Study suggests hydroxychloroquine doesn't prevent COVID-19. But questions remain

A woman is wearing a face mask on the sidewalk
A new study in The New England Journal of Medicine suggests hydroxychloroquine doesn't work in preventing COVID-19 after exposure. (Getty/filadendron)

President Donald Trump said in May that he was taking hydroxychloroquine to guard against COVID-19 infection. But does the anti-malaria drugwork as preventive measure for the novel coronavirus?

It doesn’t, a new study published in The New England Journal of Medicine suggests. However, a long list of unanswered questions remains, and one expert concludes that the drug's prevention benefits “remain to be determined.”

In what the study authors called a “pragmatic” clinical trial, 821 adults who had a previous risky COVID-19 exposure were recruited through social media to receive either hydroxychloroquine (HCQ) or placebo. By 14 days after treatment, 49 of 414 participants on HCQ and 58 of 407 on placebo developed COVID-19.

The 2.4 percentage points of absolute difference in illness incidence didn’t cross the statistical significance threshold, the University of Minnesota-led team said, even though HCQ helped cut the risks of developing the disease by about 17% on a relative basis.

But Evercore ISI analyst Umer Raffat, who previously estimated HCQ could show a benefit of around 25% to 30%, raised several questions in a Wednesday note to clients.

RELATED: Did chloroquine really fail a COVID-19 study—or was the trial design to blame?

First, evidence of an advantage for HCQ—though small—showed up at day 14 but not at day 5 or day 10. “Would this delta have expanded beyond day 14? Unclear,” Raffat said.

Secondly, HCQ’s effect appears to be driven by people who had no additional underlying health conditions. But Raffat noted there was no explanation for that.

The reason why Raffat previously held higher hopes for HCQ is that its EC50—the concentration of a drug required to provoke a response halfway between the baseline and maximum—is similar to that of Gilead Sciences’ remdesivir, which has proven at least modestly effective against COVID-19 in several carefully designed clinical trials.

So, why didn’t HCQ live up to its expectations? Were the EC50 data simply incorrect? Or, is it because this was a prophylaxis study? We just don’t know, Raffat noted.

On that last point, Myron Cohen, a virologist at the University of North Carolina at Chapel Hill, raised questions in an NEJM editorial.

Strictly speaking, the study is testing HCQ as a measure of postexposure prophylaxis. Cohen noted that, in a recent mouse study, prevention of SARS-CoV-2 was achieved only when an experimental drug was given before or shortly after exposure. Also, in HIV, postexposure prophylaxis must be used within 72 hours after suspected exposure to that virus.

However, most participants in the current study started HCQ beyond that three-day window, suggesting that “what was being assessed was prevention of symptoms or progression of COVID-19, rather than prevention of SARS-COV-2 infection,” Cohen wrote.

RELATED: Hydroxychloroquine takes another hit in failed small-scale COVID-19 study

What’s more, the study authors acknowledged that the trial didn’t involve consistent proof of exposure, so it's possible that some participants never came in contact with the virus in the first place. That wasn’t the biggest problem, though; after all, the study resembles that of a phase 3 vaccine efficacy trial, in which participants are discharged into the real world. For a study this large, we can assume that the probability of exposure between the two arms was similar.

Perhaps the more important limitation is that only a small number of COVID-19 cases were confirmed by a lab test. Instead, the researchers relied on participant-reported symptoms.

All considered, the study’s results are “more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined,” Cohen said in the editorial.

But one thing is clear: HCQ led to more than twice as many side effects than placebo, although none of them were serious.

RELATED: FDA warns hyped COVID-19 drug hydroxychloroquine is too risky outside the hospital

Much controversy has been swirling around the antimalaria drug since Trump publicly touted it as a game-changer for COVID-19.

Previously, the World Health Organization temporarily halted its large-scale trial of HCQ to treat COVID-19 patients after a study in The Lancet found patients getting the drug appeared to have a higher risk of death. However, that study itself inspired backlash, as nearly 150 doctors signed an open letter blasting the observational research for relying solely on registry analysis rather than on a randomized, placebo-controlled clinical trial.

Now, the WHO study has resumed; after reviewing available data, a safety monitoring board decided there was no reason to discontinue the global trial, the health body said Wednesday.

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