Ivermectin: The Elephant in the Room

There are a great many unknowns and controversies associated with the COVID pandemic.  Among the most urgent are those associated with appropriate therapeutic and prophylactic interventions.  Some of the most intense disputes involve repurposed therapies — i.e., drugs that have been approved for the treatment of some other condition being used as therapy for COVID.  This is the case with the anti-parasitic agent ivermectin.

Much of the controversy regarding ivermectin involves "evidence" that the drug has a benefit in the treatment of COVID.  Detractors will often use the hyperbolic claim that there is no evidence that ivermectin is useful in this setting.  The truth is that there is, in fact, some evidence.  Ivermectin has been known since at least 2012 to have antiviral activity.  It has been shown to have at least some antiviral activity against a number of viruses, including HIV-1, Zika, flaviviruses, and dengue.  It is known to have in vitro activity against SARS CoV-2, the coronavirus that causes COVID.  It has been shown to have some efficacy in Middle East Respiratory Syndrome, a disease caused by a coronavirus with similarities to SARS CoV-2.  There are plausible mechanisms proposed for why ivermectin might be useful against viral infections: it inhibits a class of proteins that are necessary for the virus to replicate within human cells.

These observations are evidence.  They are not definitive evidence.  They are probably not sufficient, or even persuasive evidence, but these assessments should not be confused with "no evidence."

Ideally, the efficacy of a pharmacologic intervention would be established by a valid, reproducible clinical trial.  This would typically be a large, randomized trial, in which the population receiving the treatment is similar to that which is not.  The trial would be double-blind and placebo-controlled, which means that neither the patients nor the physicians caring for them would be aware if the patients would be receiving the drug under study or an inert placebo, which would be expected to have no biological effect.  A large randomized, double-blind placebo-controlled trial would go a long way to resolving the controversies regarding ivermectin in the treatment of COVID-19.  The unspoken issue, the elephant in the room, is why there are no such trials.

Large drug trials are usually conducted by large pharmaceutical companies, which have the resources and expertise to conduct them.  Merck was the original patent-holder for ivermectin.  One of the discoverers of ivermectin, Satoshi Omura, who was awarded a Nobel Prize for his accomplishment, reportedly approached Merck about conducting a large, rigorous trial of ivermectin in the treatment of COVID in Japan.  Merck declined.  Governments are spending billions on COVID-related interventions, yet they show no interest in even a preliminary study of ivermectin.

An obvious lay question, requiring no expertise in pharmacology, virology, epidemiology, or any other scientific discipline, is why the apparent lack of interest in investigating ivermectin?

There are several possible answers.  The first is that what is known about the anti-viral activity of ivermectin makes it highly unlikely that further investigation will be productive.  This is a possibility, but it is curiously absent from any discussion of the topic.  Merck, in a press release dated February 4, 2021, stated that there is "no scientific basis for a potential therapeutic effect against COVID -19."  This is incorrect, as ivermectin has been shown to have in vitro activity against the virus.  Furthermore, Merck claims "there is no meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19."  This is probably true, but it simply calls attention to the elephant in the room.

The absence of evidence is not evidence of absence.  Merck appears to be concerned not so much with lack of evidence as with lack of data, and it is totally within its, or any number of large institution's, capacity to resolve this lack of data.  The company just appears to have little interest in doing so.

A cynical view is that Merck is interested in promoting its novel agent molnupiravir, a drug that it would sell to the United States government for $700 dollars per course of treatment, as compared to less than $3 a course for ivermectin.  Thus, Merck has an incentive to not only decline to investigate any antiviral role for ivermectin, but actively disparage it as well.  This is not to say this is what large pharmaceutical companies are in fact doing; it is merely to point out that this is where the incentives lie.  Merck and other large pharmaceutical companies may be completely altruistic, their assessments of ivermectin sound and reasonable, but this does not allay suspicions as to why there are no rigorous studies of ivermectin in treating COVID.

A second view is that there are political and sociological reasons to downplay potentially cheap and available COVID therapies.  A reasonable concern is that the availability of such therapies would mitigate against efforts at vaccination, or other public health interventions.  Furthermore, a great deal of political power has been accumulated in "emergency measures" prompted by the pandemic.  As with any wide-ranging policy issue, professional politicians are likely to assess the political implications of novel COVID therapies before committing to one course or another.  At a minimum, they would possibly want to be in a position to take credit for any resulting benefits.  This observation is not intended as proof of the fact of such political machinations; it is merely the recognition of the possibility of them.  Again, however, political and sociological concerns do not provide valid explanations for the absence of valid clinical studies of ivermectin, if the actual goal is to mitigate the effects of the pandemic.

Another consideration is that conducting a valid, large trial of ivermectin in the treatment of COVID will be expensive and complex.  This is a valid concern, and the underlying reason for this is significant.  A very large number of patients would be necessary for such a trial precisely because the risk of mortality from COVID is very small, and also because COVID has widely varying effects on different populations.  If 30% of the people who contracted SARS-CoV-2 infection died of COVID, it would take far fewer patients in a trial to demonstrate a 50% decline in mortality from a particular intervention than would be the case where the mortality is less than 1%.  Likewise, a large patient population would be required to provide sufficient homogeneity between the study populations, given the number of factors that may affect the effectiveness of the intervention: obesity, age, diabetes, heart disease, rheumatologic conditions, etc.  This consideration is valid and would help explain why there are not such large trials.  It does not, however, explain why there are no studies of ivermectin in more narrowly defined populations, such as those over 70, nursing home residents, diabetics, etc.  Such studies would, at least, provide data that would tend to support or refute the hypothesis that ivermectin has a role in treating COVID.

The response to the COVID pandemic has produced a number of distressing and questionable policies: mandates, lockdowns, threatening people's jobs, and contributing to the psychological effects of uncertainty and increasing authoritarianism.  The response to COVID has been associated with its own detriments, even if one wishes to assume that these were unavoidable or, on balance, necessary.  Given these costs, however, the dismissal of potential therapies on grounds of "no evidence," coupled with a refusal to investigate such evidence, suggests that the priorities in COVID policy do not begin with public health.

Image: hansgklein via Pixabay, Pixabay License.

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