The Rise and Fall of Hydroxychloroquine

Editor's Note: A week after this story was published, Lancet retracted the findings of the hydroxychloroquine study referenced in this article.

France has banned doctors from prescribing hydroxychloroquine to COVID-19 patients over fears about its safety. The decision is another milestone on the drug's journey from a common malaria medicine to a controversial potential treatment for the disease caused by the novel coronavirus.

On Wednesday, the French ministry of health withdrew a decree allowing doctors to give COVID-19 patients the drug, according to a press release. After the drug initially appeared to show promise against the disease, in late March the French government approved its use in patients hospitalized with severe COVID-19 while under strict medical supervision.

But in recent weeks several studies have emerged casting doubt on whether the drug is beneficial against COVID-19, and have suggested it could harm the heart—particularly when used alongside the antibiotic azithromycin, according to the release.

The current consensus among experts is that hydroxychloroquine should not be used for COVID-19, "whatever the severity of the infection," the health ministry stated, adding the stance may change if new evidence emerges.

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, told Newsweek he agrees with France's decision "provided it does not stop its [hydroxychloroquine's] use in randomized trials."

France is the first country to reverse its decision to use hydroxychloroquine on COVID-19 patients since the World Health Organization suspended the drug from a trial looking for potential treatments on Monday. The U.N. agency similarly flagged concerns about the safety and efficacy of hydroxychloroquine, and cited a study published in the Lancet medical journal on Friday.

Of the 96,032 participants in the trial, those who took hydroxychloroquine and its close relative chloroquine, with or without azithromycin and other similar antibiotics, were less likely to survive and were at greater risk of having heart problems. In the wake of the Lancet paper and the WHO's decision, an Australian COVID-19 trial involving hydroxychloroquine reviewed its use on Tuesday, a spokeswoman told Guardian Australia.

The Lancet study was published the same week that President Donald Trump, who has repeatedly touted the drug as a potential COVID-19 treatment, announced he was taking it as a preventative measure against the disease, despite a lack of evidence supporting this use. He has since said he is no longer taking the drug.

Experts told Newsweek that a mix of desperation in the face of an unprecedented pandemic in modern times and the influence of high profile figures saw hydroxychloroquine wrongly regarded as a potential cure for COVID-19.

Weak results blown out of proportion

There are currently no specific drugs or treatments for COVID-19, the disease which is thought to have first emerged late last year in the central Chinese city of Wuhan, Hubei province. One approach scientists have taken in the race to tackle the disease is to see if existing drugs can be repurposed. As hydroxychloroquine is used to treat autoimmune disorders such as rheumatoid arthritis and lupus, scientists hoped its effects on the immune system could help those suffering from COVID-19.

Andrew Preston, who researches microbial pathogenesis at the University of Bath, U.K., told Newsweek there have been a number of studies on viruses in labs suggesting hydroxychloroquine can act against viruses, including SARS and the coronavirus which causes COVID-19.

"Initial reports from China described the use of hydroxychloroquine in COVID-19 patients, and that small numbers of patients given hydroxychloroquine recovered. However, these were ad hoc reports, with no controls to demonstrate that it was hydroxychloroquine treatment that caused an effect, and that these weren't patients who would have recovered anyway. In most cases, moderately and severely ill COVID-19 patients receive an array of medical support," Preston explained.

However, it was research from scientists in Marseille, France, that "really ignited the debate" around hydroxychloroquine as a COVID-19 drug, said Preston. The team claimed the drug seemed to help clear patients of the virus, and the effects were reinforced by the antibiotic azithromycin.

The findings were first shared as a pre-print, meaning they weren't peer reviewed, on March 16. The mainstream hype around the drug built in a matter of days. On March 18, a lawyer citing the pre-print wrongly claimed on Fox News' Tucker Carlson Tonight that the research was peer-reviewed and hydroxychloroquine had a "100 percent cure rate."

The day after, President Donald Trump promoted the drug and chloroquine for the first time, and later tweeted hydroxychloroquine and azithromycin "taken together, have a real chance to be one of the biggest game changers in the history of medicine."

The findings were published in the International Journal of Antimicrobial Agents on March 20, but the publisher later issued a statement saying that it did not meet their "expected standard." The study was found to have a number of flaws because it had deviated from the gold standard for clinical trials, as it wasn't double-blinded or randomized.

HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains - Thank You! Hopefully they will BOTH (H works better with A, International Journal of Antimicrobial Agents).....

— Donald J. Trump (@realDonaldTrump) March 21, 2020

The drug appeared to become a beacon of hope in an unprecedented pandemic, although there was no robust evidence to support this view. In late March, the U.S. Food and Drug Administration issued an Emergency Use Authorization for the two antimalarial drugs to be used experimentally for COVID-19 patients, leading to a shortage for those who need them for conditions such as arthritis and lupus. This was followed in April by a drug safety warning that hydroxychloroquine and chloroquine shouldn't be used on COVID-19 patients outside of a hospital setting due to the risk of "serious and potentially life-threatening heart rhythm problems."

President Emmanuel Macron Macron met the co-author of the French study in April, and hundreds of thousands of people in signed a petition asking for chloroquine and hydroxychloroquine to be used more widely to treat COVID-19.

Evans said an accurate summary of the situation would be to say that "weak results [were] blown out of proportion."

The perceived safety of hydroxychloroquine allowed it to be used off-label, while proper clinical trials were set up, Preston explained. "Numerous medics used hydroxychloroquine ad hoc, many believing the drug to be safe to use in humans due to the long history of use. Thus, it was a case of 'might do some good, won't do any harm,'" he said.

As the results of these trials have come in, hydroxychloroquine has lost its shine as a possible COVID-19 treatment.

"Now, we are seeing the initial results of some of these proper trials and two things are emerging: there is no data supporting a therapeutic effect of hydroxychloroquine for the treatment of COVID-19," said Preston. "In some patients, it appears to be causing serious side effects such as heart arrhythmia, leading to some trials being halted, and the WHO to release its recent cautionary statement."

hydroxychloroquine, getty
A pharmacy tech holds a pill of hydroxychloroquine at Rock Canyon Pharmacy in Provo, Utah, on May 20, 2020. EORGE FREY/AFP via Getty Images

Preston stressed: "It's clear that the apparent safety for use in humans observed over many years may not apply to very ill people suffering from COVID-19. The disease seems to cause major circulatory and cardiac pathology, and this may be a background in which hydroxychloroquine can be harmful."

Other trials are looking at hydroxychloroquine as a preventative measure. However, Evans is not optimistic they will have positive results.

"While it is theoretically possible that hydroxychloroquine could be effective in prevention but harmful in treatment, this seems unlikely," he said.

"We are very sure that it will, rarely, cause abnormalities in heart rhythm, and to do this in otherwise healthy people makes the balance of benefit and harm lean towards harm unless there is very convincing evidence it prevents COVID-19 or reduces its severity being given prior to infection."

He added: "I wouldn't take it for precaution unless WHO proves otherwise."

Ian Hall, professor of molecular medicine at the University of Nottingham told Newsweek the promotion of hydroxychloroquine is an example "of people allowing the emotion of the moment get in the way of the evidence.

"There was some weak evidence to suggest it could be useful, and hence formally assessing its utility was entirely reasonable. However, recommending its use outside of clinical trials until we knew whether or not the drug worked was, I think, a mistake."

The situation demonstrates that controlled trials must be carried out before a drug can be declared as effective, said Preston, "and to be fair most scientists and medics have said this throughout."

He added: "The involvement of some high profile personalities complicated the situation greatly—but in the end, the data will speak loudest."