On 20 March, a group of French scientists claimed to have shown that hydroxychloroquine – a drug commonly used for malaria, rheumatoid arthritis and lupus – could be used to treat patients with Covid-19. They recommended, based on the results of their study, that doctors give Covid-19 patients the drug in combination with the common antibiotic azithromycin to “cure their infection and… curb the spread of Covid-19 in the world”.
This trial was fraught with problems. It was an “open label” trial, meaning patients knew whether they were receiving the treatment or not, and the subjects were not allocated to the two groups randomly, as should ideally happen. The editor-in-chief of the journal that published the research was also one of the paper’s co-authors, which is highly unusual. The normally lengthy peer-review process, during which experts scrutinise research and assess suitability for publication, took 24 hours. And in February, Didier Raoult, the microbiologist leading the study, had co-authored an article hyping up the potential of the drug before it was clinically tested. “The whole thing stinks,” says Lawrence Young, a virologist and pro-dean at the University of Warwick.
The results, too, were suspect. The 20 patients who were treated and recorded as having completed the study fared better than other subjects – but this group originally had 26 patients. Six dropped out; one left the hospital, another felt too ill to carry on, three were sent to intensive care, and one patient died. In any other year, the study would have been dismissed out of hand.
Three days later, a 61-year-old woman from Arizona noticed that a substance she used to remove parasites from her pet fish contained chloroquine phosphate, the same compound found in anti-malarial drugs. She and her husband, 68, mixed the chemical into their drinks. Within a few hours she was in a critical condition and her husband had died. They had drunk the powerful chemical because, as she later told NBC News from hospital, they were “afraid of getting sick” from coronavirus.
The line between the French trial and the dead man in Arizona passes through Washington, DC. “Hydroxychloroquine & azithromycin, taken together, have a real chance to be one of the biggest game changers in the history of medicine,” Donald Trump tweeted on 21 March, citing Raoult’s paper. He later called the treatment a “gift from God”.
“We saw Trump on TV – every channel – and all of his buddies [saying] that this was safe,” the Arizona woman said. “Trump kept saying it was basically pretty much a cure.”
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The idea that hydroxychloroquine and chloroquine (as the name suggests, they differ by a single hydroxide ion) could treat Covid-19 is based on a scientific rationale, says Michael Barrett, professor of biochemical parasitology at the University of Glasgow. The compounds target structures within cells called acidic vesicles, which coronavirus uses to release itself more widely into the body. “Chloroquine changes the pH of those acidic vesicles, and that prevents [viruses] getting released once they’ve been taken up,” Barrett explains.
Chloroquine was first formulated in 1934 as an analogue to quinine, a chemical found in the bark of the cinchona plant that has been used as an antimalarial for centuries. It became widespread after the Second World War, but in the 1950s strains of malaria had already begun to show resistance. Now, according to the US Centers for Disease Control and Prevention, “there are only a few places left in the world where chloroquine is still effective”. But by this time the drug had also been shown to have some effect on autoimmune diseases, which cause the body’s immune system to attack its own tissues, such as rheumatoid arthritis and lupus. Nevertheless, Lawrence Young describes it as “a very, very blunt tool”.
The distance between a useful dose and a toxic dose is short, and list of potential side effects is long. “You don’t have to go much higher than the [usual] doses for those side effects to kick in,” Barrett explains. “And if you start pumping it into lots and lots of people [in trials], different people have a different propensity to allow those side effects to kick in.”
The risks posed by more widespread use of these drugs are becoming more evident. A trial in Brazil was cut short after a number of patients on high doses of hydroxychloroquine died. In Sweden, several hospitals in the Västra Götaland region stopped prescribing chloroquine for Covid-19 because of side effects, including patients losing their peripheral vision. On 24 April, the US Food and Drug Administration (FDA) – which had previously issued an “emergency use authorisation” for hydroxychloroquine, prompting doctors to give it to thousands of patients – warned that the drug should only be used in clinical trials or hospitals where patients can be closely monitored for heart problems. The risk of side effects may increase when it is combined with azithromycin, the FDA said.
The hydroxychloroquine hype has had political consequences, too. Soon after Trump urged Americans to consider taking it, India – where much of the world’s supply is manufactured – stopped exports to ensure its own supply. Lupus patients across the world ran close to running out of the drug, including in the UK, where the charity Lupus UK has written to the Health Secretary, Matt Hancock, to ask the government to secure the drug’s supply. In the US, the FDA has posted a notice of shortage of hydroxychloroquine; pharmacists in New York have been forced to ration it.
“Right after Donald Trump mentioned it, I went, ‘OK, this could be a problem,’” says Dr Anna Valdez, a clinical nurse and professor at Sonoma State University who suffers from lupus. Her local pharmacies quickly ran out of the drug, and she only had 14 days’ worth left. Without it, she says, she would have had to increase the doses of other medicines, including the steroid prednisolone, further weakening her immune system and making a potential Covid-19 infection more dangerous. “I was panicking,” she says. That stress caused her illness to flare up. Thankfully, she’s now filled her prescription.
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The evidence that hydroxychloroquine could yet help tackle coronavirus remains, at best, inconclusive. Some small-scale studies have been encouraging; others have shown no significant benefit. None have met the scientific gold standard of a large, double-blind (as opposed to open label), randomised trial, although such studies, including the 5,000-patient Recovery trial being led by Oxford University, are currently underway. Until they are complete, hydroxychloroquine will remain unproven as a Covid-19 treatment.
And yet doctors, including in Italy and France, continue to prescribe the drug – and scientists continue to prioritise it. “I find it quite mind-boggling that there are 442 interventional drug trials registered around the world [right now], and 110 of those are on hydroxychloroquine,” says Danny Altmann, professor of immunology at Imperial College London. “A quarter of trials on planet Earth are on this drug, which probably isn’t our best candidate.” He likens it to the early days of the HIV/Aids epidemic in the 1980s, where “enormous quackery” led to unsuitable treatments being promoted. “This is logarithmically more enormous because it’s [happening] in the social media age.”
Young says the pressure of competition could also be contributing to the disproportionate interest in hydroxychloroquine. “There’s loads of money, and we’re all tempted… There’s all this about, ‘We’re fighting the virus, we’re not fighting each other,’ but actually, it’s human nature to become competitive, and to want to find funding for your own pet treatment.”
“In some ways it feels enormously responsive,” Altmann says, “and in other ways, it’s the Wild West.”
It normally takes at least six months for a scientific proposal to get funding. In the frenetic pace of the pandemic, says Altmann, “if somebody has an idea on Monday, by Friday week they’re reporting it on social media”. While this is “enormously exciting”, it is not without its risks.
Michael Barrett agrees that “fast-track science” is eroding the checks and balances of evidence-based medicine. “I think shortcuts are being made,” he says. Lawrence Young, too, worries that some researchers, including respected figures in the UK, are so eager to publish that they might do so prematurely and, in the case of hydroxychloroquine, fuel hysteria. “It worries me that what you’ve got here is a lot of people jumping on bandwagons, everybody desperately trying to publish stuff.” This has built, Young says, “a massive head of steam for a drug that doesn’t work.”
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On 23 April, Donald Trump used his daily press conference to discuss whether bleach could kill the virus inside the human body. “Is there a way we can do something like that, by injection inside, or almost a cleaning? … It’d be interesting to check that,” he said.
Trump has since claimed that this episode was sarcasm, “just to see what would happen”. What happened was that poison control centres across the US recorded a spike in calls from people ingesting harmful household products. New York City’s Poison Control Center received 30 calls in the 18 hours after Trump’s remarks. Elsewhere in the US, public health officials reported patients using household cleaning products to rinse their sinuses and mouths.
This is what is at risk when research is pushed through at maximum speed in an environment of political populism powered by social media. Scientists must now consider that their findings, which would previously have been analysed and built upon by their colleagues, will now be used to support the rhetoric of politicians eager to offer their public the news they want to hear.
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