This weekend, Donald Trump used his daily White House coronavirus briefings to again urge Americans to take hydroxychloroquine, an anti-malaria drug that has not been shown to be safe or effective against Covid-19.
“What do you have to lose? Take it,” the president said on Saturday as he boasted that the US had amassed 29m doses of the drug. On Sunday, facing questions from the press about his aggressive promotion of an unproven treatment, he argued against waiting for the completion of clinical trials. “In France, they had a very good test,” he said. “But we don’t have time to go and say, ‘Gee, let’s take a couple of years and test it out, and let’s go and test with the test tubes and the laboratories.’”
Meanwhile, Dr Anthony Fauci, the country’s top infectious disease doctor, has repeatedly warned that there is no conclusive evidence to support using the drug. Asked whether it should be considered a treatment for Covid-19, he said on 24 March: “The answer is no.”
The story of how hydroxychloroquine was anointed the Trump administration’s miracle drug for the coronavirus pandemic is a distinctly modern tale of misinformation within a global information ecosystem beset by widespread uncertainty, fear, media fragmentation and hyper-partisanship. Belief in the drug’s potential to cure patients infected with the virus followed an extraordinary trajectory from a small study conducted in France (Trump’s “very good test”) to Silicon Valley social media influencers, Fox News and the largest bully pulpit: the White House.
But it’s also a story as old as medicine itself. When an epidemic killed thousands in ancient Rome, said Aaron Shakow, a research associate at Harvard Medical School and historian of medicine, the chief physician of the emperor Nero circulated a recipe for an old miracle cure.
“It was an attempt by Nero to sustain his legitimacy in the midst of this catastrophic event,” Shakow said. “Epidemics are dangerous to rulers.”
A deeply flawed study
In early March, as the coronavirus pandemic accelerated its spread around the globe, a group of scientists in Marseille, France, launched an experiment to see whether hydroxychloroquine, a well-known old malaria drug, could be what everyone was searching for: a cure.
Most small scientific studies live and die within the rarified domain of academic journals, but the French trial had a much more auspicious debut. Before the study was even published, in the International Journal of Antimicrobial Agents (IJAA), a lawyer falsely claiming an affiliation with Stanford University appeared on Fox News’s Tucker Carlson Tonight to declare the results: a “100% cure rate against coronavirus”. From Fox News, it was only a matter of time (hours, in fact) before the drug was being hailed as a “game changer” by the president of the United States.
Trump made his first endorsement of hydroxychloroquine on 19 March. Export controls, shortages, overdoses and scientific recriminations rapidly ensued, but the controversy could not extinguish the power of presidentially endorsed hope. Across the globe and throughout diverse communities on the internet, hydroxychloroquine had been anointed the miracle cure for Covid-19.
The only problem? The study that all this fervid hope is based on doesn’t show what its authors claim it does.
The gold standard for a clinical trial is a double-blinded, randomized controlled trial (RCT). What this means in plain English is that the study has been designed to reduce biases that would render its results meaningless. Neither the physician nor the patients knows whether they received the drug (“double-blinded”), a safeguard that reduces the possibility that the doctor will treat the two groups differently. The researchers also do not get to choose which patients go into which group (“randomized”) and the makeup of the two groups is roughly equivalent (“controlled”).
The French hydroxychloroquine study did not follow any of these rules.
The treatment group and the control group were drawn from separate populations: the treatment group were all patients at the institution where the researchers worked, the Méditerranée Infection University Hospital Institute in Marseille, while the control patients came from other hospitals in the south of France.
The treatment group (mean age 51.2) was significantly older than the control group (mean age 37.3), introducing another variable that could undermine the meaning of the results. The study was “open label”, meaning the physicians and patients knew which treatment they were receiving.
The French researchers also treated some but not all of the treatment group patients with azithromycin, a common antibiotic, another complicating factor that was not randomized.
But even more important than these shortcomings in the design of the study is how the researchers chose to measure and report their results. Forty-two patients were initially included in the study. Three were transferred to the intensive care unit; one died, one left the hospital, and one stopped taking the treatment due to nausea. The other 36 eventually recovered, and those who received the drug cleared the virus from the system faster than those who did not.
If you had only heard about this study from the Fox News assertion of a “100% cure rate”, you might assume that the four patients with poor clinical outcomes (the three ICU visits and one death) had been unlucky enough to be in the group that did not receive the “cure”.
And yet, those four patients, as well as the patient with nausea and the one who left the hospital early, were all part of the treatment group. They were excluded from the topline results of the study because of the way that the researchers chose to measure and report the results: strictly based on the measurable presence of viruses in nasal swabs taken each day of the study. Since the patients were in the ICU or dead, their samples could not be taken and they were left out of the final analysis. Based on the nasal swabs of just the 36 patients who completed the study, those who received the drug cleared the virus from their systems faster than those who did not.
This is how an experiment in which 15% of the treatment group and 0% of the control had poor clinical outcomes could end up being reported as showing a “100% cure rate”.
On 3 April, two weeks after the study was first published online, the International Society of Antimicrobial Chemotherapy, which publishes the IJAA, said in a statement that the group’s board “believes the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety”.
Didier Raoult, the corresponding author for the French study, did not respond to questions from the Guardian.
Andrew Noymer, a professor of public health at the University of California, Irvine, described the results of the French study as “meaningless”. “They should have done an RCT,” he said.
“This idea that we’re all manning the lifeboats and there’s no time for that is just absurd,” Noymer added. “They could have already done it. They could have had the answer by now … Doctors have always gone with their guts and saved many lives, but I don’t know. If they had done RCTs on Thalidomide” – a drug that caused birth defects – “they would have figured out its dangers a lot sooner.”
From Silicon Valley to Fox News
So how did one interesting but flawed study out of the south of France make its way to Fox News’s prime time and the White House?
It was not surprising that scientists were interested in testing hydroxychloroquine (and its close relative, chloroquine), a well-known and understood drug, as a potential treatment against Covid-19. It is one of a number of possible treatments that scientists in China and South Korea looked at in the early stages of the coronavirus outbreak, including in vitro (ie lab-based) experiments that showed promising (though not conclusive) results. The drug was also selected as one of four that the World Health Organization included in its large-scale international clinical trial.
But while hydroxychloroquine was garnering some interest in the early days of the pandemic, other possible treatments, such as Gilead’s antiviral Remdesivir, were drawing more. Google trends data shows that people were searching for Remdesivir more than hydroxychloroquine throughout most of February.
What Remdesivir lacked that hydroxychloroquine had, however, was a team of dedicated hype men who appeared more interested in publicizing the drug as a cure than they were in discovering whether the drug was effective.
SOURCE : The Guardian