Is ivermectin the new hydroxychloroquine?
While the two drugs are different in composition, many infectious disease experts would agree they have both been wildly overhyped as a possible treatment for COVID-19. Last year, there was an obsession with hydroxychloroquine as a COVID-19 treatment among the American right, to the extent that the drug was hyped by President Donald Trump himself — despite limited scientific evidence at the time for its efficacy. This year, hyping Ivermectin as a COVID-19 treatment has, peculiarly, become the norm on many American right-wing news channels and forums — suggesting that even little-known pharmaceutical drugs are not immune to the feverish culture wars.
Ivermectin is an off-label anti-parasite drug used for the treatment of some parasitic worms in people and animals. Since it is Food and Drug Administration (FDA)-approved, it can be prescribed by any U.S.-based physician, usually to those with intestinal strongyloidiasis and onchocerciasis — two conditions caused by parasitic worms.
Without a prescription, the only way for a layperson to obtain Ivermectin would be at a feed store or farm supply store, which sell the drug as a horse dewormer. As Salon previously reported, some tractor supply stores around the country posted signs reminding their customers that the ivermectin they sell is only for horse consumption.
Crucially, the FDA has not recommended ivermectin as a treatment for COVID-19. In fact, the public health agency warns against it.
"The FDA has not reviewed data to support use of ivermectin in COVID-19 patients to treat or to prevent COVID-19; however, some initial research is underway," the FDA stated. "Taking a drug for an unapproved use can be very dangerous."
The FDA says that even approved use of ivermectin "can interact with other medications, like blood-thinners."
"You can also overdose on ivermectin, which can cause nausea, vomiting, diarrhea, hypotension (low blood pressure), allergic reactions (itching and hives), dizziness, ataxia (problems with balance), seizures, coma and even death," the FDA states. "There's a lot of misinformation around, and you may have heard that it's okay to take large doses of ivermectin. That is wrong."
And yet, there are many reports of people acquiring ivermectin and taking it to treat COVID-19. In Louisiana, which is experiencing a surge in COVID-19 hospitalizations and deaths, a local Louisiana news outlet reported that doctors are seeing patients admitted to the hospital with COVID-19 who say they took horse ivermectin to treat COVID-19.
"It is the saddest thing to have somebody come in and say, 'but I was taking my ivermectin.' And have to admit them to a hospital, put them on a breathing machine, when we have great prevention [t]hat is the vaccine," one doctor said.
Like many myths about COVID-19 drugs, the idea that ivermectin is a viable treatment didn't appear out of thin air. The claim grew from shaky scientific evidence and was perpetuated by seemingly authoritative figures with an agenda. There was even an opinion piece published in the Wall Street Journal, titled "Why Is the FDA Attacking a Safe, Effective Drug?"; tellingly, the op-ed was co-written by a research fellow at the Hoover Institution, a right-leaning, pro-free market think tank, and a pharmaceutical industry consultant who previously worked for the company that developed and marketed ivermectin.
Shortly after publication of this op-ed, the Wall Street Journal issued a correction, noting that one of the authors' primary pieces of cited evidence, an Egyptian study on ivermectin and COVID-19, was retracted due to charges of data manipulation. Despite this, the Wall Street Journal hasn't retracted their op-ed; and despite both the retracted cited study and the authors' clear agenda, the op-ed continues to circulate widely online as "evidence" that ivermectin is an effective COVID-19 treatment being suppressed by the FDA.
The aforementioned retracted Egyptian study of 200 people was first published on the Research Square website, a platform where scientific studies are submitted before they are peer-reviewed and accepted by a journal. It was the biggest study of its kind at the time to suggest any evidence of the effectiveness of ivermectin.
Still, one retracted study does not mean that ivermectin is necessarily ineffective. Hence, scientists have not abandoned their study of ivermectin's efficacy to treat COVID-19; clinical trials like the National Institute of Health's Activ-6 study and U.K.'s PRINCIPLE outpatient trial are evaluating whether ivermectin, and other repurposed medications, can treat mild to moderate cases of COVID-19 in patients who have had fewer than seven days of symptoms.
Aside from the retracted Egyptian study, and the Activ-6 study currently in progress, is there any other scientific evidence that ivermectin is a viable treatment for COVID-19?
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Salon looked at the prominent studies of ivermectin as a drug to treat COVID-19, and asked experts for their thoughts on what they meant. These consisted of four major ivermectin studies related to COVID-19, including another (non-retracted) one referenced in the WSJ op-ed. While some studies had language that suggested that ivermectin was helpful for patients, scientists explained to Salon that these studies, due to the their small size, should be taken with a grain of salt. Details about each study are included in a footnote at the end of this article.
Notably, two of the scientific studies had some positive language from the researchers that, to a layperson, might sound bullish on ivermectin as a treatment for COVID-19. "A 5-day course of ivermectin was found to be safe and effective in treating adult patients with mild COVID-19," wrote the authors of one PubMed randomized controlled trial, titled "A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness."
Yet while a layperson might take this title as a signifier that ivermectin is a COVID-19 wonder drug, that thesis is belied by statistics. All of the prominent studies Salon looked at, including the above PubMed study, were very small, which means that statistically they are unlikely to lead to a gold-standard result that would allow scientists to draw specific, unequivocal conclusions.
This is one reason why experts like David Boulware, a professor of medicine at the University of Minnesota's Medical School and a co-chair of the National Institutes of Health (NIH) ACTIV-6 trial steering committee, says there is definitely not enough scientific evidence to believe that ivermectin is an effective treatment.
"The whole problem with all of the ivermectin data is there are a bunch of small studies, that include a dozen of people or a couple dozen people — maybe 100 people — but it's all very small," Boulware said. (Indeed, Salon could find no study with even 100 patients.) "There hasn't really been a large phase three clinical trial, up until the Together Trial, which is the first one."
Boulware was referencing a forthcoming large scientific study out of Brazil. This study, known as the Together Trial, consisted of nearly 2300 participants, and is a Phase 3 randomized, double blind, placebo-controlled trial. While the results have yet to be published or peer-reviewed, they were presented at an Aug. 6 NIH symposium where investigators said ivermectin appeared to have no significant effect on reducing emergency room visits or hospitalizations.
Smaller studies, Boulware added, tend to look and see if ivermectin has an impact on a patient's viral load. Yet there is debate as to whether viral load is a meaningful metric.
"The question in COVID, which is kind of unknown, is whether that actually means anything," Boulware said. "It sounds great — making the virus go away faster is probably a good thing — but the virus is going to go away eventually anyway with your immune system. What is the clinical benefit of the treatment? "
Boulware said larger clinical trials are needed to answer more significant questions.
"Does it prevent hospitalization? Does it shorten the duration of symptoms? Or lessen symptom severity?" Boulware said. "These larger trials are necessary to define what the clinical benefit is."
Advocates of ivermectin have pointed to a study that ivermectin can stop the replication of SARS-CoV-2 in a test tube — but that is nothing new when it comes to viruses.
"Ivermectin has been shown to inhibit a broad spectrum of DNA and RNA viruses with no underlying unifying logic (HIV, influenza, Dengue, Zika, pseudorabiesvirus, polyoma virus, adenovirus)," said Dr. Benhur Lee, a Professor of Microbiology at Icahn School of Medicine at Mount Sinai, via email. "These results were all based on in vitro test-tube/cell culture work; to a virologist, that raises eyebrows."
"In vitro" refers to studies that take place in test tubes, petri dishes, or otherwise outside of human patients. Lee used an example to explain how what happens in vitro might not necessarily translate to the human body.
"I can increase the concentration of sodium chloride (table salt) by 50% to my tissue culture cells and show inhibition of most viruses," Lee said. "But I don't go asking people to eat as much salty food as possible to combat virus infections, much less SARS-CoV-2."
Lee added that hoping ivermectin works based on "in vitro efficacy studies" is "magical thinking."
"Do I know for sure whether it will NOT work in vivo? No," Lee said. "But if it is shown to work in rigorously controlled clinical trials (which is ethically indefensible these days), then its mechanism of action has nothing to do with the in vitro studies that the trial was based on in the first place."
In the literature, Lee said, "you will hear about [terms like] 'IC50' or 'EC50' – that is, what is the concentration of drug that will inhibit 50% of the virus replication." Lee explained that the level of drug concentration needed to stop replication in the body "simply cannot be achieved."
"The concentration of drug required to inhibit 90% of virus replication in the body – a minimal standard when it comes to antiviral drug action – simply cannot be achieved based on the known pharmacology of the drug," Lee added in a follow-up interview.
This is all to say that the evidence does not look good for ivermectin as a COVID-19 treatment.
So that leaves the question: why is it so important for some op-ed writers, individuals and politicians to promote ivermectin as a COVID-19 treatment? And why has it gained momentum as a COVID-19 treatment in some countries in Latin America and in India?
"I understand why low and middle income countries hold so many trials in the hopes that ivermectin works — it's cheap, it has been around for decades," and is reputed to have minimal side effects, Lee said, noting that ivermectin's side effects are often more prominent than promised. "But to extrapolate from how much drug is needed to work in the test tube to how much it is required to work in a human being against the virus makes these trials and all the meta-reviews published less than worthless – it's dangerous."
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For this article, Salon looked into the following studies on ivermectin as a COVID-19 treatment:
Study: "A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness" in PubMed
This study, published in December 2020, was a randomized, double-blind, placebo-controlled trial conducted to "determine the rapidity of viral clearance and safety of ivermectin among adult SARS-CoV-2 patients." It was tested on 72 hospitalized patients — a very small number — and found that "a 5-day course of ivermectin was found to be safe and effective in treating adult patients with mild COVID-19."
"Larger trials will be needed to confirm these preliminary findings," the authors note.
Study: "The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with mild COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial" in ResearchSquare
This was a pilot study, and also a "double-blind, placebo-controlled, single-center, parallel-arm, superiority, randomized clinical trial that compared a single dose of ivermectin with placebo in patients with mild COVID-19 and no risk factors." The study started by assessing 94 patients, but found that "50 did not meet eligibility criteria, 20 declined to participate and 24 were randomized."
The researchers found that "patients in the ivermectin group reported fewer patient-days of any symptoms than those in the placebo group."
Study: "Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial" a preprint in The Lancet
This study was a "pilot, randomized, controlled, outcome-assessor blinded clinical trial with the goal of evaluating the antiviral activity of high dose IVM in COVID-19 patients."
It included 45 randomized patients.
The researchers concluded that "there was no difference in viral load reduction between groups, but a significant difference in reduction was found in patients with higher median plasma IVM levels (72% IQR 59 – 77) versus untreated controls (42% IQR 31 – 73) (p=0·004). The mean ivermectin plasma concentration levels also showed a positive correlation with viral decay rate (r:0·47, p=0·02). Adverse events were reported in 5 (33%) patients in the controls and 13 (43%) in the IVM treated group, without a relationship between IVM plasma levels and adverse events."
Study: "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro," published in Antiviral Research (and referenced in the aforementioned Wall Street Journal op-ed as "evidence" that ivermectin was effective in treating COVID-19).
This was an in vitro study, meaning it took place in a test tube; hence, the number of people in the trial was zero.
The researchers concluded that their results "demonstrate that ivermectin has antiviral action against the SARS-CoV-2 clinical isolate in vitro, with a single dose able to control viral replication within 24–48 h[ours] in our system."
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