Ivermectin and COVID-19: What’s Going On?

[This document is a part of a series of discussion notes addressing fundamental questions about the COVID-19 crisis and response strategies. These documents are based on the best scientific information available and may be updated as new information comes to light.]

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Written by Carlos Chaccour, Assistant Research Professor and Chief Scientific Officer for the BOHEMIA project at ISGlobal and medical researcher at the Clínica Universidad de Navarra, this document offers an account about how ivermectin, in the response to the COVID-19 pandemic, has been in the spotlight as an example of the risks of rushed and scientifically unfounded debates. It extracts as well some lessons that could be useful in the future.

Ivermectin is an antiparasitic agent with a broad efficacy spectrum. It was originally developed by Merck, company that decided to donate it for the treatment and control of river blindness and lymphatic filariasis in an initiative known as the Mectizan Donation Program. This programme has distributed more than 4 billion treatments over the past 30 years. Ivermectin is also licensed for the treatment of strongyloidiasis and scabies in some countries.

Given its broad spectrum of activity, ivermectin has been extensively studied and, like many other drugs, has shown have partial efficacy against targets beyond its primary indication. The drug is known to inhibit the replication of several RNA viruses including dengue, for which there are some recent results available.

The Origin of the Problem: Two Opposing Reactions Based on Scant Data 

In April 2020, Caly et al. published results from in vitro experiments showing that ivermectin inhibits the replication of SARS-CoV-2 at relatively high concentrations. This caused two opposing reactions among the scientific community, health authorities and the general public, neither supported by much evidence:

• On the one hand, many scientists dismissed ivermectin altogether as a potential COVID-19 treatment.
• On the other hand, on the basis of the in vitro data and a preprint (non-peer reviewed paper) that was later retracted, as well as local experience with the drug, several countries in Latin America included ivermectin in their national guidelines for COVID-19 management.

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Ongoing and Completed Trials

Since 2020, at least 60 trials with Ivermectin for COVID-19 have been registered at ClinicalTrials.gov, 19 of which have been completed. These studies are heterogeneous and have resulted in a very heterogeneous matrix from which it is difficult to extract conclusions. Moreover, since only a small fraction of the registered studies have published results, the literature may be affected by a publication bias (a phenomenon in which only positive results are published while negative findings are not), as the apparently negative results of a recent large trial in Colombia suggest. 

Nonetheless, the results of several trials do point towards a potential effect but this needs to be confirmed before widespread clinical or public health use is considered. 

Contradictory messages and heated debates

Several groups have conducted reviews of the evidence from published and unpublished data. This has led to mixed messages and caused confusion in the general public, fuelling conspiracy theories and sometimes leading to contradictory recommendations and statements from national authorities and international groups.

Throughout this period, proponents and opponents have engaged in heated debates on social media and amplified the discussion many-fold, sometimes with vicious attacks and even threats directed at the people highlighting the need for proper evidence 

Latest Developments

Ever since the second wave of interest in ivermectin for the treatment of COVID-19 was sparked by the FLCCC in December 2020, several countries have included the drug in their national therapeutic guidelines. This is the real problem currently facing the international community: implementations in the field without clear guidelines on doses or regimens, solid evidence of efficacy or, even more worryingly, of safety for this particular indication. 

These recent approvals have triggered a second wave of statements from international organizations and even from Merck, the original manufacturer of ivermectin. The US National Institutes of Health has updated its statement on ivermectin use as follows: “there are insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19”. This is a balanced statement that appropriately reflects the current state of the evidence. 

Some of the expected consequences of this surge in demand without clear guidance on indication, dosage or regimens are beginning to appear. Most worrying is the circulation of low-quality formulations in South Africa that include undeclared and potentially dangerous substances, such as benzodiazepines, antiplatelet agents and even anticonvulsants. The same report also warns of profiteering, with some formulations sold at ZAR 1000 (US$ 68), way above the usual price. Experience with antimalarials teaches us that when anti-infective drugs become very profitable, counterfeit formulations do not take long to enter the market. In the case of ivermectin, the question is whether or not counterfeits are already in circulation. 

Lessons for the Debate on COVID-19

There is evidence to suggest a potential role for ivermectin in the management of COVID-19, but there is no definitive data on the safety or efficacy of the drug in this indication or on the doses/regimen required. Scientific rigour and an open mind are both essential for the rational evaluation of the available, emerging and future data. Ivermectin is a live-saving medication for millions of people affected by neglected tropical diseases worldwide every year. While its potential as treatment for COVID-19 is of great interest, unexpected negative consequences can occur with misguided approvals, recommendations or roll-out.

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