OK, WTF Is Hydroxychloroquine and Can it Treat Coronavirus?

A drug that was originally synthesized as a treatment for malaria has had a breakout week after a small, inconclusive study made its way across the internet. In just three days, word of the study and the drug, hydroxychloroquine, traveled from Elon Musk’s Twitter to President Donald Trump’s mouth.

“It’s shown very, very encouraging early results,” Trump said at a press conference on March 19.

“It's been around for a long time, so we know if things don't go as planned it's not going to kill anybody,” Trump said. Four days later, a man died after he tried to prevent coronavirus infection by ingesting a fish tank cleaner that contained chloroquine, a closely related drug.

There is now a national shortage of both drugs, and one woman told Buzzfeed News that her healthcare provider ended a hydroxychloroquine prescription that she takes for her lupus. And in the absence of comprehensive studies in humans, public health experts warn against Trump’s proclamation.

“In this context, it is quite hazardous saying that this drug could work and should be used without data and evidence supporting it,” said Kelly Searle, an assistant professor in the Division of Epidemiology and Community Health at the University of Minnesota School of Public Health. “I think the scientific community overwhelmingly right now is saying, ‘Wait until we have more data on this, because we don't know if it works or not.’”

This all begs the questions: WTF is hydroxychloroquine, and why do some people think it could be a promising treatment for coronavirus in the future?

Hydroxychloroquine is a derivative of the compound quinoline, which also gives rise to quinine, the bitter ingredient in tonic water. In particular, hydroxychloroquine is a type of 4-aminoquinoline—the name refers to the specific location of a compound on quinoline’s chemical ring structure, and that group also includes the drug chloroquine.

While quinine occurs naturally in some trees’ bark, hydroxychloroquine and chloroquine are manmade and trace their roots back to pre-World War II Germany. The scientist Hans Andersag synthesized chloroquine in 1934, but the Germans abandoned it in 1936 after having mistakenly deemed it “too toxic for practical use in humans.” During the war, the U.S. led an Allied effort to search for new drugs to treat malaria. SN 7618, or chloroquine, became the most important out of all 16,000 candidate compounds screened. It was less toxic than the standard antimalarial at the time and more effective, and it quickly became the new first-line treatment.

Alexander Surrey and Henry Hammer tinkered with chloroquine’s tried and true structure in 1946 by replacing a single hydrogen atom with a hydroxyl group, otherwise known as an oxygen bonded to a hydrogen. The tiny change created hydroxychloroquine and made a slight but noticeable clinical difference—today, hydroxychloroquine is more frequently prescribed than chloroquine since it may be less toxic and cause fewer side effects.

However, the use of these drugs to treat the infection they were intended to treat has waned over the past decades, said Searle, who studies malaria transmission. One of the parasitic species that causes malaria has gained widespread resistance to chloroquine since the 1950s; for these infections, the drug artemisinin is the first-line treatment.

Malaria is a disease caused by a single-celled parasite, but studies have found that chloroquine and hydroxychloroquine can also effectively treat some viral infections and autoimmune disorders. Because of chloroquine and hydroxychloroquine’s broad-spectrum effectiveness, scientists have pointed to the drugs as promising treatments for emerging viruses even before the Covid-19 pandemic.

Most relevantly, chloroquine and hydroxychloroquine studies in cell culture and animals suggest that the drugs may be able to treat infections from SARS and the common cold, two coronaviruses other than the novel SARS-CoV-2 we're facing now. To be clear, neither drug has been approved by the Food and Drug Administration (FDA) to treat coronaviruses.

One way that hydroxychloroquine and chloroquine may be able to help the body fight off infections from coronaviruses is by blocking the viruses from entering a person’s cells. SARS-CoV-2 and other coronaviruses need the machinery found inside a human cell in order to replicate, and they get transported inside the cell through a process called endocytosis. Hydroxychloroquine and chloroquine have slightly basic pHs, so once they find their way into the cell, they raise the pH inside and render endocytosis impossible.

The “very encouraging early results” that Trump mentioned came from a study in France on 36 Covid-19 patients. The authors chose 20 patients to give hydroxychloroquine and azithromycin, an antibiotic, and tracked each person’s coronavirus test results daily. They concluded that there was a difference in the outcomes of people whom they gave the drugs and recommended “that COVID-19 patients be treated with hydroxychloroquine and azithromycin to cure their infection and to limit the transmission of the virus to other people in order to curb the spread of COVID-19 in the world.”

Trump tweeted explicitly about the study on March 21, writing in part “HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine.”

But the design, results, and presentation of the study has given scientists pause. The same day that it was posted online, commenters on the discussion forum PubPeer began criticizing it for not adhering to clinical trial best practices such as randomizing or "blinding" participants with placebos.

Elisabeth Bik, a scientific integrity consultant with an active Twitter presence, detailed what she termed “serious problems” with the paper in a blog post. The lack of randomization, she wrote, introduced the potential for confounding, which occurs when a separate and unaccounted for variable influences both the independent variable (in this case, use of hydroxychloroquine and azithromycin) and dependent variable (coronavirus test results). Bik also noted that at least four patients treated with the drugs worsened, one of whom died. Because they did not complete the entire drug regimen, these people were not included in the analysis, which Bik wrote was strange.

Didier Raoult, the senior author of the study, did not respond to a request for comment. In an interview on Monday with the French newspaper Le Parisien, Raoult stood by his results and said that based on his findings, he believed that it would be immoral not to administer these drugs to Covid-19 patients.

“I’m convinced that at the end of this all, everyone will use this treatment. It’s only a matter of time before people eat their hats and say, ‘It’s what we must do,’” he told Le Parisien.

With any clinical application of hydroxychloroquine to treat Covid-19, safety is another cause for concern. Searle said that multiple studies published so far have recommended doses of chloroquine and hydroxychloroquine that are higher than those proven safe for treating malaria. In the France study, for example, members of the treatment group who completed the regimen were given 6000 mg of hydroxychloroquine over 10 days, which is more than would be used in that time period to treat or prevent malaria.

“Chloroquine is safe for malaria treatment and for prevention in some cases, but when you get to the upper limits, there is toxicity,” she said. These drugs also have side effects like headache, dizziness, nausea, vomiting, and psychiatric reactions.

Of 18 clinical trials currently listed on clinicaltrials.gov as investigating the safety and efficacy of hydroxychloroquine to treat Covid-19, only one has been completed. That study, conducted by researchers in China, randomized 30 patients to receive either hydroxychloroquine and conventional treatments or just conventional treatments. The scientists did not find statistically significant differences between the outcomes of the two groups.

There have been more hydroxychloroquine Covid-19 experiments conducted in vitro, or outside living organisms, than in vivo to date. Searle said that while these types of studies allow scientists to study Covid-19 and potential treatments in highly controlled environments, they can’t replace clinical trials “because we don’t exist in petri dishes.”

Even in light of ongoing clinical trials and promising in vitro results, Searle said that people should not assume that there will be a treatment for coronavirus anytime soon.

“Nobody should read about chloroquine, or any of these treatments that haven't completely been studied, and think that there's going to be a treatment soon and so they shouldn't be physical distancing, and staying home, and doing non-pharmaceutical interventions," Searle said. "We all need to do those, because right now, there is not a treatment.”