidence about hydroxychloroquine in a neutral fashion have resulted in death threats.

But despite the extreme response, Caulfield pointed out that hydroxychloroquine is far from the first example of an unproven medical treatment that has received criticism and whose defenders have responded with over-the-top rhetoric.

Supplements have their own share of rabid proponents who tout their benefits in the face of evidence against it, as does naturopathy. Like those who insist in believing in alternative medicine despite evidence against it, hydroxychloroquine’s defenders lean heavily on anecdotes and unreliable observational studies as evidence for efficacy while disregarding or disputing the validity of RCTs showing a lack of it.

What sets hydroxychloroquine apart from alternative medicine is the rapidity of its rise, taking place over the course of only a few months, and without the backing of well-heeled industry and professional organizations. The likeliest explanation is the immediacy of Covid-19’s threat and the widespread desire for life to return to normal. Conspiracy theories may have helped the process along as well.

“The hydroxychloroquine story fits in with other conspiracy theories – the idea that Bill Gates started this and wants people to get vaccinated,” Caulfield said.

And among people with this type of worldview, conspiracies naturally lurk in the federal government too. West said online conversations cite the FDA’s revocation of hydroxychloroquine’s EUA and the National Institutes of Health halting studies of the drug as evidence of a coverup.

But hydroxychloroquine would never have received the attention it did were it not for the relentless promotion of the drug by those in power and even some health experts.

As soon as Trump began promoting the drug, so did his media surrogates like Ingraham, Sean Hannity and Dr. Mehmet Oz. Even after interest died down, it quickly spiked again in May when Trump said he had been taking it to prevent Covid-19.

While White House testing chief Brett Giroir has recently said the drug is not effective, other administration officials, like Peter Navarro, the president’s trade adviser, have continued promoting it.

In a phone interview, Navarro suggested it was not accurate to say that no RCT had shown hydroxychloroquine to be effective. When asked to provide an example of one that had shown the contrary, he said, “This focus on randomized, controlled trials is just very misplaced in a pandemic.”

Navarro added that the emergency of the pandemic meant there was insufficient time to subject hydroxychloroquine to RCTs, thereby making emergency use authorizations necessary. But as stated before, the RCTs of hydroxychloroquine to date have already been conducted, yet come up empty, while those of drugs like Gilead Sciences’ antiviral remdesivir and the generic steroid dexamethasone – used to treat the inflammation associated with Covid-19’s worst symptoms – have successfully shown a benefit to patients.

“This medicine is likely to work based on the science and studies I’ve seen, only in early-treatment use,” Navarro said. “That means you’ve got to get this medicine in the first couple of days. If you can do that, it performs just like in vitro studies say it will in terms of killing the virus or slowing its replication.”

Navarro and Dr. Harvey Risch, a professor of epidemiology at Yale University maintain that the RCTs’ negative results to date are not due to hydroxychloroquine lacking efficacy – as such outcomes would indicate in virtually any other disease state – but because the drug is being used too late in the course of disease and not in the right group of patients. Risch published an op-ed in Newsweek last month promoting hydroxychloroquine as a “key to defeating Covid-19,” based on a paper he had published in May.

And last week, Navarro distributed a brief that Risch had filed with the FDA to support a new authorization of hydroxychloroquine in high-risk outpatients early in the disease. In a subsequent phone interview, Risch noted that Navarro had recommended he file the brief in order to persuade the FDA to change its position after seeing him on television, but that the two do not have a formal relationship.

“Every one of these studies that has been invoked to say the medicine doesn’t work smears over those precise distinctions,” Risch said, saying that Covid-19 in hospitalized patients is a “different disease” from its earlier stages. “It would be like someone having abdominal pain, and you treat them for asthma.”

But SARS-CoV-2 – whether in high-risk or low-risk, early-stage or late-stage, hospitalized or ambulatory patients – is still the same virus.

In a blog post responding to Risch’s Newsweek op-ed, Dr. David Gorski – a surgical oncologist at Wayne State University and outspoken critic of hydroxychloroquine who has compared it to acupuncture – wrote that if a drug strongly inhibits coronavirus replication, there is no reason to think it could not be effective in either advanced or early disease or as a prophylactic. Moreover, he noted, it wasn’t long ago that the drug’s proponents were suggesting it would be effective in severely ill, hospitalized patients, pivoting to the argument that it had to be given early as evidence against late-stage use mounted.

Indeed, the aforementioned RCTs of hydroxychloroquine – blinded and open-label alike – were not only negative, but strongly so, failing to show statistically significant differences in outcomes between patients receiving hydroxychloroquine and those in the control groups.

By contrast, the Phase III RCT that led to the FDA’s emergency use authorization for remdesivir showed a statistically significant difference versus placebo on the primary endpoint of patients’ time to recovery, with a p-value less than 0.001. That’s comfortably below the typical threshold of 0.05 used to indicate statistical significance and thus shows a real effect of the drug while making it highly unlikely that it was due to chance. On the secondary endpoint of patient survival, the p-value was 0.059, favoring remdesivir, which while just a tad above the 0.05 threshold, is nevertheless insufficient to rule out chance.

But in the Brazilian study, the p-value for the primary endpoint was 1.00 – not even remotely indicating a benefit from the drug, despite the study authors leaving open the possibility, based on the range of the odds ratio, that the drug could provide one. In the University of Minnesota early-disease study, 56% of 423 patients were enrolled within one day of showing symptoms, and dozens were smokers or had high-risk comorbidities like diabetes, asthma or hypertension – yet that study likewise failed to show a benefit.

Still, hydroxychloroquine’s proponents soldier on.

The reasons why physicians and other healthcare professionals have continued supporting hydroxychloroquine may differ from those of the general public, and West said the latter seem to have generally done so in good faith. Neither Perry nor Caulfield wished to speculate directly about the mindset behind various healthcare professionals’ promotion of the drug, but they suggested the culture of academia could play a role. Perry said that professors, even those at prestigious universities, often make a name for themselves by being iconoclasts, regardless of the consequences, while Caulfield said those in academia often become associated with particular positions, which take on a momentum of their own.

“It becomes difficult to turn that ship around,” Caulfield said.

Among the public, it ultimately boils down to human nature.

“As humans, we want something that’s going to be good news, so we gravitate to the potential good news, but that’s not how science works,” West said.

And so, interest in hydroxychloroquine remains.

ClinicalTrials.gov currently lists more than 100 studies worldwide of hydroxychloroquine and the drug of which it is an analogue, chloroquine, in Covid-19 that are recruiting participants. Meanwhile, only 16 studies are listed as suspended or terminated.

The FDA’s initial EUA for the drug, obtained through a public records request, stated, “The clinical community has shown substantial interest in potential uses of these drugs in this public health emergency. Because of the limitations and inconsistencies of the available data, continuation and expansion of assessment in well-designed clinical trials is considered to be highly important, at the same time that emergency uses of these products in carefully selected crisis settings might be considered.”

That was in March. Now, the results of well-designed clinical trials are in, and while they have the sorts of limitations that all studies do, they have consistently shown hydroxychloroquine to be ineffective as a treatment for Covid-19. Bayer Pharmaceuticals and Sandoz, Novartis’ generics unit, are listed on the EUA as the drug’s manufacturers. Sandoz has since halted its Phase III trial due to poor enrollment.

“The early discussions that gave hydroxychloroquine momentum were not driven by a robust body of evidence,” Caulfield said. “They were driven by prominent individuals hyping an unproven drug.”

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