Hydroxychloroquine does not prevent Covid-19 infection if exposed, study says

The malaria drug hydroxychloroquine did not help prevent people who had been exposed to others with Covid-19 from developing the disease, according to the results of an eagerly awaited study that was published Wednesday in the New England Journal of Medicine.

Despite a lack of evidence, many people began taking the medicine to try to prevent infection early in the Covid-19 pandemic, following anecdotal reports it could be effective and claims by President Trump and conservative commentators. Trump, too, said he took hydroxychloroquine to prevent infection.

But the new study, the first double-blind randomized, placebo-controlled trial of hydroxychloroquine, found otherwise.

“I think in the setting of post-exposure prophylaxis, it doesn’t seem to work,” said Sarah Lofgren, an assistant professor at the University of Minnesota who is a co-author of the study.

Other studies of hydroxychloroquine are ongoing. Also Wednesday, the World Health Organization said it is resuming a clinical trial testing hydroxychloroquine as a treatment after pausing it over safety concerns.

“This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.”

The same group of researchers is also planning to publish the results of trials testing the drug as a treatment and as a “pre-exposure prophylaxis” — that is, before any exposure to SARS-CoV-2, the virus that causes Covid-19.

The latest trial enrolled 821 patients who were either living in the same household as someone with Covid-19 or who were health care workers who had been exposed to someone with Covid-19 without adequate protective gear. While the initial infections had to be confirmed with a diagnostic test, the researchers also counted patients who had symptoms consistent with disease, in part because testing wasn’t available.

Approximately 12% of those given hydroxychloroquine developed Covid-19, compared to 14% who were given the vitamin folate as a placebo. There was no further benefit among patients who chose to take zinc or vitamin C. Nearly 40% of patients on hydroxychloroquine experienced side effects such as nausea, upset stomach, or diarrhea. However, the study did not see a significant increase in disturbances of heart rhythms, or an imbalance of deaths.

Even though the study used the gold standard methodology of conducting clinical research, outside researchers saw significant limitations. The study was conducted in an unusual way: over the internet, without patients being seen by study doctors. 

“It just continues to extend the case that the drug is lacking significant efficacy,” said Eric Topol, the director of the Scripps Research Translational Institute. He said that the results are consistent with small randomized trials that were conducted in China and with most observational studies. But while he said that the safety results are encouraging, he worried that the study, because of size and other limitations, might not completely rule out such issues.

Steven Nissen, a cardiologist and veteran clinical trialist at the Cleveland Clinic, was much harsher. The fact that patients self-reported their data and that one in five did not take all their doses of the study drug, as well as the study’s small size, made him less than confident that the study could entirely rule out that hydroxychloroquine had some preventative effect. He emphasized that more studies of the drug, which was widely prescribed during the initial months of the Covid-19 pandemic, have not been completed.

“Absence of evidence is not evidence of absence,” Nissen said. “Poor quality data does not help it only confuses the world. That’s exactly where we find ourselves, in a state of confusion.”

David Boulware, a professor of medicine at the University of Minnesota Medical School, said he thought up the study, which was also far cheaper to run than a conventional clinical trial, precisely because he saw a need to get something done with minimal resources.

On March 8, as it became clear that the U.S. was about to face the brunt of the pandemic, he was in the airport on the way back from a grant meeting at the National Institutes of Health in Washington. His team had been scheduled to go to a major meeting on HIV, but the meeting was canceled. With four days of uninterrupted work time, he set his team to creatively working out how to get a trial up and running. He bought $5,000 worth of hydroxychloroquine, and borrowed the self-reporting methodology from randomized studies that have been run in the social sciences. He said he requested a U.S. government grant to support the study, but was rebuffed.

Robert Califf, the former Food and Drug Administration commissioner who now works at Alphabet, said there were “lots of flaws” in the study but it was still “a great effort,” providing the best evidence yet about hydroxychloroquine’s utility. He said he would favor doing another study with viral testing. The dozens of other clinical trials being conducted may give a clearer answer.