Turmoil continues for hydroxychloroquine

Two large clinical studies suggest that the antimalarial drugs chloroquine and hydroxychloroquine do not help treat or prevent COVID-19. And on Monday, the US Food and Drug Administration revoked the emergency use authorization that allowed doctors to freely treat COVID-19 patients with the drugs. Citing data from the new studies, the FDA said the drugs are unlikely to be effective antivirals and that their risks no longer outweigh their potential benefits.

The FDA’s announcement is the latest gust in a whirlwind of developments that bode poorly for anyone hoping the drugs may help in the ongoing pandemic. Yet some scientists continue to study chloroquine and hydroxychloroquine, particularly as measures for preventing infection in the first place.

In late May, a high-profile study published in the Lancet concluded that the drugs may increase the risk of death in COVID-19 patients. That study prompted several groups, including the World Health Organization (WHO) and the pharmaceutical company Sanofi, to suspend or terminate trials of the drugs. But the authenticity of the data was soon called into question, leading to the paper’s retraction during the first week of June.

Just as WHO was resuming trials of the drugs that week, two other groups announced results from large trials that concluded the drugs neither treated nor prevented infections of SARS-CoV-2, the coronavirus that causes COVID-19.

One was by researchers at the University of Minnesota, who conducted a study of 821 people to see if hydroxychloroquine could prevent sickness in those who were recently exposed to someone with COVID-19, a treatment strategy known as post-exposure prophylaxis (PEP). Among those who received the drug, 11.8% became sick, versus 14.3% who received a placebo, a difference that was not statistically significant (N. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2016638).

Benjamin Rome, a primary care physician at Brigham and Women’s Hospital, applauds the trial’s rigor. “This is exactly the sort of evidence we need,” he says, adding that the results suggest that hydroxychloroquine is unlikely to protect against COVID-19. “If there is any benefit, it would have to be quite small to not be picked up by this trial.”

Two days later in the UK, investigators announced preliminary results from a study involving more than 4,600 people hospitalized with COVID-19. In the study, called the RECOVERY Trial, 25.7% of 1,542 people who got hydroxychloroquine died after 28 days, compared with 23.5% of 3,132 people who received standard care. Again, the difference was not statistically significant.

There are more than 130 active or planned clinical trials testing the ability of hydroxychloroquine or chloroquine to treat or prevent COVID-19. With two major trials showing negative results, some scientists now wonder if the chloroquine craze is over. “RECOVERY is an excellent trial, and probably the best evidence we will have,” says Paul Glasziou, director of the Institute for Evidence-Based Healthcare at Bond University. “We need more trials on other treatments.”

Yet other groups still see potential for the drugs as cheap preventative measures and contend that the Minnesota study is not the final word. They are continuing their own PEP studies to assess whether the drug can help prevent infection in thousands of people recently exposed to SARS-CoV-2.

Researchers are also proceeding with even larger pre-exposure prophylaxis (PrEP) studies this summer, in which tens of thousands of healthyhealth-care workers will be given chloroquine or hydroxychloroquine to see if the drugs can prevent infection. Results are expected by late summer or early fall.

Chloroquine and hydroxychloroquine were first identified as potential treatments for COVID-19 in February, when scientists in Beijing and Wuhan, China, found that the drugs blocked SARS-CoV-2 from infecting monkey cells in a petri dish. In March, a small study of 36 people hospitalized with COVID-19 in France suggested that people who got hydroxychloroquine were more likely to clear the virus from their body than people who didn’t.

US President Donald J. Trump tweeted that report and called the drugs potential “game changers” for fighting the coronavirus. A few days later, FDA granted chloroquine and hydroxychloroquine emergency use approval—a formal, but temporary, green light allowing doctors to freely treat COVID-19 patients with the drugs.

Researchers say the widespread emergency use of hydroxychloroquine early in the pandemic delayed rigorous studies to prove whether or not the drug is actually useful. Since April, the NIH has discouraged doctors from using chloroquine or hydroxychloroquine to treat COVID-19 patients unless the treatment is part of a clinical trial. FDA finally made a similar recommendation on June 15, when it revoked the emergency use authorization.

“The US government should have been much more proactive in doing proper science—in organizing and conducting randomized clinical trials,” says David Boulware, an infectious disease specialist at the University of Minnesota who led the PEP study at the university. Even when clinical trials of the drug did begin, many were conducted by single institutions, meaning they lacked the scale that comes with collaborative, multi-site clinical trials that can provide a more definitive conclusion about a drug.

For instance, clinicians in Brazil stopped giving their patients a high dose of chloroquine after a trial of 81 people suggested that the high dose led to more deaths than the low dose. On the other hand, a study in China found that COVID-19 patients who got chloroquine appeared to clear the virus faster than a historical control group of people who didn’t get the drug. And in Paris, a small trial reported no difference in death rates between those who got hydroxychloroquine and those who didn’t. That study was stopped early after 8 people who got the drug experienced altered heartbeats—a dangerous, and potentially lethal, side effect of the drug.

Scientists are trying to make sense of these inconsistent results. In late May, C. Michael White, head of the department of pharmacy practice at the University of Connecticut School of Pharmacy, published a review of 23 small studies of chloroquine or hydroxychloroquine and concluded that evidence for the drugs’ effects—be it benefit or harm—was “very weak and conflicting.” The poorly designed studies made it impossible to disentangle the effects from many other confounding variables, he tells C&EN. “It wasn’t much more helpful than doing nothing at all.”

The now-retracted Lancet study emerged in the midst of this chaos. The paper purportedly analyzed data from 96,000 COVID-19 patients from 671 hospitals around the world. It concluded that people who received chloroquine or hydroxychloroquine, nearly 15,000 of them, were about twice as likely to die compared to people who received neither drug.

The startling conclusion upended several studies of the drugs. WHO put a hold on using chloroquine and hydroxychloroquine in its international SOLIDARITY trial, which is testing several existing drugs as potential COVID-19 treatments. The Lancet study also spurred some European governments, including France and Italy, to ban doctors from using the drugs outside of clinical trials.

But soon after the study was published, scientists began pointing to inconsistencies in the data, which came from an obscure company called Surgisphere. After the company refused to share its data for independent vetting, the authors on the paper not associated with Surgisphere successfully pushed for a retraction.

By that point, President Trump’s promotion of the drug had polarized public perception. The Lancet paper and its subsequent retraction made a complicated situation even worse.

“It spooked everybody,” says Laurence Lovat, a gastroenterologist leading a study of the drugs at University College London. “The regulators are shaky, and now recruitment will be much trickier because we will have to do much more explaining.”

Despite these challenges, some researchers, including Lovat, are planning large studies of the drug, mainly in a preventative role. Lovat is running one of several large trials to see if the drug can prevent COVID-19 as a PEP or PrEP therapy.

The rigorous trials will be randomized and placebo-controlled, in which patients are randomly assigned to receive either the drug or a dummy pill. Such trials reduce the risk of bias that can arise when a doctor chooses who gets the experimental treatment. The trials are even better when they are double-blinded, meaning that neither the patient nor the physician knows who gets the drug or the placebo.

The University of Minnesota’s PEP trial was the first peer-reviewed study to provide data from a double-blind, randomized, placebo-controlled trial of hydroxychloroquine. It concluded that the drug did not offer any significant protection against SARS-CoV-2 infection.

The study was widely reported and led at least one hospital—Sanford Health in Sioux Falls, South Dakota—to quickly cancel its own PEP study of the drug.

But several scientists are not fully convinced by the Minnesota study. Only 20 participants who thought they had COVID-19 confirmed it with a laboratory test, since diagnostic testing was in short supply when the study was conducted. The researchers relied on self-reported symptoms from another 103 participants to conclude that they likely had COVID-19, and that hydroxychloroquine offered no benefit compared to the placebo.

The lack of conclusive diagnosis “makes additional studies incredibly important,” says Anna Bershteyn, a population health scientist at NYU Grossman School of Medicine.

Bershteyn is co-leading a trial called the COVID-19 PEP Study with Ruanne V. Barnabas, an infectious disease physician-scientist at the University of Washington. The study, supported by the Bill & Melinda Gates Foundation, will compare a 2-week treatment of hydroxychloroquine to a placebo in up to 2,000 people.

Importantly, the researchers will “test all participants every day,” Barnabas says. That should provide more definitive evidence for or against hydroxychloroquine than the Minnesota study. Five hundred people have joined so far, she adds. “Recruitment has fluctuated with the hydroxychloroquine news cycle, but we hope to continue to enroll and have results by the end of the summer.”

Even larger studies are in the works to test chloroquine and hydroxychloroquine as PrEP therapies that prevent infection in healthy people. One of these trials, the international Crown Coronation study, will give up to 30,000 health-care workers one of three doses of chloroquine to see if the drug can prevent SARS-CoV-2 infection in the first place, or decrease the severity of COVID-19, compared to a group who receives placebo pills.

The trial will be led by researchers at Washington University in St. Louis, University College London, and the University of the Witwatersrand in Johannesburg. Mary Politi, one of the trial’s investigators at Washington University, says the study will begin soon. She anticipates that the first results could arrive in late summer or early fall.

Lovat, who is University College London’s lead investigator for the trial, says the team is working on recruiting hospitals from more countries, particularly in Africa, to join the trial. “The pandemic is only starting to take off in Africa,” and if chloroquine is effective for preventing COVID-19, it could be a lifesaver for resource-poor countries, he says. “Chloroquine is cheap, its toxicity profile is very well known, and it can be rolled out quickly.”

The drug’s safety has been a major point of contention during the pandemic. Lovat points to a 2017 report from WHO that assesses chloroquine’s cardiotoxicity risks and concludes that there are no reports of “sudden unexplained deaths” linked to the drugs. The Brazilian study that linked the drugs to an increased risk of death early in the pandemic used a “huge” dose of 1,200 mg per day, he says. In the Crown Coronation study, participants will receive much smaller doses: 300 mg weekly, 300 mg twice weekly, or 150 mg daily. “We wouldn’t do it if we thought it was risky,” he says.

Minnesota’s Boulware agrees that the drug appears safe as a prophylactic, and he says PrEP trials are “absolutely still worth doing.”

The Crown Coronation study is funded with $9 million from the COVID-19 Therapeutics Accelerator—which itself is backed by the Gates Foundation, Wellcome, and Mastercard. The Accelerator is also backing another large PrEP trial called COPCOV, which may recruit up to 40,000 healthy people who will get chloroquine or hydroxychloroquine.

Some scientists hope the ongoing trials will provide evidence to answer the question of hydroxychloroquine’s role in preventing or treating COVID-19 once and for all. “The higher-quality trials coming out now and still underway were desperately needed,” UConn’s White says. Yet he, like many others, can’t help but wonder if these answers could have arrived sooner.

“Everyone wants to be the captain of the ship, from the big-name investigators to institutions, but we could have made more progress in finding a very effective regimen to treat COVID-19 if everyone worked together to vet these therapies as efficiently as possible,” he says. “That doesn’t seem to have happened.”