Monday Article #18: Ivermectin in the treatment of Covid

Joyce Ong

Ivermectin is a semi-synthetic antiparasitic drug. It belongs to a series of highly-active broad-spectrum antiparasitic agents known as the avermectins. The avermectins are a group of 16- membered macrocyclic lactone derivatives with potent insecticidal properties. These naturally occurring compounds are generated as fermentation products by Streptomyces avermitilis, a soil actinomycete. Ivermectin itself is a mixture of two avermectins, comprising roughly 90% 5-O-demethyl-22,23-dihydroavermectin A1a (22,23-dihydroavermectin B1a) and 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a (22,23-dihydroavermectin B1b).

Ivermectin is mainly used in humans in the treatment of onchocerciasis, but may also be effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis and enterobiasis). Applied topically, it may be used in the treatment of head lice infestation.

Mechanism of action

Ivermectin binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells. This binding causes an increase in the permeability of the cell membrane to chloride ions and results in hyperpolarization of the cell, leading to paralysis and death of the invertebrate parasite. Ivermectin is safe for mammals (at normal therapeutic doses) because mammalian glutamate-gated chloride channels only occur in the brain and spinal cord: the causative avermectins usually do not cross the blood–brain barrier, and are unlikely to bind to other mammalian ligand-gated channels.

Claims and concerns of Ivermectin as a treatment for Covid-19

Throughout the pandemic, ivermectin has attracted much attention, particularly in Latin America, as a potential way to treat COVID-19. Although the World Health Organization advises against taking ivermectin as a COVID-19 treatment outside clinical trials, some view it as a stopgap until vaccines become available in their areas, even though it has not yet been proven effective. This is commonly due to misinformation being widely spread around claiming its benefits without being backed by scientific evidence.

Early on, scientists showed that ivermectin could inhibit the coronavirus SARS-CoV-2 in cells in laboratory studies. Following this, about 86 clinical trials investigating ivermectin for COVID-19 have been registered globally. From late 2020 onwards, multiple groups produced meta-analyses that reported that ivermectin had a significant effect on survival, hospitalizations, clinical recovery, and viral clearance[1] . Our meta-analysis was first presented in January 2021 and published in July 2021. It suggested that ivermectin resulted in a significant 56% improvement in survival, favourable clinical recovery, and reduced hospitalizations. These optimistic results from multiple analyses have escalated public interest in using ivermectin for the treatment and prevention of COVID-19, despite the World Health Organization (WHO) only recommending its use within clinical trials[2].

However, some studies were identified to be potentially fraudulent. For example, on July 15, 2021, a study by Elgazzar et al. from Egypt was retracted from the preprint server Research Square due to “ethical concerns”[3]. It has been reported that the data for approximately 79 participants were duplicates, some deaths were recorded on dates before the trial had started, and cases of plagiarism were identified in the text. Similarly, a study conducted in Lebanon by Raad et al. was also identified to have duplicate data for multiple participants when the patient-level database was analysed in September 2021. Before these inconsistencies were identified, the Elgazzar and Raad studies had been included in multiple meta-analyses, which suggested significant benefits for ivermectin in the treatment of COVID-19. These instances suggest that the data available to the support the use of ivermectin for COVID-19 are not reliable.

It is also important to note that the FDA has not authorized or approved ivermectin for use in preventing or treating COVID-19 in humans or animals.

Conclusion

According to the FDA, clinical trials assessing ivermectin tablets for the prevention or treatment of COVID-19 in people are still ongoing. Until high-quality, peer-reviewed data regarding both the safety and efficacy of ivermectin for COVID-19 in humans becomes available, the use of ivermectin for these purposes should be avoided in favour of therapies that have been scientifically proven to be effective.

References

[1] Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther. In press.

[2] https://www.who.int/publications/i/item/ WHO-2019-nCoV-therapeutics-2021.2.

[3] Elgazzar A. Notice of retraction: Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. https://assets.researchsquare.com/files/rs-100956/ v2/c11416a2-d0bd494f-abc8-3cbf8c605b10. pdf?c=1631861037.