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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.

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“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.

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“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.

  • Sloppy science reporting. A straw man argument is presented to prove that hydroxychloroquine does not prevent viral infection. Duuuhhh, it is not and has not been touted as an antiviral.

    The scientific rational (consistent with its observed mechanism of action) is that it could attenuate the cytokine storm. This is why so many medical professionals are taking it, along with non-clinicians like the President and Chris Cuomo and half of Beverly Hills.

    So no, it will not prevent infection. Why would the quoted assistant professor (and the reporter) assume that disproving that hypothesis was an objective of the study?

  • HCQ and Zinc could be therapeutic in helping CoVid 19 patients with breathing issues. It could help in Protecting integrity of RBC and oxygenation in lungs . It might not cure but definitely alleviate harah symptoms

  • Please inform medical people to look at the chemical structure of hydroxychloroquine. That compound absolutely cannot prevent infection of any cell. Stop wasting time, money and risking health of any participants
    in their planned trials. Off course being medical directors they will not listen. Perhaps they should listen to science.

  • India’s ICMR still recommending HCQ and published a peer reviewed paper in support. WHO restarted HCQ trials after Lancet study was exposed.
    Stat still touting for its masters. No wonder!!

    • Nonsense

      No, ICMR paper was not peer reviewed, was not an RCT and shows that HCQ worsens outcomes after 2-3 doses ! That alone indicates a confounding issue.

      WHO resumed trials because HCQ does not cause harm (which this study says also). But neither does it do any good.

  • Dear Sirs,
    I had a look at the hydroxychloroquine comments and I am very surprised to read: “did not help prevent people who had been exposed to others with Covid-19 from developing the disease”, “it doesn’t seem to work”, “It just continues to extend the case that the drug is lacking significant efficacy”.
    For your information, Morocco, Algeria and Israel have all been using it with excellent results, as their statistics prove. On other side, how is it possible to ignore the results of the french world leading authority in epidemics Dr. Didier Raoult? at his hospital in Marseille, about 4000 people were treated with Hydroxy. with extraordinary results. This is the link to his comments a few days after the Lancet disapproval of his treatment and the WHO’s banning of its use in hospitals. Sorry that it is in french. https://youtu.be/zUbiYhknaK0

    For your information when the Covid-19 epidemy started in China, they called him to get his opinion on the matter. In 2005 he visited China and was surprised to find a Hospital health system with many years of advance on the french system. Back to France he got the approval from ths Health authorities to build a few hospitals on the Chinese model.
    He is in charge at the Institut Hospitalo Universitaire in Marseille.

    IHU – Méditerranée Infection
    19-21 Boulevard Jean Moulin
    13005 Marseille
    ACCUEIL IHU: + 33 (0)4 13 73 20 01

    Best regards
    M. A. Bengio

  • Dear Marty,

    Supplementary table shows 22.4% took #Zinc. Data in the Appendix Table S8. There was no effect of zinc on prevention. 15% with HCQ+Zinc versus 15.3% with placebo+Zinc. Overall, those reporting not taking any zinc had lower (not statistically significant) incidence of symptomatic

  • Did the study include zinc? Dr Zelenko found that adding zinc to HCQ with Azt is effective. See paper: early outpatient treatment of symptomatic, high-risk covid-19 patients that should be ramped-up immediately as key to the pandemic crisis.

    • 1. It takes more than a small study to suss out a treatment with a modest effect size.
      2. While they have a place, studies of treatments by inventors/advocates of said treatment are not enough to draw firm conclusions. There’s a saying is science “The easiest person to fool is yourself.”

  • STAT is finished, much like the CDC they have been exposed and there is no going back. They must stop hiding behind the appearance of being an actual medical site and just come clean: STAT is a financial newsletter touting stock picks, market trends, and nothing more. They are manipulating information in the service of corporate masters and shareholders, not health of the people.

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