INTRODUCTION

To date, very few treatments have been demonstrated to reduce the burden of morbidity and mortality from COVID-19. Although corticosteroids have been proven to reduce mortality in severe disease,¹ there has been little convincing evidence on interventions that may prevent disease, reduce hospitalizations, and reduce the numbers of people progressing to critical disease and death.

Ivermectin is a well-known medicine that is approved as an antiparasitic by the World Health Organization and the US Food and Drug Administration. It is widely used in low- and middle-income countries (LMICs) to treat worm infections.^2,3 Also used for the treatment of scabies and lice, it is one of the World Health Organization’s Essential Medicines.⁴ With total doses of ivermectin distributed apparently equaling one-third of the present world population,⁵ ivermectin at the usual doses (0.2–0.4 mg/kg) is considered extremely safe for use in humans.^6,7 In addition to its antiparasitic activity, it has been noted to have antiviral and anti-inflammatory properties, leading to an increasing list of therapeutic indications.⁸

Since the start of the SARS-CoV-2 pandemic, both observational and randomized studies have evaluated ivermectin as a treatment for, and as prophylaxis against, COVID-19 infection. A review by the Front Line COVID-19 Critical Care Alliance summarized findings from 27 studies on the effects of ivermectin for the prevention and treatment of COVID-19 infection, concluding that ivermectin “demonstrates a strong signal of therapeutic efficacy” against COVID-19.⁹ Another recent review found that ivermectin reduced deaths by 75%.¹⁰ Despite these findings, the National Institutes of Health in the United States recently stated that “there are insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19,”¹¹ and the World Health Organization recommends against its use outside of clinical trials.¹²

Ivermectin has exhibited antiviral activity against a wide range of RNA and some DNA viruses, for example, Zika, dengue, yellow fever, and others.¹³ Caly et al¹⁴ demonstrated specific action against SARS-CoV-2 in vitro with a suggested host-directed mechanism of action being the blocking of the nuclear import of viral proteins^14,15 that suppress normal immune responses. However, the necessary cell culture EC₅₀ may not be achievable in vivo.¹⁶ Other conjectured mechanisms include inhibition of SARS-CoV-2 3CLPro activity^17,18 (a protease essential for viral replication), a variety of anti-inflammatory effects,¹⁹ and competitive binding of ivermectin with the viral S protein as shown in multiple in silico studies.²⁰ The latter would inhibit viral binding to ACE-2 receptors suppressing infection. Hemagglutination via viral binding to sialic acid receptors on erythrocytes is a recently proposed pathologic mechanism²¹ that would be similarly disrupted. Both host-directed and virus-directed mechanisms have thus been proposed, the clinical mechanism may be multimodal, possibly dependent on disease stage, and a comprehensive review of mechanisms of action is warranted.

Developing new medications can take years; therefore, identifying existing drugs that can be repurposed against COVID-19 that already have an established safety profile through decades of use could play a critical role in suppressing or even ending the SARS-CoV-2 pandemic. Using repurposed medications may be especially important because it could take months, possibly years, for much of the world’s population to get vaccinated, particularly among LMIC populations.

Currently, ivermectin is commercially available and affordable in many countries globally.⁶ A 2018 application for ivermectin use for scabies gives a direct cost of $2.90 for 100 12-mg tablets.²² A recent estimate from Bangladesh²³ reports a cost of US$0.60—US$1.80 for a 5-day course of ivermectin. For these reasons, the exploration of ivermectin’s potential effectiveness against SARS-CoV-2 may be of particular importance for settings with limited resources.²⁴ If demonstrated to be effective as a treatment for COVID-19, the cost-effectiveness of ivermectin should be considered against existing treatments and prophylaxes.

The aim of this review was to assess the efficacy of ivermectin treatment among people with COVID-19 infection and as a prophylaxis among people at higher risk of COVID-19 infection. In addition, we aimed to prepare a brief economic commentary (BEC) of ivermectin as treatment and as prophylaxis for COVID-19.²⁵

METHODS

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