Large study adds to questions about safety, usefulness of hydroxychloroquine for COVID-19
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Editor’s note: The Lancet retracted the study mentioned in this story after questions were raised about the validity of the reported data. You can read a story about the retraction here.
In late March, the FDA authorized emergency use of hydroxychloroquine for COVID-19. It later approved an abbreviated new drug application for the drug in response to a surge in demand.
Recent developments suggest improper and off-label use of hydroxychloroquine can increase a patient’s risk for arrhythmia, and the American College of Physicians has recommended against its use for COVID-19 outside of a clinical trial.
According to a recent study published in The Lancet, researchers were not able to confirm any in-hospital benefits from hydroxychloroquine or chloroquine when used alone or alongside a macrolide antibiotic. Results from the study, which enrolled more than 96,000 patients with COVID-19 from 671 hospitals on six continents, suggested that hydroxychloroquine and chloroquine regimens “should not be used outside of clinical trials and urgent confirmation from randomized clinical trials is needed,” the researchers wrote.
They found that each of the regimens “was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.”
Rachel A. Bender Ignacio, MD, MPH, an Infectious Diseases Society of America spokesperson and assistant professor in the University of Washington’s division of allergy and infectious diseases, told Healio that further research is still needed to determine the hydroxychloroquine’s effectiveness and safety as a COVID-19 treatment option.
“Observational studies, including the one published in The Lancet, suffer from what's called confounding by indication, meaning that people who are sicker are more likely to be treated more aggressively,” Bender Ignacio said. “Even though they attempted to use rigorous statistical analysis in this paper and in the New York City cohort recently published in the New England Journal of Medicine, there's always that part of observational studies that is difficult to work around no matter how well they're analyzed, meaning that we don't ultimately control who got the drugs and why different choices were made. And often the very decisions that are being made of who gets which drug is predicated on how sick the person is."
In response to the study in The Lancet, WHO has temporarily suspended the hydroxychloroquine arm of its Solidarity Trial. At a press briefing this week, WHO Director-General Tedros Adhanom Ghebreyesus, PhD, MSc, said the drug is still “generally safe” for patients with malaria and that WHO will work “night and day for solutions, science and solidarity.”
According to Bender Ignacio, aside from remdesivir, no COVID-19 therapeutics currently have a clear enough benefit to be given outside of a trial. She said it is imperative to test the drug’s efficacy in both inpatient and outpatient settings.
“I think that it's really important to evaluate that drug in combination with a macrolide such as azithromycin in each of those settings because it is possible that we will see a signal of positive effect or benefit in one of those populations but not the other,” she said. “Due to the nature of the retrospective or observational data that's been published so far, it's really difficult to tease out, 'Is there a particular population for whom this drug may be of benefit?'”
Bender Ignacio said understanding hydroxychloroquine’s underlying mechanisms is essential to determining its efficacy for patients with COVID-19.
“What we know about how antivirals work is that they tend to work best in the early course of disease,” Bender Ignacio said. “This was true for remdesivir. When they looked at the subgroup of people who were receiving mechanical ventilation at the time of enrollment in the trial, that there was no benefit for those people. But people who were relatively earlier in the course of the disease or who were less sick when they began remdesivir were the ones who received benefit.”
“If hydroxychloroquine does have antiviral effect in people like it does in the lab, we would presume the same to be true,” she added. “We might see treatment effect only earlier in the disease course, including possibly for the prevention of infection, in persons not sick enough to be hospitalized or in hospitalized patients who do not yet have respiratory failure.” – by Eamon Dreisbach
References:
Geleris J, et al. N Engl J Med. 2020;doi: 10.1056/NEJMoa2012410.
Mehra MR, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31180-6.
WHO. WHO Director-General's opening remarks at the media briefing on COVID-19 - 25 May 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020. Accessed May 28, 2020.
Disclosures: Bender Ignacio reports research funding from the NIH and Novartis.
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