Hydroxychloroquine Studies Retracted, Early Evidence Lacking
By Shawn Radcliffe
This story was originally published on Healthline on June 4, 2020.
However, claims about the effectiveness of this "miracle drug" against the new coronavirus have far outpaced the available clinical data.
Some small clinical trials have shown possible benefits, while others have shown the opposite.
On April 24, the FDA again warned consumers against taking hydroxychloroquine or chloroquine unless closely supervised by a healthcare professional, such as in a hospital setting or as part of a clinical trial.
This move comes after the agency received reports of "serious" side effects such as abnormal heart rhythms and rapid heart beats in COVID-19 patients who were treated with one of these drugs. In some cases, patients died.
Retracted Studies on Drug Mean More Confusion.
Despite an early study finding evidence that hydroxychloroquine might help ease symptoms of COVID-19, subsequent studies have been less positive.
A larger study on hydroxychloroquine released last week in the medical journal The Lancet has been retracted this week, complicating what we know about the drug.
Researchers who published the study looked at more than 96,000 people hospitalized with COVID-19.
It was initially reported that the study found the drug didn't help patients with COVID-19.
The study was retracted due to data used in the study that hadn't been directly obtained by the researchers themselves.
In their retraction letter, the researchers from Brigham and Women's Hospital in Boston said they worked with the company Surgisphere Corporation to obtain data.
After other medical experts raised concerns about the company, the researchers conducted a review of the data. However, the Surgisphere Corporation wouldn't give the full dataset to the reviewers, meaning they couldn't do a full independent analysis.
This led them to retract their study.
In the now-retracted study, the drug had been found to not improve people with COVID-19 and more people died after taking the drug.
Additionally, the New England Journal of Medicine also retracted a study on COVID-19 and cardiovascular health since it also used data from the same company.
Earlier Studies Don’t Show Much Improvement With the Drug.
One of the first studies to suggest that hydroxychloroquine, in combination with the antibiotic azithromycin, might work as a treatment for COVID-19 was done in France.
The French study, though, had several design flaws, including its small size and how people were enrolled in the study.
Despite these flaws, results from this study were shared on social media as "proof" of the drug's effectiveness.
The New York Times later reported that Trump had a "small personal financial interest" in Sanofi, the French manufacturer that makes Plaquenil, the brand-name version of hydroxychloroquine.
In addition, results from other small trials and paper preprints suggest that hydroxychloroquine isn't effective against COVID-19.
One part of a small study in Brazil was stopped early after COVID-19 patients taking a higher dose of chloroquine developed potentially fatal irregular heart rates.
The results were posted April 11 on medRxiv, an online server for sharing medical articles before they've undergone peer review by other researchers.
The higher-dose group of patients was given 600 milligrams of chloroquine twice daily for 10 days. By day six, 11 patients had died, leading researchers to stop this arm of the study early.
The lower dose group — 450 milligrams for 5 days, twice daily only on day one — didn't have enough patients for researchers to know if the drug was effective for people with severe COVID-19.
A French retrospective study posted April 14 on medRxiv found that hydroxychloroquine didn't help patients hospitalized with the coronavirus.
Doctors reviewed the records of 181 patients. About half had been given hydroxychloroquine within 48 hours of being admitted to the hospital.
Of patients taking the drug, 20.2 percent were admitted to the intensive care unit (ICU) or died within 7 days of hospitalization. Of those who didn't take the drug, 22.1 percent went to the ICU or died.
Looking just at deaths, 2.8 percent of patients who were given hydroxychloroquine died within 7 days of hospitalization, while 4.6 percent of patients who didn't take the drug died.
Neither of these differences was statistically significant, which means they could have occurred simply due to chance.
In another retrospective study of 368 patients posted April 21, researchers found that U.S. veterans taking hydroxychloroquine had a higher risk of dying compared to those not taking the drug.
Patients who received both hydroxychloroquine and azithromycin had a similar risk of dying compared to those who didn't receive either.
Researchers also found that patients who were given one or both drugs had a similar risk of mechanical ventilation compared to people not taking either drug.
This wasn't a randomized clinical trial. Instead, researchers reviewed the medical charts of patients who had already been treated. So there could be bias that affects the results.
Because papers posted on medRxiv haven't undergone peer review, the results should be viewed with caution.
On April 30, a clinical review published in the FASEB: Journal found that there's still no good evidence that hydroxychloroquine will help treat people with COVID-19.
Dr. Mark Poznansky, PhD, a Harvard Medical School associate professor and director of the Vaccine and Immunotherapy Center in the Infectious Disease Division of Massachusetts General Hospital, said he wanted to understand the risks to his patients who were coming in with COVID-19.
"It was evident to me and my colleagues that there were both risks and benefits of the widespread initial use of hydroxychloroquine in the context of COVID-19," Poznansky said in a statement. "This was based on seeing patients who, for whatever reason, appeared to be doing poorly despite the use of this medication."
While in a lab setting the virus helped stop viral update in cells, in actual patients there's a risk that the drugs could inhibit the immune system.
As a result, Poznansky said that it's not clear that the medication will help people fight off the disease and there are serious risks of taking the medication while sick.
Anecdotal Reports Are Not Enough.
Beyond the few small studies of hydroxychloroquine, a lot of the "evidence" for its benefits is based on reports in the news and on social media about people getting better after being given the drug.
Unfortunately, these anecdotal reports don't really show whether the drug works, and just as importantly, whether it's safe.
"Most people with coronavirus get better on their own. So if you give hydroxychloroquine to somebody who was going to get better anyway, it looks like the drug works," said Dr. Allison Bond, an infectious disease physician at the University of California, San Francisco.
Many factors affect whether someone recovers from COVID-19. Older adults and people with underlying medical conditions are at higher risk of serious illness.
People being treated in hospitals overwhelmed with COVID-19 patients may also be less likely to recover due to lack of medical resources.
Anecdotal reports can't account for these factors.
They also can't answer other important clinical questions like what medication dose works best, when to give the medication, or whether you should be giving a combination of drugs.
"The only way we can know if an agent actually worked or had efficacy is to do a clinical trial," said Dr. Steven K. Libutti, director of the Rutgers Cancer Institute of New Jersey and senior vice president of oncology services at RWJBarnabas Health.
Bond said these trials should include not just a larger number of patients, but also a wide variety of patients.
"That way, you can see how the drug interacts not only with the infection itself, but also with the patient's preexisting medical conditions," Bond said.
Clinical trials are also needed to know if a drug is safe.
Doctors already know a lot about the side effects of hydroxychloroquine and chloroquine because the drugs have been around for years.
But Bond said patients with COVID-19 who are being treated may need a higher dose of the drug than what's used for other conditions.
"Even though it's a drug that we already use, we're using it at a different dose," she said. "With that [higher dose] you would be more prone to side effects."
Better Clinical Trials Underway
The Infectious Diseases Society of America (IDSA) released guidelines on April 11 with recommendations about the use of hydroxychloroquine or chloroquine for the treatment of COVID-19.
Given the current "knowledge gap," the IDSA recommends that these drugs — alone or with azithromycin — be used in the context of a clinical trial.
The guidelines also emphasize that the use of hydroxychloroquine or chloroquine plus azithromycin carries a greater risk due to the possibility of irregular heart rhythms in patients.
Limiting the use of these medications to a clinical trial would enable doctors to potentially help patients, while gathering data needed to know if the drugs actually work for people with severe COVID-19.
Several larger clinical studies of hydroxychloroquine have already been started, including ones at the National Institutes of Health, the University of Washington, and Rutgers Cancer Institute.
Libutti is one of the researchers running the Rutgers trial.
In this study, people with COVID-19 will be randomly enrolled into one of three groups: hydroxychloroquine alone, hydroxychloroquine and azithromycin, or supportive care for 6 days followed by hydroxychloroquine.
"We're looking to see if these drugs, alone or in combination, can actually lower the patient's viral load," said Libutti.
This study is similar to the French study but is more rigorously designed.
First, people are randomized into the groups, which minimizes bias. Without randomization, you could get mostly healthier people in one of the drug groups — this would make it seem like the drug worked.
There's also a control group — people receiving only supportive care — which allows researchers to see how these people do compared to those taking one or both drugs.
Researchers will also look separately at people with mild, moderate, or severe COVID-19 symptoms, as well as those treated on an inpatient or outpatient basis.
"We're going to look at those subgroups to get an idea of whether the drug worked better at certain times in the course of the disease versus others," said Libutti.
The trial is moving ahead quickly. After they've finished enrolling the 160 people, he expects to have results in about 2 weeks.
Although this study may not answer all questions about hydroxychloroquine, the results should provide doctors with more data on how best to help people with COVID-19.
"If the [drug or drug combination] works, we need to deploy the strategy much more broadly," said Libutti. "If it doesn't work, then we need to be focusing on other strategies."
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