Malaria Drug Hype Reels in Macron as Hope Gets Ahead of Science

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A 65-year-old malaria drug that hasn’t been proven to work against the new coronavirus appears to have captured the imagination of another president.

France’s Emmanuel Macron unexpectedly flew to Marseille Thursday and spent more than three hours meeting with Didier Raoult, the researcher whose work has propelled a medicine called hydroxychloroquine from fringe to famous in just three weeks. Raoult’s unconventional studies won over U.S. President Donald Trump, who suggested he’d be willing to take the medicine himself.

Doctors say the hype has gotten ahead of the science, though many have tried hydroxychloroquine on patients because they don’t have anything better. Based on little more than a small but encouraging study, the U.S. has stockpiled 29 million doses. India temporarily banned its export. Patients in Nigeria poisoned themselves with it. And others still, who need it for chronic illnesses, are now finding it’s in short supply.

“The message that President Macron is sending is one of support, which is detrimental to the scientific community,” Christine Rouzioux, a virologist at Necker Hospital in Paris and a researcher at Paris Descartes University, said on BFM TV. “Professor Raoult certainly has an interesting personality, but one doesn’t heal with personality.”

Folk Hero

Raoult has become a folk hero to some in France — especially the former Yellow Vest movement that disrupted the country for much of last year — for his willingness to bend the rules, shun Parisian politics and blame the pharmaceutical industry for the state of research. People have lined up outside his hospital to seek treatment. He’s also suggested politicians were disregarding his work, a claim that may lose traction after Macron’s visit.

Presidential advisers say rather than being an endorsement, the trip was intended to show the president listens to a wide swath of scientific opinions.

Highlighting the confusion over the medicine, Sanofi, France’s largest drugmaker, said Friday it would donate 100 million doses of hydroxychloroquine to 50 countries, while repeating that there isn’t enough clinical evidence to conclude that the medicine works and is safe for Covid-19 patients.

Whether the drug helps or harms such patients — or makes a difference at all — may not be clear for weeks or even months.

Lupus Treatment

“This molecule needs to prove itself,” said Vincent Dubee, a doctor at the university hospital in the French city of Angers, who’s leading one of the many studies worldwide that will attempt to settle the debate. “We know it well for other diseases, but it’s not something we have been prescribing to 75-year-olds who are in respiratory distress.”

In fact, just how the drug works isn’t well understood, something that isn’t unusual when it comes to older medicines. Hydroxychloroquine and its more toxic cousin, chloroquine, are synthetic compounds that were designed to replace quinine — the active ingredient in the bark of the chichona tree — as a malaria treatment around the middle of the last century. Later, doctors began to use them against chronic inflammatory diseases such as lupus and rheumatoid arthritis. Both can be dangerous for patients with heart conditions, and just doubling the daily dose could prove fatal.

Both showed some promising results in animals against SARS and MERS, two other coronaviruses. China’s National Health Commission was the first national authority to suggest using chloroquine to treat the new coronavirus on Feb. 19, but it didn’t reveal the patient trial results that backed the recommendation. And caveats quickly followed.

In Hubei province, the region where the coronavirus emerged, health officials asked hospitals to watch closely for potential side effects. On Feb. 29, national authorities published a list of patients who shouldn’t get the medicine, including people with heart, liver and kidney disorders.

With little published data out of China, the old malaria drugs still were a medical gamble. But as the coronavirus spread in Europe, filling hospital wards, desperate doctors started using them anyway.

Then came Raoult’s work at the IHU-Mediterranee Infection hospital in Marseille. The iconoclastic doctor, who wrote a paper in early March comparing the new coronavirus to the common cold, was giving hydroxychloroquine — a medicine he’d worked with for decades — to growing numbers of Covid-19 patients.

He published results on March 16 showing that the drug reduced the presence of the virus in the respiratory tract of 24 patients. In some of them, he combined the medicine with an antibiotic called azithromycin, a drug the Chinese authorities had explicitly advised against using with chloroquine.

Readers around the world seized on the results. Three days later, Trump made his first endorsement of the medicine after it was touted on Fox News. He tweeted that the combination could be “one of the biggest game changers in the history of medicine.”

Doctors and clinical trial experts have pointed out several weaknesses of Raoult’s study (and a subsequent one where all but two of 80 patients improved). They cite the small number of people taking part, the questionable inclusion and exclusion of some patients and the lack of a control group, which means the results could be an accident.

“The only way to know if you’re doing something worthwhile is to run a controlled study,” said Derek Lowe, a drug-discovery scientist. “It’s sad but it’s true.”

Another complication is that patients hospitalized with Covid-19 tend to be older and have other types of sicknesses, compared with those who normally take these medications for malaria or chronic diseases.

“We need to see this drug in a whole array of patients,” said William Schaffner, professor of preventive medicine and infectious diseases at the Vanderbilt University Medical Center in Nashville, Tennessee. “This is not a trivial drug.”

Unorthodox Approach

Raoult insists he’s right — and that in most cases not using hydroxychloroquine and azithromycin may be unethical. He argues there’s no need to put a group of patients on a placebo to draw conclusions on the medicine’s impact.

“In infectious diseases, it’s extremely easy to measure whether the virus disappears,” meaning there’s no real need for large patient samples or to follow the traditional method of comparing two random samples of patients, one of which gets experimental drugs and the other a dummy, Raoult told France’s Radio Classique on April 1. “This isn’t science, it’s a habit,” he said of placebo-controlled studies. He declined to be interviewed for this article.

That line of argument leaves clinical-trial experts wringing their hands. Because four out of five patients are able to clear the virus from their system on their own, a comparison is the only way to show “how much is related to the drug and how much is related to the patient’s own immune system,” said Navin Jacob, a pharma industry analyst at UBS AG in New York. “It could be that the drug actually did the job; we just don’t know.”

So for science to catch up with the hype, some Covid-19 patients will need to show altruism in the face of a disease that currently has no treatment. Instead of demanding the drug for themselves, they’ll need to volunteer for studies where they might not get it.

Enlisting Subjects

Dubee, the doctor from Angers, said patients are responsive when he explains the need for reliable scientific data. But he’s heard from colleagues who are struggling to enlist people because some want only hydroxychloroquine.

The study he’s leading will enlist a maximum of 1,300 patients age 75 or older who will be randomly split in two groups: one will get the active drug and the other a placebo, in addition to standard treatment. Some people in both groups will get azithromycin, which will put Raoult’s results to the test. After 14 days, scientists will compare how many people died or had to be put on a ventilator in both groups.

A slew of similar trials are looking at the same thing around the world, including studies backed by the World Health Organization and National Institutes of Health, as well as more than a dozen trials in China. Some early results could be coming in weeks, but doctors say it may be months before the matter is settled.

— With assistance by Dong Lyu, and Rudy Ruitenberg

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