Ivermectin's Messy Science and Politics: What’s the Reality?

Shin

Ivermectin’s situation reminds me of vitamin D.

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Ivermectin is oddly popular among health officials and the public alike in some countries —notably Latin America, South Africa, and Indonesia — as the ‘cure’ or ‘miracle drug’ against Covid-19. The price of ivermectin has skyrocketed as a result, even more so in the black market. But the World Health Organization (WHO) and Food and Drug Administration (FDA) have not approved the use of ivermectin to treat Covid-19 outside clinical trials.

As such, there are two main schools of thought about this:

  • Ivermectin is ineffective or not very effective against Covid-19. Using it to treat Covid-19 may be unsafe and pose unnecessary risks.
  • Ivermectin is effective or highly effective against Covid-19. But accepting so doesn’t bring much profit to big pharma, which may have suppressed its recognition or approval.

Which one is correct? The answer lies somewhere in the middle, to spill the beans, which is why the situation is messy and controversial. But let’s see what’s going on with a critical eye.

Ivermectin in brief

Ivermectin — first identified from soil bacteria in the 1970s in Japan — is an FDA- and WHO-approved oral drug that’s safe, cheap, and widely used to treat parasitic worm infections. Ivermectin is on the WHO’s list of essential drugs, and it’s one of the most valuable drugs in human and animal medicine worthy of a noble prize.

Despite being an anti-parasite drug, cell culture and animal studies have found that ivermectin also has antiviral effects against various viruses, such as Zika virus, dengue virus, West Nile virus, human immunodeficiency virus (HIV), and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The precise antiviral mechanisms of ivermectin may vary, depending on the type of virus. For SARS-CoV-2, ivermectin is thought to inhibit (i) virus entry into cells, (ii) virus’s enzymes that are essential for viral replication, and (iii) excessive inflammation.

The cell culture study that discovered the anti-SARS-CoV-2 effects of ivermectin was promising— a 5000-fold reduced virus replication within 48 hours. But note that the ivermectin dose used in this cell study is higher than usual. Still, this study has quickly kickstarted ivermectin’s clinical research. But the clinical data of ivermectin is really messy, tainted by fraudulent research and possible political motives.

The fabricated data that deceived nations

I. Surgisphere

Ivermectin’s clinical journey began with an observational study released as a preprint in April 2020, which found that ivermectin treatment is associated with better survival of Covid-19 patients. (Preprints are papers that have not undergone peer-review or published in journals.)

But it turned out that the preprint study used data from Surgiphere, a small company in the U.S. that claimed to store data from more than a thousand hospitals worldwide. Studies published in reputable journals have also used Surgisphere data, which got retracted later after independent auditors concluded that Surgisphere’s data are fabricated.

So, unsurprisingly, the first ivermectin preprint disappeared one month after its release. Another preprint showing that ivermectin reduced Covid-19 mortality by 6-fold also relied on Surgisphere data and was retracted.

But the damage has been done. Latin American authorities cited those preprints as evidence for ivermectin’s efficacy against Covid-19. By June 2020, health authorities of Peru, Brazil, and Bolivia had endorsed ivermectin as a Covid-19 treatment. It was only a few months later that the authorities realized that they were informed by fake data, admitting that they could not afford to wait for peer review at that time.

II. Elgazzar et al. study

The largest clinical data fabrication scandal by far is the preprint study of Dr. Ahmed Elgazzar et al. (2020), released in November 2020. Dr. Elgazzar is a professor emeritus at the University of Behna in Egypt. This randomized clinical trial (RCT) enrolled 600 participants and showed that ivermectin reduced Covid-19 mortality by a staggering 90% compared to placebo. This RCT is the largest one ivermectin has thus far.

But it was only in July 2021 that Jack Lawrence, a medical student in London, found out that the study’s data may be fabricated. Chucks of paragraphs of the preprint paper were also plagiarized. Further analyses by Nick Brown, a data analyst specializing in examining scientific errors, and Gideon Meyerowitz-Katz, an epidemiologist working on chronic diseases and Covid-19, confirmed that the Elgazzar study data were most likely fabricated, not an innocent mistake.

Soon, the preprint server has withdrawn the Elgazzar study. But, again, the damage has been done. Such spectacular results have made the Elgazzar study the pillar supporting ivermectin’s potential in fighting Covid-19.

The Elgazzar study has been cited at least 30 times by other papers — even the ones published in eminent journals — which were, in turn, cited hundreds of times by other papers. Many organizations — such as the U.S. Front Line COVID-19 Critical Care (FLCCC) Alliance and British Ivermectin Recommendation Development (BIRD)— and individual doctors and pharmacists have used this study to justify giving ivermectin to thousands, if not millions, of SARS-CoV-2-infected people worldwide.

“Because the Elgazzar study is so large, and so massively positive — showing a 90% reduction in mortality — it hugely skews the evidence in favor of ivermectin,” Meyerowitz-Katz said. Published meta-analyses favoring ivermectin for treating Covid-19, which have garnered much media attention, have indeed included the Elgazzar study. “As I’ve shown before, excluding just this single piece of research from various meta-analytic models almost entirely reverses their results,” he wrote. “It’s not an exaggeration to say that this one piece of research is driving almost all of the benefit that people currently attribute to ivermectin.”

Meyerowitz-Katz and others have also emphasized that it’s shameful that professional scientists, medical doctors, and major medicines regulators cited or looked through the Elgazzar paper without noticing the fraud for over seven months. And it shouldn't take a medical student first to notice it. The Elgazzar study, in essence, managed to deceived nations.

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The more reliable data and big pharma

Setting the not-so-reliable preprints aside, let’s look at more trustworthy randomized controlled trials (RCTs) on ivermectin and Covid-19. Although many of them are still preprints, preprints are not necessarily unreliable. Even peer-reviewed published papers can be unreliable at times.

To this end, Sebastian Rushworth, MD, junior physician and independent writer, has done a meta-analysis on ivermectin and Covid-19, based on studies he deemed worthy as of May 2021. Although his meta-analysis is an informal blog post, it’s the least biased one I could find. As mentioned, even peer-reviewed published meta-analyses on ivermectin and Covid-19 included the Elgazzar study, but Dr. Rushworth’s one did not.

Dr. Rushworth included every double-blind, placebo-controlled RCTs — the gold-standard design for clinical trials — with at least 150 participants that he could find in both the preprint and published literature. He picked mortality as the endpoint because it’s the least biased measurement. “Either someone’s dead, or they’re alive. End of story,” he wrote.

After harmonizing data from seven RCTs totaling 1,327 participants, Dr. Rushworth calculated that ivermectin reduced the Covid-19 mortality rate by 62%, which means that ivermectin could prevent three out of five Covid-19 deaths.

This efficacy is rather high and may even be overly optimistic. The first lifesaving Covid-19 drug discovered, dexamethasone, only decreased the mortality rate by 20–35% only among Covid-19 patients on supplemental oxygen or mechanical ventilation.

Ironically, the meta-analyzed RCTs were conducted in Bangladesh, Iraq, Nigeria, India, Iran, Argentina, and Colombia — countries that desperately need the affordable ivermectin to be proven effective. Put it another way, high-income countries don’t seem interested in studying ivermectin, Dr. Rushworth noted.

He further pointed out that authors of the Colombian RCT, published in the reputable Journal of American Medical Association (JAMA), may have a financial conflict of interest. The authors were receiving payments from pharmaceutical companies that make remdesivir (Gilead) and vaccines (Janssen, Glaxo-Smith-Kline, and Sanofi-Pasteur), and that is developing two new expensive Covid-19 drugs (Merck).

Possibly to the delight of big pharma, the Colombian RCT found no effects of ivermectin in hospitalization duration or mortality in a sample of 400 patients with mild Covid-19. But the participants’ median age is only 37 years, with 79% of them having no medical comorbidities. Only one death occurred in the placebo group. So, this RCT has basically tested ivermectin on people that might not even need treatment to begin with.

“Considering the conflicts of interest of the authors, my guess is that this was the goal of the study all along: Gather together a number of young healthy people that is too small for there to be any chance of a statistically significant benefit, and then get the result you want,” Dr. Rushworth wrote. “The media will sell the result as “study shows ivermectin doesn’t work” (which they dutifully did).”

Ivermectin is an off-patent drug, so big pharma would not profit from its widespread use. Still, this doesn’t prove that a conspiracy is going on, and we can only speculate. After all, let’s not forget that dexamethasone — a cheap, off-patent drug just like ivermectin — is widely used globally as it’s one of the few confirmed lifesaving drugs for Covid-19.

Still not reliable enough

However, Dr. Rushworth also admits that the RCTs he meta-analyzed RCTs have major flaws, a stance consistent with the review of the U.S. National Institute of Health (NIH).

The NIH has summarized key points from 16 out of 32 human studies (both RCTs and observational studies) on ivermectin and Covid-19 available as of July 2021. Only 16 studies were summarized — and compiled nicely in a table here — as the others were not informative. (The Elgazzar study is not among those 16 RCTs that the NIH selected and summarized.)

But even though those 16 studies (13 RCTs and 3 observational studies; 10 published papers and 6 preprints) are the best ones available, the NIH still concluded that those studies suffer from limitations in small sample sizes and flawed study methods.

So, the NIH cannot recommend ivermectin for treating Covid-19 due to insufficient concrete evidence. The WHO and FDA also do not endorse using ivermectin to treat Covid-19 outside clinical trials for the same reason.

Nonetheless, other RCTs are ongoing. For example, researchers at the University of McMaster in Canada are working alongside Brazil and South African on an RCT with 3,200 participants. This RCT will test the effects of ivermectin, metformin, and fluvoxamine in preventing Covid-19 progression. This RCT is funded by the Bill and Melinda Gates Foundation and Fast Grants, so there should be no financial conflict of interest. The preliminary results should be known sometime this year.

The Front Line COVID-19 Critical Care (FLCCC) Alliance viewpoint

Rejection after successful peer review almost never happens in scientific journals. Yet, it happened in March 2021 when editors of Frontiers in Pharmacology decided to reject publishing a meta-analysis that passed peer review in January 2021. Still, the meta-analysis’s abstract had over 85,000 views on the journal’s webpage before the rejection.

The meta-analysis authors, members of the FLCCC Alliance, obviously did not take the rejection well and called it outright censorship. The FLCCC Alliance is organized in the U.S. in March 2020 by physicians to update themselves with the latest science on Covid-19.

(The rejected meta-analysis is available at the FLCCC Alliance’s website, which pooled data from over ten studies and calculated that ivermectin hastened recovery by 1.4 days and decreased mortality by 71% in Covid-19 patients compared to standard care.)

Frontiers in Pharmacology rejected the meta-analysis because it promoted its own ivermectin protocol, a bias that may have clouded the paper’s analyses and results; for example, biased statistical methods and criteria for study inclusion and exclusion. Moreover, over half of the studies incorporated in the meta-analysis are preprints, including the Elgazzar study.

But the FLCCC Alliance has no financial ties with ivermectin companies. They have admitted that they make no money from promoting ivermectin. So, the rejection is also questionable to some extent.

Still, the FLCCC Alliance can be a controversial group. They touted ivermectin as the ‘miracle drug’ that could prevent Covid-19 transmission and illness in the U.S. Senate hearing in December 2020. They fully believe in ivermectin’s efficacy that they said it’s unethical to give a placebo to patients when there’s a cure. As follows, they always publish observational studies for their treatment protocols rather than RCTs.

(The FLCC Alliance has also used observational studies to promote its MATH+ protocol — consisting of methylprednisolone, ascorbic acid (vitamin C), thiamine, and heparin, plus statin, zinc, vitamin D, famotidine, melatonin, and magnesium — to treat Covid-19. This was even before the RECOVERY trial proved dexamethasone’s efficacy at lowering Covid-19 mortality. So, the FLCC Alliance was right about methylprednisolone — a steroid similar to dexamethasone — being useful against Covid-19.)

One of the FLCCC’s leaders, Pierre Kory, MD, a critical care physician and lead author of the rejected meta-analysis, told MedPage Today that:

Everyone in medicine will yell and scream that this paper is not a randomized controlled trial [RCT]. We didn’t believe in an RCT. We believe we’re supposed to doctor and use our expertise. If you’ve been doing this for decades, and you trust your assessment of the disease and your knowledge of medicine, it’s OK to doctor…If someone wants to discount those [observation] studies … and says they want to do an RCT with placebo, that’s problematic for me. I could not have a patient admitted to my care and give placebo knowing what I know about ivermectin.

(Interestingly, Dr. Kory had also advocated for the use of steroids to treat Covid-19 patients, which was not taken favorably by others until the RECOVERY trial showed that Dr. Kory was right in June 2020.)

Dr. Kory may have a point, but one that’s controversial to science. Steven Joffe, MD, MPH, a pediatric oncologist and medical ethicist, argued that the FLCCC should be pushing for a robust RCT if they genuinely believe that ivermectin would work. The trial can even be stopped early if the results are as remarkable as they think. “If in fact it is effective, the only way to convince the clinical and scientific community and allow patients all over the world to benefit is to prove the case in such a trial,” Dr. Joffe said.

Observational studies cannot determine causation because they are not randomized. So, the comparison between test and control groups would not be entirely fair, and there are bound to be uncontrolled factors that may influence the results.

Only RCTs can prove cause and effect, but RCTs — especially large-scale and high-quality ones — are costly and time-consuming. RCTs also often have limitations in generalizing their results to the broader population. But sadly, per the NIH’s conclusions mentioned earlier, there are still no definitive RCTs that prove ivermectin's usefulness in treating Covid-19.

Does this mean that ivermectin mustn’t be used now? Not necessarily. Sometimes, real-world circumstances may beg to differ, and rules may need to be bent a bit.

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When ivermectin use may be justified

In Malaysia, where I reside, people with mild Covid-19 usually get turned away from hospitals that are operating at over 100% capacity. They were asked to self-quarantine at home instead, without any treatments provided. Most will probably survive, but there will be a few that progresses to severe Covid-19 that could be fatal or cause long-term health problems.

Other low- to middle-income countries are probably facing similar situations, where expensive authorized treatments like remdesivir and monoclonal antibodies are not readily available and affordable.

Here is where ivermectin might help. If ivermectin is safe at its usual dose and may even stop SARS-CoV-2 replication, taking ivermectin may be better than taking nothing. While clinical trials on ivermectin are ongoing, time is always in short supply, especially when there’s no better treatment choice available. This may be why some doctors willingly prescribe ivermectin, even though it’s still unauthorized and scientifically unproven, simply because there’s no harm doing so, and it just might help.

Studies before the pandemic have confirmed that ivermectin — the version used in humans, not animals — is safe. Published meta-analyses and reviews of the literature have concluded that ivermectin is safe across all ages at doses up to 0.4 mg/kg (and even up to 0.8 mg/kg) taken orally. For pregnant women, ivermectin’s safety data is relatively scarce and inconclusive, but the data thus far have noted no obvious harm of using ivermectin during pregnancy. Safe means there’s no difference in rates of adverse events between ivermectin and non-ivermectin control groups.

Looking at the abovementioned NIH’s review of 13 RCTs and three observational studies, there’s also no indication of ivermectin harming Covid-19 patients. Published meta-analyses (that included the Elgazzar study) also noted no danger signal of using ivermectin to treat Covid-19. But weak and inconclusive evidence suggests that ivermectin might help treat Covid-19, at least in some cases.

Ivermectin’s situation also reminds me of vitamin D. While there are observational studies and small RCTs that support vitamin D’s efficacy in treating Covid-19, one large-scale RCT failed to find benefit. But no studies have found harm in giving Covid-19 patients vitamin D. So, like ivermectin, vitamin D is either useless or useful against Covid-19. Like ivermectin, vitamin D is cheap and safe at reasonable doses.

In the end, though I’m no physician, it may be about balancing the art and science of medicine. We need the science in distinguishing between real and fake, reliable and unreliable data. We need the art to know when exceptions are justified. And we need a balance of both to understand that ivermectin isn't a miraculous drug, and despite its controversial reputation and clinical efficacy, it isn’t harmful, and it just might help.

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MSc Biology student | 5x first-author academic papers | 100+ articles on coronavirus | Freelance medical writer

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