Dr. Buzz Hollander: Lessons from the Ivermectin debacle

Buzz Hollander MD is a family physician on the Big Island of Hawaii with no ideological axes to grind. He tweets @buzzhollandermd. This first appeared in RealClear Science.

When podcast king and comedian Joe Rogan reported that he was ill with Covid-19, a media firestorm commenced. This was no surprise, given the interest the public has in celebrities diagnosed with Covid-19, especially celebrities with a history of expressing ambivalence towards the highly-effective vaccines. However, the headline was not typical at all: Joe Rogan Says He Has Covid, Taking Bogus Ivermectin ‘Cure.’

How did we get here, to a place where Forbes Magazine leads off a celebrity news bit with a slap at a long-used medication, currently being seriously studied for possible benefit against the disease in question? Ivermectin’s is a fascinating story, in a rubbernecking-past-the-highway-accident kind of way; and depressing, too, given the mess that we’re left to clean up. Truly, the story of ivermectin in this pandemic is a cautionary tale of the perils of hubris in science, medicine, and public health. We would do well to learn its lessons.

The Good, The Bad, and The Ugly About Ivermectin for Covid-19

It’s worth taking a bit of time first to understand the basis behind the excitement for ivermectin as a possible agent against Covid-19, as well as the reservations expressed by the medical establishment. Ivermectin, much more than a “horse dewormer,” is a genuinely useful anti-parasitic medication, used widely in our own species primarily for tropical diseases like onchocerciasis and lymphatic filariasis. While never tested in human subjects for possible antiviral properties prior to the arrival of SARS-CoV-2, it had been studied in the laboratory setting for theoretical properties against multiple viral pathogens. The potential for anti-inflammatory properties – the sort that, like fellow old generic, dexamethasone, could prove useful against Covid-19’s infamous cytokine storm – was also known. Topically applied, it has been shown to be anti-inflammatory, and is prescribed for the autoimmune skin condition, rosacea; and systemically, there exists some in vivo evidence (albeit in mice).

What are the chances that an antiparasitic with mere hints of anti-viral and anti-inflammatory properties would amount to the most effective medication on the face of the planet against SARS-CoV-2 on both counts? Slim, indeed. Much of the skepticism that I, and most of the medical establishment, felt towards ivermectin can be explained through that lens: the prior probability of these rather remarkable assertions being true was so low, that the bar for evidence was set rather high.

The evidence stacks up in rather complicated fashion. If your blister pack of ivermectin is half-full, you might find the arguments in favor of ivermectin’s efficacy convincing. Biological plausibility for its antiviral potential was established in April 2020, by an Australian team led by Dr Leon Cary, Dr Kylie Wagstaff, and Dr David Jans, who showed that, in a laboratory in vitro setting, ivermectin rapidly cleared SARS-CoV-2 RNA from cells. Doubts were raised that real world human dosing of ivermectin could ever reach those experimental concentrations, but a single modeling study concluded that it would at least be a possibility in lung tissue. In any case, the race to study ivermectin in humans was on. Given the dismal circumstances in the spring of 2020, many regions, especially South America, began both to embrace and to study the use of ivermectin against Covid-19 on the premise of this hope.

The positive reports have been numerous. There are country-level, “ecologic” reports of Covid-19 cases, hospitalizations, and deaths improving after large scale distribution and/or deployment efforts, such as in Peru. The most visible supporter of ivermectin among physician groups, the controversial Front Line Covid-19 Critical Care Alliance (“FLCCC Alliance”), led by respected intensive care specialist, Dr Paul Marik, and his protégé, Dr Pierre Kory, is keen to share anecdotal reports of physicians seeing remarkable success via prescribing ivermectin both as prophylaxis (prevention before becoming infected with SARS-CoV-2) and treatment of early/mild as well as severe disease. A multitude of favorable observational studies has been published, which generally involve studying how patients treated with ivermectin did in contrast to those left untreated; these are described in detail on the FLCCC Alliance position paper.

Finally, dozens of our evidential gold standard, the randomized control trial, have been performed, and the vast majority have found benefit to using ivermectin. A recent ivermectin meta-analysis by outspoken ivermectin advocate, Dr Tess Lawrie, Dr Andrew Bryant, and their team, combining data from 24 such trials, found an overall 62% reduction in risk of death when used for treatment, but has been fairly questioned for including a fraudulent study. Another meta-analysis by Yuani Roman et al., which had excluded the study in question, expressed concerns over trial quality and concluded that ivermectin was “not a viable option” for covid-19 treatment, but did find a similar mortality benefit of around 60%, albeit without statistical significance.

And if your blister-pack is half-empty? There are many valid reasons to view the data on ivermectin with healthy skepticism.

Ecologic studies, anecdotal reports, and case series are useful in science, but primarily to signal the need for higher quality studies, not as validation for adopting a novel treatment. Regional epidemic curves shift and swerve constantly, for a variety of reasons which can confound any effort to attribute causation to one factor; some of the same people who credit improvements in Mexico or India to ivermectin campaigns are less sanguine if told that a lockdown or mask mandate was the cause of a Covid-19 outbreak leveling off. As a physician, I might be tempted to give a patient a steroid injection for an arthritic knee because my personal experience tells me that I am usually a hero afterwards; but broader study of this practice tells me I should not overvalue my own experiences.

Most importantly, there are real concerns about the quality of the many RCTs performed on ivermectin. Many trials were unregistered or unreported (opening the door for mid-stream protocol changes and publication bias); a large number were self-funded; and the only trial performed at what might be considered a major medical academic center, at Spain’s University of Navarra, was one of the only trials with negative results. While I might be termed an “-ist” of some sort for saying this, it’s easier for me to trust the scholarship of major institutions oozing with grant money and filled with talented researchers skimmed from the rest of the world than from places with a very limited history of performing and publishing clinical trials.

Adding to these concerns, the issue of fraud has reared its head on several important ivermectin studies. One of the first papers claiming a mortality benefit for ivermectin in hospitalized patients was taken from the tainted (or quite possibly imaginary) Surgisphere database, and was quickly retracted (but not before influencing policy in South America). So, too, was the hugely influential Elgazzar et. al. study from Egypt, which claimed a 90% reduction in mortality, but was rather convincingly exposed to be fraudulent this past July. Finally, the remarkable study from Argentina’s Dr Hector Carvallo, finding a head-scratching 100% effectiveness at preventing Covid-19 infection among health care workers (none of the 788 workers taking ivermectin and carageenan contracted the disease, while 57% of those using standard PPE did), fell at the end of August, with compelling arguments that it is nearly inconceivable that it even happened as advertised.

To be clear, I do not see any suggestion of a Big Pharma conspiracy or cover-up here. Surgisphere’s other biggest retraction was related to the study which unfairly bashed the safety of ivermectin fellow-traveler, hydroxycholoquine. Oxford researcher Andrew Hill, one of the most visible, respected scientists supporting the utility of ivermectin in Covid-19, retracted his team’s positive meta-analysis once the Elgazzar study was withdrawn.

Even biologist-turned-podcaster, Dr. Bret Weinstein, high on the list of vocal ivermectin supporters, has concurred that Dr Carvallo will not share his data from Argentina, and that “we should rate the evidentiary value of this study as zero.”

Where does this leave us? Cautious, I would say, but still curious. Evidence of fraud is not evidence of ineffectiveness. After all, I and most of my colleagues still prescribe valsartan, a very useful blood pressure medication, despite one set of researchers being caught in the act of making up data in a published trial. Other compelling trials already existed on its behalf. In the case of ivermectin, there is still a plethora of un-debunked studies, even if they are not of the highest quality.

In all, the matter of ivermectin’s value as a Covid-19 therapeutic is still an open question under investigation. In fact, several of the sorts of large, high-quality trials most of us covet are currently underway. One, the TOGETHER trial, presented interim results last month that were unfavorable to ivermectin, announcing the study arm was being stopped due to futility. However, I observe the modest trend towards a (statistically insignificant) 9% improvement in ER/hospital stays and 18% mortality reduction, and wonder: “perhaps the other studies will show some real, if not miraculous, benefit?”

Supporters of ivermectin like to use the word, “safe,” in discussing the medication. Indeed, it has a decades-long history of mass deployments with an admirable safety record; the FLCCC Alliance website links to a very thorough review of the existing safety data. Aside from limited safety data in young children and first trimester pregnancy, concerns are mostly for transient neurologic side effects and gut intolerance. However, I observe that most of our knowledge of ivermectin’s excellent tolerance profile is based on one-time dosing of the FDA-cleared 0.2 mg/kg dose, or about 14mg for an average-sized adult. Nearly all of the studies showing a positive effect for ivermectin treating or preventing covid-19 utilized a dose in this range, often repeated again after 2 days. Truly, there is little concern for safety in this dosing range.

However, the FLCCC Alliance has recently updated their ivermectin protocol, increasing the doses to 0.4mg/kg twice weekly for long-term prophylaxis, and 0.4-0.6mg/kg every day for 5 days for treatment in the era of the delta variant. This concerns me, given the limited studies assessing safety for daily doses in this range. One malaria study found a modest (roughly 10%) but higher rate of neurologic side effects, especially visual disturbances, in the 0.6mg/kg group than placebo; another small pilot study exploring high doses for covid-19 found a high rate (43%) of adverse effects for those taking 0.6mg/kg doses for 5 days, but not significantly more than placebo (33%) – and also reported worse health outcomes for the high dose ivermectin group, but again not statistically significant.

I have a hard time endorsing the new dosing protocol. In an attempt to understand what data drove the change, I scoured the FLCCC Alliance website and was disappointed to find only two video updates explaining the shift. In one, Dr Kory candidly admits, “We don’t have data on this,” basing the decision instead on having “talked to a number of experts” – conspicuously naming none other than Dr Hector Carvallo. In the next update, describing ivermectin “breakthrough infections” with the delta variant, he rhetorically inquires, “Should it be 0.4 [mg] twice a week? We have no idea!” and later shares, “I’ll be honest – we just kinda pulled it out of the air.” I have no reason to doubt this, coming from the mouth of Dr Kory himself, posted on their own website. I do have reason to doubt the quality of the science behind the new protocols. Given the lack of large scale safety data for these higher doses and the equal lack of trial data in their support, I find these recommendations frankly irresponsible.

Handling Uncertainty in Science in Ivermectin; or, “How Not To”

If you’ve made it this far, you probably get people the picture: intelligent people (including physicians) could look at the data on ivermectin for Covid-19 and reach the conclusion that it is quite safe, at least in reasonable doses, and potentially effective. It’s also understandable to review the body of evidence and decide it’s not worth a try. This is essentially the conclusion of the NIH: “There is insufficient evidence… to recommend either for or against the use of ivermectin for the treatment of Covid-19.” And yet – we have absolutely lost our collective minds over this medication!

I think the ivermectin boosters are sincere in their beliefs. Truly, I have empathy for anyone who deeply believes that ivermectin could end the suffering this pandemic is caused, and yet watches the public health authorities repeatedly not heed their calls. However, I cannot grasp how someone with a background in science like Bret Weinstein could be so convinced by a single incredibly positive study from Argentina that they would take the message to millions via Joe Rogan’s podcast that ivermectin is more effective than vaccination to prevent Covid-19, without critically examining the study first. I do not understand how intelligent and experienced physicians like Paul Marik and Pierre Kory could issue a 30+ page position paper describing the dozens of studies on ivermectin for Covid-19 without a single mention that most of the studies had obvious flaws. It baffles me that respected researchers like Andrew Hall and Tess Lawrie would stake their professional reputations on the quality of trials that had red flags popping up all over them. All I can imagine is that they only engaged with each other, and not those who disagreed with their conclusions. There is no safe place for hubris in science.

I would argue the same for the public health community, physicians, and pharmacists, who have often treated ivermectin more as a threat than a potential therapeutic. For example, the NIH has made the same “neither for nor against” recommendation for other therapeutics with mixed evidence for Covid-19, like colchicine, fluvoxamine, and inhaled steroids; however, while no one is struggling to get their colchicine-for-Covid-19 prescription filled, some pharmacists will not fill ivermectin prescriptions for that same purpose. Reminder: per the American Medical Association, 10-20% of all prescriptions are off-label uses, and: “Once a drug is FDA-approved for a specific indication, legally it can be used for any indication.”

Last week that same American Medical Association released a formal statement on ivermectin for Covid-19, writing: “We are alarmed by reports that outpatient prescribing for and dispensing of ivermectin have increased 24-fold since before the pandemic and increased exponentially over the past few months. As such, we are calling for an immediate end to the prescribing, dispensing, and use of ivermectin for the prevention and treatment of COVID-19 outside of a clinical trial.” Now, I wonder why we are hearing so many reports of humans purchasing veterinary ivermectin and calling poison control? Perhaps because those wanting to be treated with ivermectin either cannot get a prescription from their duly-warned doctor, or they can obtain a prescription but their pharmacist will not fill it.

Filed in the “unintended consequences of bad public health messaging” category: sometimes you make people sicker when you are trying to protect them.

For the curious: a typical 7.3 gram tube of veterinary equine-grade 1.87% ivermectin is about 135mg of ivermectin, or ten times a normal dose; as someone who has had to calculate mg/kg doses at midnight on pediatric wards, this sort of math always makes me nervous. What really makes me nervous is the Proprietary Component A, B, and C that make up the other 98.13% of the tube – please, please do not ingest this stuff.

Rather than lampoon those desperate enough to purchase ivermectin at a feed store, as the FDA opted to do with their “You are not a horse” announcements, the FDA, CDC, AMA, and most any other three-lettered health organization, would probably be better served to recognize the genuine interest many people have towards ivermectin, and encourage them to speak to their doctors — rather than encourage their doctor not to speak to them. People diagnosed with Covid-19 can be pointed towards an ongoing trial and get paid to increase our understanding of ivermectin’s value. The certainty with which our guiding health authorities seems to feel that ivermectin has clearly failed to show evidence of benefit strikes me as exceeded only by those even more convinced of ivermectin’s benefit. If “science is curiosity,” certainty is its enemy.

Certainty drifting into righteousness has also led to censorship in the ivermectin discussion. The makers of this balanced article and video, which were some of the only non-dogmatic efforts I’ve found on the topic, seemed genuinely concerned they would be censored, simply for giving Dr Lawrie the chance to speak and address the concerns raised by two ivermectin skeptics – and indeed they (briefly) were! I struggle to fathom the hubris of a tech platform which deems the need to censor someone for supporting a medication with an excellent safety history and a beguiling narrative on its behalf for a potential role in aiding a generational pandemic. This is not calling out “fire” in a crowded theatre. This is… discussing science, complicated bits and all.

A different form of ivermectin censorship has been the bizarre choice of many hospitals to refuse to offer ivermectin to seriously ill patients whose family members desperately want them to have it. We are talking about a legal medication with little risk of harm and some plausible benefit. Speaking of hubris, what institution would rather be sued and defend themselves in court rather than have a family member sign a waiver, administer the $75 drug, and let everyone feel like they were heard? It astounds me, and yet it has happened over and over!

The Cost of One-Sided Messaging

One price of our medical institutions consistently demeaning the possible benefits of ivermectin has been yet another erosion of trust between public health and the public. In a rather striking recent poll (taken with a grain of salt, of course), 56% of Republicans thought ivermectin was “possibly effective” or “very effective” for Covid-19, while only 18% thought it “dangerous;” among Democrats, the numbers were almost inverted, at 19% and 64%! How does that 56% of Republicans (and 35% of adults regardless of political affiliation) respond to the AMA calling for an immediate end to ivermectin prescribing; or the CDC telling them to knock off consuming horse dewormer? Answer: probably not in a way which will make them more receptive to their next message about the importance of vaccination.

Therein lies the real rub. I have read many a blog post and interview with contrarian thinkers in the medical field that run a lot like this: “I’m fully vaccinated against Covid-19, my children are vaccinated according to CDC guidelines, and I believe in vaccination; however, if you are a healthy adult under 50, vaccines are not really necessary for you; and besides, we have safe and effective treatments if you are infected with Covid-19.” That “safe and effective” treatment is often going to be none other than ivermectin. This is where the polarization around ivermectin has the capacity to do the most damage: when people fully convinced by the FLCCC Alliance, America’s Front Line Doctors, or Senator Ron Johnson that ivermectin will save them, and fully disgusted with whatever the CDC has to say about the matter, decide they don’t need a vaccine.

I imagine this is the real reason for our nation’s institutional disdain for ivermectin: a well meaning if poorly executed desire to discourage anything perceived to be an alternative to vaccination, especially among those who consider themselves “low risk.” The 18-49 age group is a bigger contributor to US Covid-19 hospitalizations right now than the 50-64 or >65 age groups. About 1/175 Americans in their 40s have already been hospitalized with covid-19. A healthy 37 year old man, or healthy 45 year old woman, with no comorbidities (not even obesity), would have about a 1 in 25 chance of ending up in the hospital if diagnosed with covid-19. Remaining unvaccinated in 2021 is one of the riskiest choices even healthy, young people could make; and it’s the choice about 50% of those under 50 have made. I’m not confrontational about vaccines, but I think it’s important people receive honest information about their own risks. We have abundant evidence for a 85-95+%, possibly enduring, protection against hospitalization and death from Covid-19 that a vaccine provides relative to someone without immunity. I would be absolutely thrilled if the next ivermectin trials showed a statistically significant 20-25% reduction in hospitalization or death. Thrilled, and pleased as punch to prescribe it. However, there is almost zero chance ivermectin can protect an individual, or a hospital system, as well as a vaccine.

Talking About Science Instead of Shouting

Everyone involved in the ivermectin debacle can take responsibilty for their own part, and resolve to do better with the pandemic’s next turn. I wish those with large public platforms, who saw only the promise of ivermectin and not the pitfalls, had been more balanced in their descriptions of the medication, and had sought out counsel from those with expertise that perhaps they lacked. For those of us, myself included, who rose to maximum skepticism at the first message of a “miraculous” drug, I wish we’d behaved better, with fewer eye rolls and haughty put-downs of the studies. Our public health institutions would have done better to be curious and open to novel treatments, and message support over chagrin. The public, both believers and doubters in ivermectin, could have tried harder to seek different viewpoints and interact more civilly with those who disagreed. Social media platforms did not need to stoke the fires of conspiracy theories by censoring those who wanted to tout ivermectin. We all could have done better.

We might get another chance with another potential repurposed, generic medication, the SSRI fluvoxamine. That same TOGETHER trial reported unpublished data showing about a 30% decrease in hospitalization and death among the nearly 750 Covid-19 patients randomized to fluvoxamine, echoing the promise of an earlier, smaller trial. If the data holds up to scrutiny, how will we respond? Already I have seen a snarky social media comment about unvaccinated people showing up with the (exceptionally rare) SSRI side-effect of serotonin syndrome. I sincerely hope we do better this time, and avoid the extremes of hype, dismissal, and censorship – even if some people who have denounced vaccines or touted ivermectin decide to push fluvoxamine.

Yet again, this pandemic has reminded us that science’s attempts to describe reality are fraught with uncertainty. Our greatest gift, when confronted with uncertainty, is to recall that none of us really know the truth. Real intellectual humility in science – not the “I’m humbled to be named coach of this great football program” variety of humility, but truly questioning whether we know what we think we know, and choosing to update our pre-conceived notions regularly — is the smoothest path to advancing medical science. It’s dearly needed now.

As to Joe Rogan: I’m glad the apparently fit, martial arts enthusiastic is doing better. I don’t think he should have promoted the mind-bending array of therapeutics he pumped into his body once diagnosed with Covid-19; to say that combining monoclonal antibodies, prednisone, azithromycin, IV vitamin B3, and ivermectin in a “kitchen sink” approach, was not evidence-based is a great understatement. He also burned through the better part of $20,000 worth of therapeutics, two of them involving IV infusions, and ended up with a case of Covid-19 that sounded more severe than the average breakthrough infection someone might have after a free vaccine. I hope he does not claim to his myriad followers that he got better because of this protocol. But taking some ivermectin? I won’t fault him for it. And I definitely wouldn’t fight him over it.