Ivermectin, the science versus the fiction.

 Lately there have been a slew of reports of patients requesting ivermectin, of poison control centers getting calls about ingestion of toxic doses of the medication and advocacy either for its widespread use or for its avoidance¹. The NIH is taking a neutral stance², and depending on which studies one chooses to quote, a case can be made for or against the use of the medication as part of the pharmacopeia for the treatment of Covid-19^3,4. The bewildering part of this controversy is that absent zealots with agency, eminent scientists can be found on either side of the issue.

There are aspects over which clinicians will not disagree. The proverbial “horse pill” that patients dread is very real in this case when people choose to ingest livestock-grade of the medication that can contain several-fold the recommended human dose. It is even more concerning because ivermectin is given as a specific weight-based dose for each condition, i.e. no two conditions use same dose, and usually as a one time⁵. This can help explain the surge of calls to poison control centers when laymen (or laywomen) self-medicate with livestock-grade doses. This simple truism seems to be lost and folks, eager to find the magic bullet, throw away caution and end up harming themselves unnecessarily and along the way the drug becomes associated with nefarious side effects and it gets a black eye. An objective evaluation of this issue will assume that success or failure of any intervention will be based on the use of human-grade dose and whenever possible comparing identical doses to evaluate outcome fairly.

That ivermectin would be at the center of such polarization runs counter to the halo of good will it has accumulated since its discovery. It has helped eliminate onchocerciasis, aka river blindness, is very effective against filariasis (Loa loa), scabies, ascaris, Cutaneous Larva Migrans, Strongyloides, head lice, rosacea⁵. Such vaunted success has rewarded its discoverers, the Japanese Satoshi Omura of Kitasato University and William Campbell of Merck pharmaceutical the Nobel Prize of Medicine and Physiology in 2015 for their majestic work dating back to 1975⁶. The discovery of the drug has become part of medical lore. It is well chronicled at the American Chemical Society website, acs.org. Let’s also remember that Merck in 1987 donated the drug gratis for the treatment of river blindness. Ivermectin has earned the rarefied status of “wonder drug” and is placed by the WHO among the “List of Essential Medications.”⁷ Ivermectin has also found a niche among animals and is used widely for deworming. All of this is the easy part.

The FDA, CDC, WHO have recently taken the stance against the use of Ivermectin for the treatment of Covid-19 unless as part of a clinical trial^8,9,10. That in of itself ought to have made this an open and shut case. However, reality is a bit complicated. WHO has also “issued a  recommendation against the use of remdesevir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesevir improves survival and other outcomes in these patients.” in its Newsletter on November 20, 2020¹⁰. However, this expensive medication   is widely used in the USA. A colleague who is an ID expert sheepishly confessed to me that “he would be hard pressed to come up with the convincing data to support its continued use.” Why it is still so popular  is a cautionary tale of the nexus of vested interests, fear of legal consequences of not heeding demands of patients requesting access to a drug approved by the FDA and the hope that however marginal the benefit may be that one ought to try it.

So, what is behind the effort to use Ivermectin in the case of Covid-19? Peer-reviewed published data show that in vitro, it inhibits the spike protein of the virus, this mechanism by the way is the linchpin of the success of the mRNA Covid-19 vaccine. It also inhibits viral replication by binding to the Covid-19 RNA-dependent RNA polymerase¹¹. A confluence of powerful forces has created a coercive atmosphere for nations under assault by the pandemic. The lack of any outstanding treatment, the above scientific features of ivermectin, its low-cost and the sociopolitical pressure of the significant mortality rate associated with the pandemic, have created  an impetus for the search  and use of alternative treatment of the condition. So far, so good.

The dilemma comes when two metanalyses come up with opposite conclusions. For example, Marik of the eponymous Covid-19 protocol fame, from Eastern Virginia Medical School¹², penned a review article that cites several successful interventions in the third world, including the Dominican Republic, Brazil, South Asia. Its conclusion, “as of December 14, 2020, there is accumulating evidence that demonstrates both the safety and efficacy of ivermectin in the prevention and treatment of Covid-19. Large-scale epidemiologic analyses validate the findings of in vitro, animal, prophylaxis and clinical studies. Epidemiologic data from regions of the world with widespread ivermectin use have demonstrated a temporally associated reduction in case counts, hospitalizations and fatality rates.”¹³

At the same time, Maria Popp from Germany looked at 14 published studies through the Cochrane Covid-19 Study Register up to May 26, 2021¹⁴. The conclusion was the following: “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.”¹⁴

What can one say about this as an objective clinician? The in vitro data are intriguing and there may be something in this product. The question becomes: does it work in vivo? Again, the data from the third world prompt reason for cautious optimism. Lest we jump ahead of ourselves, we need to remember the kerfuffle over the hydroxycholoroquine debacle after its widespread embrace based on a dearth of data. If indeed ivermectin does have therapeutic advantages, this should be proven in large-scale trials and society will benefit from it because it’s inexpensive, time-tested and has shown its mettle over the years.

References:

1. fda.gov Covid-19 Update, August 31, 2021.
2. Covid19treatmentguidelines.nih.gov
3. Hellwig, M. A Covid-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin. Int. J Antimicrob Agents, 2021 Jan: 57(1):106248
4. Camprubi, D et al. Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients. PLos One. 2020; 15(11): e0242184.
5. drugs.com
6. nobelprize.org
7. who.int/medicines/publications/essentialmedicines/en
8. fda.org
9. cdc.org
10. who.int
11. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. Vivo. 2020;34:3023–3026.
12. evms.edu
13. Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021 Apr 22;28(3):e299-e318
14. Z. Popp, M et al. Ivermectin for preventing and treating COVID-19. Cochrane Database of Systematic Reviews 2021, Issue 7. Art. No.: CD015017.

Reynald Altéma, MD.

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