As regular readers know, I was on vacation last week. In my absence, guest blogger Dr. William Paolo provided an excellent fourth installment for our “Ivermectin is the new hydroxychloroquine” series, in which he discusses the epic misunderstanding of the role and conduct of meta-analyses in the medical literature, a misunderstanding that (among other misunderstandings) has led Bret Weinstein to proclaim ivermectin as, in essence, a miracle cure for COVID-19. A few weeks earlier, I had noted Weinstein’s conspiracy mongering over ivermectin, as well as that of others. Little did I suspect as my vacation wound down and I contemplated what I would write for my first post after returning that I’d be adding “take 5” to our “Ivermectin is the new hydroxychloroquine” series. It came in the form of a Tweet by Peter Kory, who has been featured in previous installments:

Of course, there are few better topics to ease me back into the groove of blogging after over a week away, so I figured: What the heck?

Dr. Pierre Kory, as you might recall, has featured prominently in past installments of this series as one of the most prominent advocates promoting ivermectin as a miracle cure for COVID-19. Indeed, he is president of the Frontline COVID-19 Critical Care Alliance (FLCCC) and has testified before Congress. During that testimony, Dr. Kory claimed that ivermectin, used with other medicines such as vitamin C, zinc, and melatonin, could “save hundreds of thousands of people”, and cited more than 20 studies.

As I’ve discussed before, ivermectin is an anti-helminthic drug used as a dewormer in veterinary medicine and to treat parasitic diseases in humans, including internal nematode infections such as Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis, as well as for oral treatment of ectoparasitic infections, such as Pediculosis (lice infestation) and scabies (mite infestation). However, as I’ve also discussed before (and will again in this post), there is no good evidence that ivermectin is effective against COVID-19, although there are low quality studies and, yes, meta-analyses. Worse still for ivermectin as a COVID-19 treatment, the prior plausibility on the basis of basic science is low, because the in vitro cell culture studies that showed activity against SARS-CoV-2, the coronavirus that causes COVID-19, required a much higher concentration of ivermectin than is achievable in the blood with standard (or even high) doses of the drug. So, as I have said repeatedly, it’s possible that ivermectin might have activity against COVID-19 in humans, but not very likely and, even if it does, it’s even less likely that it will be as efficacious as is being claimed.

My first reaction was: So somebody published a review. My second reaction was to see the sorts of things being posted on social media about it. As you might imagine, there was a lot of conspiracy mongering:

Of course, I’m partial to this one:

Yes, I must admit that I’m hard pressed to remember ever having seen a title of an ostensibly scientific article so obviously click-baity. Then there are the authors. Whenever considering an article, it is always useful to consider the source, and the authors of this review are…quite something.

The authors

The review is as bad as you might imagine, given certain members of its author list. What do I mean? Let’s just say that at least one of the authors should be familiar to regular readers of this blog: Peter McCullough.

I first encountered Dr. Peter McCullough in May, when he was promoting an imminent “Holocaust” due to COVID-19 vaccines. At the time, he was being billed by the likes of Joe Mercola and Mike Adams as “doctor with the most citations in the National Library of Medicine on these topics” (i.e., COVID-19). He’s also a consultant cardiologist and Vice Chief of Medicine at Baylor University Medical Center and Principal Faculty in internal medicine for the Texas A & M University Health Sciences Center who’s been making the rounds on the COVID-19 conspiracy circuit. By June, I encountered him promoting the idea that COVID-19 vaccines are designed for “global depopulation“. By July, I noted “holistic cardiologist” Dr. Joel Kahn citing Dr. McCullough for the purposes of fear mongering about COVID-19 vaccines.

Thomas Borody is a real scientist from Australia, known for having developed antibiotic triple therapy for Helicobacter pylori infections that cause duodenal ulcers, after Robin Warren and Barry Marshall had described and then cultured spiral bacteria from the stomachs of patients with gastritis and gastric and duodenal ulcers. Unfortunately, like a fair number of formerly reputable scientists, he appears to have fallen down the ivermectin rabbit hole. as a search for his name quickly reveals, complete with a number of interviews in which he touts a triple therapy including ivermectin as a near-cure for COVID-19, some dating back to last summer. He is the closest thing to an absolute “Giant in Medicine” in the list.

David Scheim, I had never heard of before. However, a quick search of his name revealed that he has authored books claiming that the mafia killed John F. Kennedy, Jr. He does, however, list his affiliation as being a Commissioned Officer, US Public Health Service, Inactive Reserve, Blacksburg, VA. He has also been promoting ivermectin to treat COVID-19 since at least June of last year. I couldn’t find what “Inactive Reserve” means (maybe someone in the USPHS can explain), but there is a “Ready Reserve“, consisting of three main components: Selected Ready Reserve (SELRES), Individual Ready
Reserve (IRR), and Retired Reserve. Then I found this article:

After 15 years as chief of NEI’s Management Information Systems Branch, Dr. David Scheim has retired. He will remain on “inactive duty” as a commissioned officer.

Scheim joined NEI in 1981 as chief of the computer support branch. NEI has been a wonderful place to work and a “privileged life of technology,” he says, because NEI management allowed him the opportunity to explore and work with state-of-the-art computer hardware and software. “Most of what I’ve done at NEI is database development,” he says.

Scheim was one of the pioneers of client-server database technology at NIH. He designed and implemented several such extramural computing systems, and demonstrated client-server concepts and methodologies at various intercampus forums. He also was a member of the NIH Architectural Management Group.

So Mr. Scheim is a retired computer database developer and hasn’t been an active member of the NIH or the US Public Health Service for 25 years.

Dr. Alessandro Santin, it turns out, is a gynecological oncologist and researcher at Yale. He, too, has apparently fallen into the ivermectin rabbit hole and has been touted by Frontline COVID-19 Critical Care (FLCCC):

Most of his prominence in the ivermectin promotion circuit has come from Italy, however, for example, this article, having been quoted as saying, “Ivermectin can really be the game-changer against Covid 19. It works. Now the literature is going in one direction only.” (I can’t help but note that Dr. Santin is correct that the literature is going in one direction with respect to ivermectin. Unfortunately for him, it’s not the direction that in which he claims it’s going.)

Finally, Morimasa Yagisawa is a visiting professor at Kitasato University, Omura Satoshi Memorial Institute in Tokyo, and, yes, he believes that ivermectin is a very effective treatment for COVID-19, having given a statement to the World Health Organization declared that “ivermectin is almighty for prophylaxis, for treatment of early and late stage, and also for long COVID-19 (or) post-acute sequelae (of SARS-CoV-2).” Well, even given potential issues with English aside, that’s a rather…bold…statement.

So it’s clear that the authors of this review are very much fans of ivermectin. Of course, that doesn’t necessarily mean that they don’t make some good points (although I’d be more inclined to be less skeptical of them if they hadn’t included Dr. McCullough as a co-author, given just how utterly bonkers his ramblings about COVID-19 are). Still, after reading this post, it became clear to me that this was more propaganda than science, as you will see.

In praise of an unproven drug: The Nobel gambit

What amused me as I read the article is the whole framing of ivermectin. It’s clear that all the criticism of ivermectin proponents and the poor quality of evidence that they marshal to make their cases has gotten to them, particularly sarcastic cracks about using a horse or sheep dewormer to treat or prevent COVID-19. So the authors bend over backwards to discuss just how awesome a drug ivermectin is—for worms and parasites, that is:

The 2015 Nobel prize for the discovery of ivermectin (IVM) and an antimalarial treatment was the Nobel committee’s first award for treatment agents for infectious diseases since that of 1952 for streptomycin [1]. A macrocyclic lactone of multifaceted potency [2, 3], IVM as deployed worldwide since 1987 has made major inroads against two devastating tropical diseases, onchocerciasis and lymphatic filariasis [4]. During the year since IVM treatment of another global scourge, COVID-19, was first applied [5], results from more than 20 randomized clinical trials (RCTs) of IVM treatment of COVID-19 have been reported [2, 6, 7], with inpatient and outpatient treatments of COVID-19 conducted in 25 countries [2]. A likely biological mechanism has been indicated to be competitive binding with SARS-CoV-2 spike protein sites, as reviewed [8, 9].

I remember this well. The antimalarial treatment included in the 2015 Nobel Prize was artemisinin, which is a derivative of a compound used in traditional Chinese medicine (TCM). As I noted at the time, just because artemisinin came from TCM did not mean that TCM’s precepts were scientifically valid, leading me to point out that artemisinin was a triumph of natural products pharmacology and the scientific method, not TCM. Scott Gavura, for his part, echoed this criticism, pointing out that the 2015 Nobel Prize in Medicine did not validate herbalism or naturopathy, while Steve Novella pointed out that artemisinin had low bioavailability and a short half-life, meaning that it had to be chemically modified (that pesky natural products pharmacology again!) before it could be an effective antimalarial drug.

Why do I mention this? Simple. TCM proponents are still pointing to artemisinin as “evidence” that TCM has a scientific basis, and the arguments in the ivermectin review article reminds me of the same tactic. Basically, the authors are pointing out how awesome ivermectin is as a drug to treat various parasites and worms—so awesome that its developers shared a Nobel Prize—and using that glow to argue that the drug is also highly effective against SARS-CoV-2 infections, even though antiviral activity is a much different thing than activity against parasites. In fairness, ivermectin is a pretty awesome drug for worms and parasites, as this pre-pandemic review from 2011 points out:

There are few drugs that can seriously lay claim to the title of ‘Wonder drug’, penicillin and aspirin being two that have perhaps had greatest beneficial impact on the health and wellbeing of Mankind. But ivermectin can also be considered alongside those worthy contenders, based on its versatility, safety and the beneficial impact that it has had, and continues to have, worldwide—especially on hundreds of millions of the world’s poorest people. Several extensive reports, including reviews authored by us, have been published detailing the events behind the discovery, development and commercialization of the avermectins and ivermectin (22,23-dihydroavermectin B), as well as the donation of ivermectin and its use in combating Onchocerciasis and lymphatic filariasis.) However, none have concentrated in detail on the interacting sequence of events involved in the passage of the drug into human use.

And the effects of ivermectin on human health have been spectacular:

Ivermectin proved to be even more of a ‘Wonder drug’ in human health, improving the nutrition, general health and wellbeing of billions of people worldwide ever since it was first used to treat Onchocerciasis in humans in 1988. It proved ideal in many ways, being highly effective and broad-spectrum, safe, well tolerated and could be easily administered (a single, annual oral dose). It is used to treat a variety of internal nematode infections, including Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis, as well as for oral treatment of ectoparasitic infections, such as Pediculosis (lice infestation) and scabies (mite infestation).) Ivermectin is the essential mainstay of two global disease elimination campaigns that should soon rid the world of two of its most disfiguring and devastating diseases, Onchocerciasis and Lymphatic filariasis, which blight the lives of billions of the poor and disadvantaged throughout the tropics. It is likely that, throughout the next decade, well over 200 million people will be taking the drug annually or semi-annually, via innovative globally-coordinated Mass Drug Administration (MDA) programmes. Indeed, the discovery, development and deployment of ivermectin, produced by an unprecedented partnership between the Private Sector pharmaceutical multinational Merck & Co. Inc., and the Public Sector Kitasato Institute in Tokyo, aided by an extraordinary coalition of multidisciplinary international partners and disease-affected communities, has been recognized by many experts and observers as one of the greatest medical accomplishments of the 20th century.) In referring to the international efforts to tackle Onchocerciasis in which ivermectin is now the sole control tool, the UNESCO World Science Report concluded, “the progress that has been made in combating the disease represents one of the most triumphant public health campaigns ever waged in the developing world”.)

None of this, of course, means that ivermectin is effective against COVID-19, only that it has been spectacularly effective against certain scourges of the developing world, such as onchocerciasis, the second leading cause of blindness caused by an infectious disease, and lymphatic filariasis, also known as Elephantiasis for its ability to cause severe lymphedema and “elephant” limbs.

So, yes, ivermectin is a fantastic drug, both for animals and humans, when used for purposes supported by medical science.

But what about the evidence?

I knew there was something fishy about this review when I saw this in the abstract:

The RCT using the highest IVM dose achieved a 92% reduction in mortality vs. controls (400 total subjects, p<0.001).

That part about 400 subjects plus the 92% reduction in mortality is a narrative I had heard before. Hmmm, I wondered, Which study is that? It sure sounds familiar. It didn’t take me long to realize that this was a study out of Egypt (Elgazzar 2020) that (1) had never been peer reviewed and only been available on a preprint server; (2) as the largest randomized trial of ivermectin for COVID-19 drove seemingly “positive” results in meta-analyses even though the rest of the studies without it wound up producing a negative result; and (3) was very likely was fraudulent, complete with plagiarism and data that appeared to have been made up, leading to its retraction from a preprint server—surely the first time I had ever seen that before!

Let’s just put it this way, if the results from Elgazzar 2020 reflected ivermectin’s true activity, then, as Gideon Meyerowitz-Katz (whom I have quoted before) noted in his discussion of the potential fraud, ivermectin would be “most incredibly effective treatment ever to be discovered in modern medicine”. As a physician (opposed to an epidemiologist), I did quibble a bit with Meyerowitz-Katz (we do have treatments that are greater than 90% effective at eliminating the diseases or conditions that they treat, especially a number of vaccines), I couldn’t deny that he was certainly correct if one were to restrict this observation to antiviral drugs. If Elgazzar 2020 were accurate and generalizable, ivermectin would indeed be the most incredibly effective antiviral treatment ever to be discovered. I further noted that that result alone should have raised a number of red flags. Of course, it did among authors doing meta-analyses who were not ivermectin advocates from the BIRD Group or the FLCCC, which is why they excluded it from their analyses. Apparently it did not for the authors of this review, who accept its results as basically fact, stating again in the text:

The RCT that used the largest dose of IVM, 400 µg/kg on each of days 1-4 [22], had 2 vs. 24 deaths in the treatment vs. control groups (n=200 each), a 92% reduction in COVID-19 mortality (p<0.001).

In fairness, this review was just published, and the retractions and allegations of fraud occurred less than a month ago. Perhaps the paper was already too far along in the pipeline towards publication to note this. On the other hand, this is currently an online pre-proof of a journal article in press. There is, of course, time to correct it by removing any reference to Elgazzar 2020 and also pointing out that the meta-analyses from the BIRD Group and the FLCCC cited so prominently in this article become negative without it.

The authors make another point that seems reasonable but is definitely arguable:

Another objection that has been raised to the RCT evidence supporting IVM efficacy was that study populations were too small [31]. Yet it is well known in clinical trial design that highly effective drugs will establish statistically significant results with smaller sample sizes, with larger study populations required for minimally effective drugs [32]. For example, as noted above, the highest dose IVM treatment study for COVID-19 that tracked mortality had 2 vs. 24 deaths in treatment vs. control arms of 200 subjects each [22], with a z test p-value of 0.0006 [33]. But for a drug with a more modest RR of 75%, for example, the treatment and control arms would need more than 3,800 subjects each to yield the same statistical significance [33].

Yes and no. (Also, there they go citing Elgazzar 2020 again as if it weren’t at the least bogus and at the worst fraudulent!) In theory, yes, if an effect due to a drug on a given disease is really dramatic it should be detectable in smaller randomized clinical trials. However, smaller trials are also more subject to spurious results, particularly if they are not well-conducted. Why? Because they will have a small number of events, such that even a spurious event by random chance alone could affect their results far more than such an event could affect a larger trial. And, make no mistake, none of these trials were particularly well conducted, with many of them biased. There is one exception, though. Unsurprisingly, this trial produced a negative result for ivermectin, at least when used in adults with mild to moderate disease. In any event, I have a saying about meta-analyses:

That saying applies to every meta-analysis thus far of ivermectin, simply because the evidence base is so bad. I also have another saying, namely that equivocal clinical trials of a drug with low prior plausibility = “the drug almost certainly doesn’t work”. Again, the low prior plausibility is based on the in vitro studies in which ivermectin required a high concentration, far higher than is achievable in human blood, to exhibit antiviral activity against SARS-CoV-2. Having worked with an anticancer drug for which the effective concentration in mice was barely achievable—and then only with a potentially toxic dose—this observation alone made me very skeptical of ivermectin as a COVID-19 treatment. I always leave open the possibility that I could be wrong and the drug might be effective, but based on what I know now I think the probability that the drug will be shown to work against COVID-19 in larger randomized trials is quite low. Under normal circumstances, I’d estimate those chances as being so low that the trials aren’t worth doing, but in the current political climate, particularly with so many ideologues and grifters promoting ivermectin as a cure for COVID-19, I have to hold out hope that a negative large clinical trial might help slow the grifting or that the best result that could likely be expected, a modest effect, would at least put ivermectin into perspective. No, I’m not naïve. I know that a resoundingly negative clinical trial of ivermectin probably won’t achieve that, but I can hope, can’t I?

What about the rest of the studies cited in this review? There were two animal studies, one of which is a study in golden hamsters that’s been on a preprint server since November, not a good sign it will ever passing peer review. Interestingly, the study showed no effect of ivermectin on viral load, although it claimed to show a major effect on SARS-Cov-2-associated pathology, including loss of sense of smell. The study was not blinded, something that researchers doing animal research often forget to do, even though failure to blind can cause the same problems in animal research as in human clinical trials. The second study wasn’t even of SARS-CoV-2, but of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. This study was not blinded, either, except for the pathologist examining the liver sections for signs of viral infection. Given that it didn’t even test ivermectin against SARS-CoV-2 and didn’t really show that MHV is so similar to SARS-CoV-2 that the results would be generalizable, color me less than impressed by these animal studies.

Lastly, the authors cite data from Peru:

The clinical experience of IVM treatments of COVID-19 in 25 countries extends far beyond the RCT results summarized, yet incomplete tracking and lack of control data exclude most of this for evaluation. The record of nationally authorized such treatments in Peru provides a notable exception [42]. In ten states of Peru, mass IVM treatments of COVID-19 were conducted through a broadside, army-led effort, Mega-Operación Tayta (MOT), that began on different dates in each state. In these MOT states, excess deaths dropped sharply over 30 days from peak deaths by a mean of 74%, in close time conjunction with MOT start date (Figure 1B). In 14 states of Peru having locally administered IVM distributions, the mean reduction in excess deaths over 30 days from peak deaths was 53%, while in Lima, which had minimal IVM distributions during the first wave of the pandemic due to restrictive government policies there, the corresponding 30-day decrease in excess deaths was 25%.

Reductions in excess deaths by state (absolute values) correlated with extent of IVM distribution (maximal-MOT states, moderate-local distributions, and minimal-Lima) with Kendall τb = 0.524, p<0.002, as shown in Figure 1C. Nationwide, excess deaths decreased 14-fold over four months through December 1, 2020. After a restrictive IVM treatment policy was enacted under a new Peruvian president who took office on November 17, however, deaths increased 13-fold over the two months following December 1, through February 1, 2021 (Figure 1A).

Does this sound familiar? It’s the same sort of ecological “analysis” that an astroturf group was doing for hydroxychloroquine last year that I discussed. The methods of this study are equally awful, which is probably why this article, too, is only on a preprint server thus far, and guess what? It’s a study whose first author is David Scheim, a man with no discernable expertise in the sort of complex epidemiology that would be required to make sense of the Peruvian data, while the other author is Juan Chamie of—you guessed it!—the FLCCC. I’ll say about this study the same thing that I said about the HCQ astroturf site: This is all utter rubbish, methods, conclusion, and all, as you will see. It’s so bad that it reminds me of a study by two antivaxxers without any qualifications in epidemiology, Neil Z. Miller and Gary S. Goldman, that tried—and failed—to correlate the number of vaccines in the recommended vaccine schedules of various countries with those countries’ infant mortality rates.

Seriously, this is some really bad stuff. Let’s just put it this way. Ecological studies of the use of a drug are pretty much worthless because it’s impossible to control adequately for other potentially confounding factors or, in the case of a pandemic, the unexpected resurgence of a virus due to new variants, such as what we are seeing in the US due to the delta variant. But COVID-19 cranks do love their “real world evidence,” don’t they?

I can’t resist finishing this section with these Tweets:

This tells you a lot about the quality of this review.

A notable omission

I’ll conclude by pointing out a very notable omission of a study in this review. The authors cite meta-analyses that use what they refer to as “Cochrane methodology”, which is all well and good, except that they forget to mention that a real, honest-to-goodness Cochrane systematic review and meta-analysis of ivermectin for COVID-19 has actually been published. Its conclusions were—shall we say?—not particularly good for ivermectin:

We found no evidence to support the use of ivermectin for treating or preventing COVID-19 infection, but the evidence base is limited.

Evaluation of ivermectin is continuing in 31 ongoing studies, and we will update this review with their results when they become available.

And:

Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Coming back to small studies and small numbers of events, Cochrane noted:

Our confidence in the evidence is very low because we could only include 14 studies with few participants and few events, such as deaths or need for ventilation. The methods differed between studies, and they did not report everything we were interested in, such as quality of life.

The Cochrane Collaborative, being the Cochrane Collaborative, didn’t really include prior plausibility/prior probability in its analysis, but even without it the best that it could say about ivermectin to treat COVID-19 is that there isn’t good evidence to support it and that maybe ongoing trials will clarify the question. That’s far less…optimistic…a picture than this particular review paints.

In fairness, this Cochrane review wasn’t published until late July, and the publication date of the “Nobel”-touting review was early August. So in this case it really is possible that the authors didn’t know about the Cochrane review. I’m sure they’ll get to correcting their preprint online-only article right away to remove any mention of Elgazzar 2020 and add a citation and discussion of the Cochrane review.

The bottom line

There is a vast disinformation campaign about COVID-19, public health interventions to slow its spread, and especially vaccines. Back when the pandemic was new, hydroxychloroquine was promoted as a treatment in part because if there were a highly effective treatment for COVID-19 advocates could argue that masks, social distancing, and “lockdowns”—and even vaccines—were unnecessary. As the evidence finally convincingly showed that hydroxychloroquine doesn’t work, the same antimaskers and antivaxxers pivoted to ivermectin. Again, I suspect that there’s a reason why the FLCCC and BIRD Groups always included Elgazzar 2020 in their meta-analyses, just as I suspect that this latest clickbait “review” prominently features this same study, despite flaws and bias that were obvious even before the analysis that led it to be retracted. Basically, this review article is part of this disinformation campaign.

I originally entitled this series, “Ivemectin is the new hydroxychloroquine” because of the obvious parallels between the quality of evidence for hydroxychloroquine and ivermectin (low) and the concerted astroturf campaign designed to promote both drugs as a rationale to argue that public health interventions and vaccines to slow the spread of COVID-19 are unnecessary when a “highly effective” treatment supposedly exists. I note, though, that hydroxychloroquine advocates never went as far as ivermectin advocates have gone. Perhaps future posts in this series should be entitled, “Once, ivermectin was but the learner. Now it is the master.” The subtitle could be, “Only a master of astroturfing and grift.”

Yes, I’m still a Star Wars fan, and I had to work that quote in, even if the result was a bit awkward.

Author

Posted by David Gorski

Dr. Gorski's full information can be found here, along with information for patients. David H. Gorski, MD, PhD, FACS is a surgical oncologist at the Barbara Ann Karmanos Cancer Institute specializing in breast cancer surgery, where he also serves as the American College of Surgeons Committee on Cancer Liaison Physician as well as an Associate Professor of Surgery and member of the faculty of the Graduate Program in Cancer Biology at Wayne State University. If you are a potential patient and found this page through a Google search, please check out Dr. Gorski's biographical information, disclaimers regarding his writings, and notice to patients here.