Hydroxychloroquine does not stop people from getting coronavirus if they're exposed to disease, finds study
Taking the drug hydroxychloroquine is ineffective in preventing infection in healthy people who have been exposed to someone with Covid-19, according to the results of a clinical trial. There have been reports that despite a lack of evidence, many people started taking hydroxychloroquine to try to prevent infection early in the Covid-19 pandemic, following anecdotal accounts that it could be effective. President Donald Trump, too, has repeatedly promoted the drug and said that he had taken it himself.
In the current study, researchers conducted a randomized, double-blind, placebo-controlled trial across the US and parts of Canada. They included participants who had household or occupational exposure to a person with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). They were enrolled online.
In the trial, 821 asymptomatic adult participants were randomly assigned to the hydroxychloroquine group (414 participants) or the placebo group (407 participants). "Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days," says the study published in the New England Journal of Medicine (NEJM).
The average age of the participants was 40 years, with women accounting for 51.6% of the trial participants (424 of 821). A total of 27.4% of the participants (225 of 821) reported chronic health conditions. Health care workers accounted for 66.4% of the participants (545 of 821), the majority being physicians or physician assistants (342 of 545 or 62.8%), and nurses or nursing assistants (128 of 545 or 23.5%).
Overall, 87.6% of the participants (719 of 821) had high-risk exposures without eye shields and surgical masks or respirators. Of those, 365 received hydroxychloroquine and 354 received a placebo. Approximately 60% of the participants reported not wearing any element of personal protective equipment during their Covid-19 exposure. The analysis shows that Covid-19 developed in 107 of 821 participants (13.0%) during the 14 days of follow-up. There was no meaningful difference between the placebo group and those who took the drug. Among those taking hydroxychloroquine, 49 of 414, or 11.8% became ill. In the placebo group, 58 out of 407 or 14.3% became ill. Analyzed statistically, the difference between those rates was not significant, says the research team.
According to the researchers, analysis shows that if a person is exposed to someone with Covid-19, hydroxychloroquine is not an effective post-exposure preventive therapy. "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. This randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for Covid-19. Whether pre-exposure prophylaxis would be effective in high-risk populations is a separate question, with trials ongoing. To end the pandemic, a reduction in community transmission is needed," they said.
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Two hospitalizations were reported, one in each group. There were no deaths and no serious adverse reactions were reported such as heart rhythm disturbances. People given hydroxychloroquine were more likely to report side-effects such as nausea and stomach pain – 40.1% (140 of 349) as compared with 16.8% (59 of 351) receiving placebo. "Nausea, loose stools, and abdominal discomfort were the most common side effects. There were no serious intervention-related adverse reactions or cardiac arrhythmias," says the study.
Not everyone completed the full course: 75.4% of participants in the hydroxychloroquine group (312 of 414) and 82.6% of those in the placebo group (336 of 407) having taken all 19 prescribed tablets over 5 days. The most common reason that participants stopped taking the assigned hydroxychloroquine or placebo was side effects (17 participants in the hydroxychloroquine group and 8 in the placebo group).
An editorial accompanying the study has pointed out some limitations. It says the lack of testing made it impossible to know for sure how many participants had Covid-19, and only 75% in the hydroxychloroquine group took the full course. Besides, waiting four days after exposure to begin taking the drug may not have given it a chance to work, and starting it earlier might have had a different result, it says.
"The trial methods did not allow consistent proof of exposure to SARS-CoV-2 or consistent laboratory confirmation that the symptom complex that was reported represented a SARS-CoV-2 infection. Indeed, the specificity of participant-reported Covid-19 symptoms is low, so it is hard to be certain how many participants in the trial actually had Covid-19," says the editorial.
It adds, "In the current trial, the long delay between perceived exposure to SARS-CoV-2 and the initiation of hydroxychloroquine suggests that what was being assessed was the prevention of symptoms or progression of Covid-19, rather than prevention of SARS-CoV-2 infection. The results reported are more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined."
Study warning dangerous side-effects under fire
Two leading medical journals — The Lancet and NEJM — have expressed concern about potential flaws in the data produced by a small company to draw major conclusions about Covid-19 in two different studies. Both studies in question used patient data from Surgisphere, a Chicago-based company.
One study, which analyzed data from 96,032 hospitalized Covid-19 patients, said that those treated with hydroxychloroquine and chloroquine, are more likely to die or develop dangerous heart rhythm complications. Shortly after it was published, the World Health Organization (WHO) suspended trials of the drug over safety concerns.
More than 140 scientists and physicians challenged the validity of the study and wrote an open letter to the authors as well as The Lancet, which published the study. The letter listed 10 concerns and said that the researchers failed to account sufficiently for factors that may have influenced their results, including disease severity. The letter raised concerns about a lack of ethics review and errors in the underlying database. "In the interests of transparency, we also ask The Lancet to make openly available the peer review comments that led to this manuscript to be accepted for publication," said the letter signed by clinicians, medical researchers, statisticians, and ethicists from across the world.
On June 3, The Lancet issued an "expression of concern" to alert readers that "serious scientific questions" have been brought to the journal’s attention. "Important scientific questions have been raised about data reported in the paper by Mandeep Mehra et al — published in The Lancet on May 22, 2020. Although an independent audit of the provenance and validity of the data has been commissioned by the authors not affiliated with Surgisphere, with results expected very shortly, we are issuing an expression of concern to alert readers to the fact that serious scientific questions have been brought to our attention. We will update this notice as soon as we have further information," said The Lancet.
The WHO, meanwhile, has resumed the clinical trial to study whether hydroxychloroquine can effectively treat Covid-19. The second paper, published in NEJM, reported that taking certain blood pressure drugs including angiotensin-converting enzyme (ACE) inhibitors did not appear to increase the risk of death among Covid-19 patients, as some researchers had suggested.
Experts have raised similar concerns about the data analysis underlying that study. An independent audit of the study data has been launched. "This retrospective study used data drawn from an international database that included electronic health records from 169 hospitals on three continents. Recently, substantive concerns have been raised about the quality of the information in that database. We have asked the authors to provide evidence that the data are reliable. In the interim and for the benefit of our readers, we are publishing this expression of concern about the reliability of their conclusions," says NEJM.
Surgisphere has also issued a statement, stating, "Together, we stand behind the integrity of our studies and our scientific researchers, clinical partners, and data analysts."