Hydroxychloroquine Fails to Prevent COVID-19 in Those Exposed to the Virus: RCT

The NEJM-published study further muddies the path for this drug amid yesterday’s retraction of the dubious-data Lancet paper.

Hydroxychloroquine Fails to Prevent COVID-19 in Those Exposed to the Virus: RCT

Hydroxychloroquine doesn’t protect against COVID-19 in people who have come in contact with the SARS-CoV-2 virus at home or work, according to a randomized, placebo-controlled trial published this week in the New England Journal of Medicine.

“After high-risk or moderate-risk exposure to COVID-19, hydroxychloroquine did not prevent illness compatible with COVID-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure,” David R. Boulware, MD (University of Minnesota, Minneapolis), and colleagues say.

The possibility of prevention had been appealing, they note. “The majority of clinical studies of chloroquine or hydroxychloroquine for COVID-19 have focused on hospitalized patients. Yet, to alter the trajectory of the epidemic, it is necessary to break the chain of transmission.”

Co-author Matthew Pullen, MD (University of Minnesota), told TCTMD why they focused on prophylaxis: “The prevailing thought, just like with a lot of other viral illnesses, you really need to be ahead of the game. If you wait until somebody is very sick, they likely have millions and millions of viral particles circulating in their body. And you’re kind of behind the eight ball at that point.”

But overall, the data haven’t panned out for this use, he said. Pullen didn’t rule out the possibility that hydroxychloroquine might be helpful in the hospital setting among already-sick patients.

No medication is benign—certainly hydroxychloroquine isn’t benign. Matthew Pullen

With President Donald Trump’s public praise of hydroxychloroquine, clinicians may find themselves giving advice to patients keen on trying it. For them, Pullen suggested, “I would counsel the patient that there isn’t really evidence that it helps yet, and in the absence of any proven benefit all you’re taking on is risk. No medication is benign—certainly hydroxychloroquine isn’t benign.”

That said, “some of the cardiac risk has been overblown quite a bit in the media,” he continued. “For an average healthy person with no cardiac issues that they know of and not on any medications that cause QT prolongation, hydroxychloroquine is actually very safe. But when you start getting into the elderly population or people with cardiac issues or on cardiac medications, then it becomes riskier. And if there’s no proven benefits, all you’re assuming is that risk.”

Just yesterday, a different group of researchers, citing concerns over their data set provided by the private company Surgisphere, retracted an earlier Lancet paper that had raised the possibility of harm with hydroxychloroquine and chloroquine.

Hydroxychloroquine as Prophylaxis

For their double-blind study, Boulware et al employed a “pragmatic, Internet-based, self-referral recruitment strategy.” They enrolled 821 asymptomatic patients in the United States and Canada who’d been at a distance of less than 6 feet of a person with confirmed COVID-19 for longer than 10 minutes . Those who did so while not wearing a face mask or eye shield were considered to have high-risk exposure (87.6% of the cohort), whereas those wearing a face mask only were deemed to have moderate risk; approximately two-thirds were healthcare workers.

Within 4 days of exposure, the investigators randomized these individuals to placebo or hydroxychloroquine (800 mg once followed by600 mg 6-8 hours later and 600-mg daily for 4 more days).

More of TCTMD's coverage on our COVID-19 hub.
More of TCTMD's coverage on our COVID-19 hub.

The incidence of new illness within 14 days was 11.8% in the hydroxychloroquine group and 14.3% in the placebo group, for an absolute but nonsignificant difference of -2.4% (P = 0.35). Side effects—most commonly gastrointestinal—were more frequent with hydroxychloroquine than with placebo (40.1% vs 16.8%; P< 0.001). There were no serious adverse events, including arrhythmia or death; only one patient in each group was hospitalized.

An accompanying editorial by Myron S. Cohen, MD (University of North Carolina at Chapel Hill), points out several limitations to the current study. Overall, he concludes, the results “are more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined.”

One shortcoming of the design, says Cohen, is that COVID-19 was diagnosed most-often by symptoms rather than by testing. “An illness that was considered to be consistent with COVID-19 developed in 107 participants (13.0%) but was confirmed by polymerase chain-reaction assay in less than 3% of the participants,” he observes.

“Adherence to the interventions could not be monitored, and participants reported less-than-perfect adherence, more notably in the group receiving hydroxychloroquine,” Cohen writes. “In addition, those enrolled in the trial were younger (median age 40 years) and had fewer coexisting conditions than persons in whom severe COVID-19 is most likely to develop, so enrollment of higher-risk participants might have yielded a different result.”

All of the above limitations are acknowledged by the investigators. As Pullen said to TCTMD, “this was done based on self-reported symptoms. . . . People have recall bias and things like that, subjective reporting. And then there’s also the fact that, due to the realities of the world we lived in for several months, testing wasn’t really available for anyone in a reasonable amount of time,” even though many participants were healthcare workers.

Any false positives/negatives, however, would likely be equally distributed between the drug and placebo arms, he explained.

As to whether hydroxychloroquine merits ongoing study, Pullen said, “There’s certainly still a lot of room to look at hydroxychloroquine as an adjunct to other therapies. And there’s definitely room for people that want to refine and reproduce what we’ve done, or groups that are recruiting people in their area that they’re physically evaluating. That might strengthen the argument. They might end up seeing a small effect that we couldn’t see based on the limitations of our study. Or it might reinforce what we’ve already seen, which is equally important.”

Their own research continues, with a study on “preemptive” hydroxychloroquine (to slow progression in symptomatic patients) currently under peer review and another on high-risk professions now underway, he reported.

Cohen notes that a staggering 203 COVID-19 trials using hydroxychloroquine were listed in the ClinicalTrials.gov database as of June 1, 2020, and 60 of these were focused on prophylaxis. “An important question is to what extent the article by Boulware et al should affect planned or ongoing hydroxychloroquine trials,” he writes.

On Wednesday, the World Health Organization announced it was restarting the SOLIDARITY trial, which includes a hydroxychloroquine arm, after reviewing “available mortality data” from the Surgisphere study over the weekend.

Just today, researchers from the University of Oxford announced they would no longer enroll patients in the hydroxychloroquine arm of the RECOVERY trial, a large-scale study testing a range of drug therapies in National Health Service patients hospitalized with COVID-19. After a review by the data and safety monitoring board, researchers concluded there was “no beneficial effect” of hydroxychloroquine on the primary endpoint of 28-day mortality, nor any evidence of a beneficial effect on the duration of hospital stay.

  • Boulware reports grants from Jan and David Barcuski, the Alliance of Minnesota Chinese Organizations, the Minnesota Chinese Chamber of Commerce, and the University of Minnesota Foundation as well as nonfinancial support from Rising Pharmaceuticals during the conduct of the study.
  • Pullen reports grants from National Institute of Allergy and Infectious Diseases during the conduct of the study.
  • Cohen reports no-financial support and other from Gilead and Merck outside the submitted work.