Many of this column’s readers have likely heard of the stories using ivermectin to treat or prevent COVID-19 in humans. Last August, in a Health Alert from the U.S. Centers for Disease Control and Prevention, poison control centers across the US were seeing a sharp spike in reports of people suffering adverse health effects after taking animal ivermectin. People were purchasing various highly concentrated animal ivermectin drug formulations such as pour-on, injectable, paste, and drench intended for horses, cattle, and sheep, and taking these drugs made some people very sick. The US Food and Drug Administration asked veterinarians to help share important safety information about the misuse of animal ivermectin to prevent or treat COVID-19 in people.1
To assist, the FDA developed a sign available for download to either pass out or post in veterinary practices reminding people about the dangers of treating themselves with animal ivermectin.2 Human consumption was so widespread that the Center for Veterinary Medicine of the FDA was hearing reports of decreased availability of certain animal ivermectin products in some areas of the country.
Why was ivermectin touted as an anti-COVID-19 treatment? Surprisingly it was not misinformation, for there was a brief period when it was thought ivermectin could be an active treatment for COVID-19. It was not when the in vitro data first came out. Therapeutic concentrations were not achievable in humans. Nor when the anecdotal reports poured in and sometimes made the news. Not when the results appeared evaluating ivermectin use and lower death rates from COVID-19 in some countries, mainly from tropical regions in South America and Asia. And not when non-medically trained people pushed ivermectin with enthusiasm religious in its intensity. Their treatment “protocols,” with a hodgepodge of antimicrobials (including ivermectin), immunomodulators, and vitamins — the kitchen sink approach — strained credibility.
Infectious disease physicians’ greatest hope for ivermectin came just over a year ago, when Dr. Andrew Hill, a well-respected clinical researcher in HIV research at the University of Liverpool, UK, presented results from a meta-analysis of twenty-three randomized controlled trials.3 He would later also give this presentation to the NIH Guidelines panel. He found the risk-ratio for death with ivermectin was 0.17 (95 per cent confidence interval 0.08, 0.35), an 83 per cent reduction in the risk of dying from COVID-19. Outcomes for other endpoints (viral clearance, clinical recovery, hospitalization) also favored treatment over controls.
In retrospect, Hill acknowledged that the data were incomplete but remained strongly suggestive of clinical benefit. Furthermore, he had been regularly communicating with researchers conducting the five largest studies. They reassured him repeatedly that the data were sound. On January 4, 2021, the New England Journal of Medicine came out with a blog entitled “Ivermectin for COVID-19 — Breakthrough Treatment or Hydroxychloroquine Redux?”4
The clinical trials data for ivermectin looked stronger than they ever did for hydroxychloroquine, but the evidence was not yet at the “practice changing” level. Results from at least 5 randomized clinical trials were expected soon that might further inform the decision. However, National Institutes of Health (NIH) treatment guidelines still recommended against using ivermectin to treat COVID-19. What happened next? Hill submitted the meta-analysis to the journal Open Forum Infectious Diseases in early 2021. At that point, there were still no readily available effective outpatient treatments for COVID-19. Something inexpensive, safe, and widely available would have been most welcome. After peer review and some revisions, Hill reduced the survival effect size for ivermectin to 56% (still highly significant) due to some additional studies, and his paper was accepted for publication.5 The editors simultaneously solicited a thoughtful editorial entitled “Ivermectin for the Treatment of COVID-19 Disease: Too Good to Pass Up or Too Good to Be True?”6 And unfortunately, the second part of the title turned out to be the case — too good to be true. Many meta-analysis studies were highly flawed, and one was outright fraudulent. The fake data problem became known shortly after the meta-analysis appeared in print. Hill promptly contacted the journal when the news broke. He immediately retracted the original paper and, even better, submitted a detailed analysis of what went wrong.7 It includes a revealing figure, which shows how the effect size of ivermectin on survival drops to meaningless by excluding the fraudulent and potentially flawed studies.
The revised results highlighted the need for rigorous quality assessments in COVID-19 drug trials, for authors to share patient-level data, and for efforts to avoid publication bias for registered studies. Since then, a review has been published based on these issues.8
1. Food and Drug Administration. CVM Letter to Veterinarians and Retailers: Help Stop Misuse of Animal Ivermectin to Prevent or Treat COVID-19 in Humans. 2021; content.govdelivery.com/accounts/USFDA/bulletins/2eef57b.
2. Food and Drug Administration. Veterinary Ivermectin Safety Alert. 2021; www.fda.gov/media/151853/download.
3. You Tube. Ivermectin meta-analysis by Andrew Hill. 2020; www.youtube.com/watch?v=yOAh7GtvcOs
4. Sax PE. Ivermectin for COVID-19 — Breakthrough Treatment or Hydroxychloroquine Redux? 2021; blogs.jwatch.org/hiv-id-observations/index.php/ivermectin-for-covid-19-breakthrough-treatment-or-hydroxychloroquine-redux/2021/01/04/.
5. Hill A, Garratt A, Levi J, et al. Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection. Open Forum Infect Dis 2021;8:ofab358. doi:10.1093/ofid/ofab358
6. Siedner MJ. Ivermectin for the Treatment of COVID-19 Disease: Too Good to Pass Up or Too Good to Be True? Open Forum Infect Dis 2021;8:ofab318. doi:10.1093/ofid/ofab318
7. Hill A, Mirchandani M, Pilkington V. Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud. Open Forum Infect Dis 2022;9:ofab645. doi:10.1093/ofid/ofab645
8. Smith EM. Reimagining the peer-review system for translational health science journals. Clin Transl Sci 2021;14:1210-1221. doi:10.1111/cts.13050