Jul 16, 2020 5:52 PM

Hydroxychloroquine Still Doesn’t Do Anything, New Data Shows

Two more studies prove that the much-hyped antimalarial doesn’t treat Covid-19.

It doesn’t work.

The stalwart drug hydroxychloroquine, a decades-old antimalarial that people have more recently used to treat lupus and rheumatoid arthritis, started getting attention as a possible treatment and preventative against Covid-19 as early as February. Hydroxychloroquine and the related drug chloroquine killed the virus that causes the disease in vitro—that is to say, in petri dishes. Health care workers gave hospitalized people the drug in the early days of the pandemic (because they didn’t have much else to give), and influential voices like carmaker Elon Musk and President Donald Trump advocated for it as a possible cure.

All that happened before scientists could determine whether that was true. And with the release of two new sets of data this week, one from a massive drug trial in the United Kingdom on Wednesday and the other from researchers at the University of Minnesota today, the answer appears to be: no. Hydroxychloroquine does not appear to keep people from getting the disease after they’ve been exposed to someone who has it. It does not change how many people hospitalized with Covid-19 die of the disease. It does not reduce symptoms for people with milder cases who aren’t in the hospital.

Scientists have lots of different kinds of studies they can run. Some are observational, meaning the researchers take a group that meets some set of criteria, like “people who have Covid-19,” and follow their progress as they get different kinds of treatment. Others are retrospective; researchers go over people’s records later to see if they’ve recovered or died. It’s possible to learn from these sorts of studies, but they’re vulnerable to all sorts of errors. Sicker people tend to be more likely to improve more slowly, or die, even if they get the same drug as someone who isn’t as ill. That makes it hard to tell whether the drug actually helps—or harms.

So the so-called gold standard of drug trials is called an RCT, short for Randomized Controlled Trial. That means people sick with the thing you’re trying to study get put into one of two groups, or cohorts, from the very start. They either get the drug or they don’t, and no one—not the researchers, not the health care workers, not the participants in the study—knows who got what. (That’s called “double-blinding.”) And the researchers try to make those groups as similar as possible in every other way. They’re trying to eliminate all the possible external factors that could mess up the study.

The two sets of results that came out this week were both RCTs. The first was part of a massive trial in the UK called Randomised Evaluation of Covid-19 Therapy, or “Recovery.” The researchers running it have been sending thousands of people hospitalized with Covid-19 into one of a half-dozen groups testing different drugs against a control group, and then checking to see if they’re still alive 28 days later. Recovery is an “adaptive” trial, which means it’s designed for researchers to look at the data as it rolls in and adjust on the fly, cutting off or adding new study arms to accommodate new information. So far, the trial showed the corticosteroid drug dexamethasone reduced mortality rates and, in June, cancelled the arm of the study looking at hydroxychloroquine.

The new paper from the researchers, an un-peer-reviewed preprint, details what actually happened in the hydroxychloroquine arm—1,561 people got hydroxychloroquine, and 418 of them, 26.8 percent, were dead within 28 days. And 3,155 people got standard care without the drug; 788 of them died. That’s 25 percent. So: Hydroxychloroquine didn’t reduce mortality. Its use also correlated with longer time spent in the hospital and a higher likelihood of having to go on a mechanical ventilator. As the paper puts it: “not an effective treatment.”

“In my view, hydroxychloroquine should not be used in the hospital setting,” says Martin Landray, a physician and researcher in the University of Oxford’s Nuffield Department of Population Health and one of the heads of Recovery. “Outside the hospital setting it would be reasonable to use it in the context of a randomized controlled trial, but not otherwise.”

Speaking of which: The Minnesota study looked at people not in the hospital, so by definition not as sick. And that caused some methodological problems. The lack of easy and fast Covid-19 testing in the US meant that not everyone in the study population had a diagnosis made via PCR testing, or taking a sample via a nasal swab and analyzing it for the virus’ genetic material. For these participants, the team of researchers confirmed that they had Covid-like symptoms, and that they had contact with someone whose infection was confirmed with a test. It’s a slightly dicier set-up, but still valid.

The Minnesota team had originally intended to use death or hospitalization numbers as a marker of whether the drug helped people in the study. But even though numbers of both are sky-high in the US, the actual mortality and hospitalization rates overall are low—or too low to show up significantly in just under 500 people, the size of the group in the study. So without looking at the data, the team switched to another metric: symptom reduction. (Participants reported their own symptoms on a 10-point visual scale day by day; the most common ones were cough, fatigue, and headache.) Here, too, hydroxychloroquine made no difference. Two weeks after starting, 24 percent of the 201 people taking the drug still had symptoms versus 30 percent of 194 people taking a placebo. Again: no significant difference.

Those results were actually going to be part of an earlier paper from the team, showing that hydroxychloroquine likewise didn’t work as a preventative, keeping people from getting sick after they’d been exposed to the disease. That “post-exposure prophylaxis” paper got accepted to the New England Journal of Medicine quickly and came out in early June. But as time went on and the drug faded a bit from the news and presidential briefings, it was tougher to find a home for the paper about how the drug fared as a treatment. “The negative fact that hydroxychloroquine didn’t work was not as newsworthy, I guess. They weren’t as interested in a null study,” says David Boulware, the infectious disease physician running the team. “To design the study was eight or nine days. To do the study was seven weeks. To actually get it published was two and a half months … In a normal timeframe that’s fast. In a Covid timeframe, that’s glacially slow.”

The lack of confirmed, PCR-based testing also makes the study slightly less bombproof. “The true believers are going to criticize it. Not everyone had PCR testing, because it’s the United States and people didn’t have access to PCR testing,” Boulware says. “It’s not a perfect study, but I think it’s correct.”

By “true believers,” Boulware means people who remain unshakably convinced of the drug’s value. For months, they’ve parsed every hydroxychloroquine study for factors that they think might influence its effectiveness that the researchers did wrong—too high a dose, too low a dose, given too soon, given too late, given without supposedly important adjuncts like zinc. Proponents of the drug’s use have proposed all of those as critical to its success. In some respects, they’re right—dosage does matter. One major study of the drug in Brazil stopped early because of serious heart problems in people taking it, a known side effect. But that study was also using extraordinarily high doses, well beyond levels used preventatively or even as a treatment. The Recovery and Minnesota teams used a more typical protocol.

And for all the zinc stans out there, Boulware actually looked at that, too, this time. It didn’t change the outcome.

Like masks (but unlike less sexier anti-Covid tactics, like the drug remdesivir), hydroxychloroquine became associated with political affiliation. Influential Silicon Valley leaders said they thought the drug might be important; Trump did the same at White House briefings, and even announced that he himself was taking it prophylactically after possible exposure to someone with the disease. The Food and Drug Administration OK’d its use in hospitals and in drug trials for Covid-19 under an Emergency Use Authorization, and then revoked that authority. White House trade adviser Peter Navarro is still pointing to yet another study, this one from Michigan in the International Journal of Infectious Diseases in early July, that reported a reduction in mortality. But it was a retrospective one again, neither randomized nor controlled. “The Detroit study touted by Navarro has very poor methodology—completely observational, meaning that the choice to give hydroxychloroquine was probably also linked to other factors that explain the benefit,” says Bob Wachter, chair of the department of medicine at UC San Francisco.

Taken together and added to the larger body of well-designed studies on hydroxychloroquine and Covid-19, though, the Recovery and Minnesota trials make a clear pattern. “In my mind, this lays to rest that the drug may have early activity or post-exposure activity,” says Nahid Bhadelia, medical director of the Special Pathogens Unit at Boston Medical Center. “The philosophical question I have is, we expended so much energy and money on this question. There are still ongoing trials. My question to those trialists is: What is the cost of continuing those trials?”

The politics and social alignments that swirled around hydroxychloroquine made it hard for US researchers to enroll enough participants to make a study work. That slowed things down. An analysis by Stat showed that of the more than 1,200 Covid-19 drug trials underway or planned, 237,000 people—more than a third of volunteers in all the trials—were supposed to be enrolled in hydroxychloroquine studies. That now seems disproportionate, to say the least. “Nobody should get it,” Wachter says. “Overall, the evidence against it is strong enough that the drug should simply go away in Covid, and it would have weeks ago had it not been for the politics.”

OK, so, no chance. Except maybe. Kind of. It doesn’t seem to work as a treatment for sick people, but maybe a much bigger study could find a smaller prophylactic effect—a sparse 20 percent reduction in a person’s chances of catching Covid-19, let’s say. Studies in the US and in Asia have been trying to look for that, though enrolling new participants is getting harder and harder as the disease wanes in many countries. Some questions about hydroxychloroquine may never get answered. But as to whether or not someone sick with Covid-19 should take it—that answer is now as clear as science ever gets.