Safety of Ivermectin used as a treatment for COVID-19 at different dose regimens: A systematic review

Abstract

Abstract Background: With the rapid spread and high mortality rate of the SARS-CoV-2 virus worldwide, there has been a continuous effort to find effective treatments to help those infected. As some of the available treatment options proved ineffective in fighting the disease, the scientific community began studying the possibility of using drugs already approved for other illnesses as potential treatments for COVID-19. This practice is called drug repurposing. A strong candidate for repurposing was ivermectin. However, research has shown varying results regarding its efficacy against COVID-19. This conflicting evidence could be explained by the doses used. The approved standard dose isn’t sufficient to reach the effective concentration needed to inhibit virus replication. Research should therefor study its effects at higher doses. Although there is some evidence supporting the safety of using doses greater than those already approved, no comprehensive review has been conducted on the subject. Aims/Objectives: This systematic review aims to analyse all current data on the safety of ivermectin used at higher than approved doses, and determine if there is an increased risk of adverse events or death when using different dose regimens. Methods: A systematic search that included Pubmed, EMBASE, WHO’s International Clinical Trials Registry platform, ClinicalTrials.gov, MedRxiv, and ResearchSquare was performed. Data on adverse events and deaths reported in randomized clinical trials comparing the use of ivermectin in different dose regimens against control groups was collected. These data were analysed by calculating the risk ratios and the risk differences in presenting adverse events or death among the different dose regimens and the control groups. A random effects model was used to pool the effects from the included reviewed studies. Results: The literature review retrieved 760 potential articles among all platforms queried, from these, only 22 were included in the meta-analysis. There was no significant risk difference (RD = 0, 95% CI -0.02 – 0.02) in the probability of presenting any adverse event among the ivermectin groups and the control groups, regardless of the concentration of the doses studied or the frequency of ivermectin taken. The risk of death decreased by 1% (95% CI 0% – 2%) in the ivermectin groups, with the single high-dose studies showing the most significant decrease in risk of death by 10% (95% CI 5% - 16%). Conclusions: Multiple high doses regimens of ivermectin showed no significant difference in risk of presenting adverse events compared to that of the control groups. Finding no difference in risk for adverse effects supports the idea that ivermectin is safe to use at higher than approved dose regimens. In addition, the risk of death appears to decrease in all ivermectin groups compared to the control groups. This decrease in risk of death supports the need for further studies evaluating the beneficial effects of ivermectin on COVID-19 infected patients.