Ivermectin for COVID-19: Worth a Shot?
— Evidence base limited, including one withdrawn study with Surgisphere data
Ivermectin, an antiparasitic used to treat river blindness, is being prescribed off-label to treat COVID-19 in some parts of the world, but regulatory agencies are recommending that randomized controlled trials be conducted before widespread use is adopted.
On April 3, researchers from Monash University in Australia showed that ivermectin could inhibit SARS-CoV-2 in cell cultures, spurring a wave of enthusiasm to repurpose the drug as an antiviral at a time when few alternatives were available. Although the concentration of ivermectin used in vitro was far greater than physiological levels in human clinical use, the positive findings were quickly circulated and have since been cited in more than 450 publications.
Some physicians, citing that study, have already begun integrating the off-label use of ivermectin into their COVID-19 treatment protocol, and in Peru and Bolivia, the ministries of health formally authorized the drug for this indication. Although the drug is relatively safe, some scientists are worried that clinicians are putting the cart before the horse in prescribing ivermectin for COVID-19.
"The pandemic creates a sense of urgency and we tend to cut some corners, and that can be okay, but you don't cut all corners," said Carlos Chaccour, MD, PhD, of the Barcelona Institute for Global Health in Spain, who studies ivermectin in the context of tropical disease.
"There needs to be scientific rigor. People may say, 'What do you have to lose? It's a safe drug,' but no drug is free from side effects," he said.
Although the mechanism by which ivermectin acts as an antiviral is unknown, it has also inhibited viral replication with other RNA viruses, including dengue virus and Zika virus.
Ivermectin can lead to gastrointestinal side effects or skin rash, and can be neurotoxic in rare circumstances. In a May 1 post from the FDA, the agency said using the drug to prevent or treat COVID-19 "should be avoided" in the absence of clinical trials.
The agency also issued a warning letter 1 week after the in vitro study was published cautioning against the use of the veterinary formulation of ivermectin. Presumably, the letter was intended to protect the public against misinformation, after a man died in March from consuming chloroquine phosphate, an aquarium cleaner, when hydroxychloroquine (HCQ) was making headlines.
In Peru, the demand for the drug surged after its authorization, leading some to turn to the veterinary formulation of the drug, which is used to treat heartworm and can cause serious harm in humans.
"FDA is concerned about the health of consumers who may self-medicate by taking ivermectin products intended for animals, thinking they can be a substitute for ivermectin intended for humans," the agency stated. "People should never take animal drugs, as the FDA has only evaluated their safety and effectiveness in the particular animal species for which they are labeled."
However, in doses used off-label for scabies, for example, ivermectin has a low side-effect profile. Without many alternatives available, some physicians forged ahead of formal trials and began to prescribe it for COVID-19.
Positive Signal in Florida
Jean-Jacques Rajter, MD, a pulmonary care physician at Broward Health Medical Center in Fort Lauderdale, Florida, started using ivermectin to treat COVID-19 in critical patients after seeing the promising findings of the in vitro study back in April.
"At the time, dexamethasone, remdesivir, and convalescent plasma were not really on the market or were inaccessible because not enough people had recovered," Rajter told MedPage Today. "There was nothing else."
Rajter said he treated 15-20 patients over the latter half of April with a standard scabies dose of ivermectin and had a markedly high success rate. Soon after, colleagues at Broward Health also began prescribing ivermectin, and Rajter and his wife and partner, Juliana Cepelowicz Rajter, MD, co-authored a retrospective, preprint, study of 280 patients, published in June.
In the study, which was not peer-reviewed, ivermectin was associated with a survival benefit among patients with severe COVID-19 compared with usual care. The association remained after adjusting for differences between groups, including the use of azithromycin, hydroxychloroquine, and zinc, which was common.
"When this was released in preprint, other investigators across the world took notice in Peru, Brazil, Colombia, Bangladesh, Mexico, and Iraq," Jean-Jacques Rajter said. "The success story we had in early April has been duplicated in other smaller studies across the world."
Trials conducted in Iraq, Bangladesh, and Mexico have shown positive results with ivermectin. But the studies in Bangladesh and Mexico lacked a control arm, and the study in Iraq treated only 16 patients with ivermectin.
Matthew Spinelli, MD, of the University of California, San Francisco, told MedPage Today in an email that positive anecdotal reports are "difficult to interpret given that most patients who are infected will get better on their own, and the clinical manifestations are so variable for COVID-19."
The Next HCQ?
Parallels have been drawn with ivermectin and HCQ: Both reduced viral load in vitro and produced a signal that led to their being prescribed under compassionate use, said Zeno Bisoffi, MD, PhD, of the University of Verona in Italy.
"There were some results from observational studies claiming that [hydroxychloroquine] worked, but in fact they were small studies with very heavy methodological flaws," Bisoffi told MedPage Today. "Nevertheless, they were cited everywhere, so most clinicians around the world were using hydroxychloroquine with no evidence."
"This is a mistake we want to avoid with ivermectin," Bisoffi said.
Both drugs were also caught up in the notorious Surgisphere Corp. scandal. In late May, flawed data from the shadowy company were used in a since-retracted Lancet study to demonstrate a survival benefit with HCQ.
A lesser-known preprint study of 169 hospitals around the world also used Surgisphere data to demonstrate that ivermectin reduced the need for mechanical ventilation and death. As with the HCQ study, the scientific community identified discrepancies in Surgisphere's ivermectin data, and the paper was withdrawn -- but not before it was downloaded more than 15,000 times.
The paper influenced policy decisions in Latin America and was cited in a white paper advocating for ivermectin to be included in Peruvian treatment guidelines.
Positive findings from another study in India are also being evaluated by the country's medical review board, The Print reported. In Australia, a widely known gastroenterologist who repurposes drugs, Thomas Borody, MD, PhD, director of the Centre for Digestive Diseases in Sydney, Australia, endorsed ivermectin as one part of a triple-drug therapy, along with doxycycline and zinc, for outpatient COVID-19 cases.
"Ivermectin has been used in billions of prescriptions to date, and even with high dosing there are very few side effects when used for things like scabies," Borody told MedPage Today. "This thing in combination of the three works so well, I believe it is the way we should go."
A Call for More Research
While ICU physicians may see ivermectin as something worth trying, others believe the evidence is still too scant.
The drug should not be written off, but neither is it ready for widespread clinical use, Chaccour said. For example, it is still unclear whether it is safe to use in the context of a highly inflammatory syndrome, like COVID-19, or in combination with other drugs, he said.
Rajter said he initially used ivermectin as a "measure of desperation." But now that he has seen positive results in his hospital network, he is frustrated by an intentionally slow review process.
Certain drugs are expedited by the FDA, while "other treatments which have been shown to be quite effective -- like ivermectin -- have not seen the light of day," Rajter said.
Currently, there are more than 30 clinical trials testing ivermectin for COVID-19. Bisoffi is investigating high doses of ivermectin for mild infection and Chaccour is also conducting a trial in Spain. A team at Johns Hopkins University is comparing ivermectin versus bicalutamide and usual care among hospitalized COVID-19 patients.
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