key: cord-0882123-7th3d6wk
authors: Hellwig, Martin D.; Maia, Anabela
title: A COVID-19 Prophylaxis? Lower incidence associated with prophylactic administration of Ivermectin
date: 2020-11-28
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106248
sha: b2188d858b1d90239f3ce9932df4bbfdb7b6e20b
doc_id: 882123
cord_uid: 7th3d6wk

As COVID-19 continues to rapidly spread throughout the world, incidence varies greatly among different countries. These differences raise the question whether nations with lower incidence share any medical commonalities that could be used to not only explain that lower incidence, but that could also provide guidance for potential treatments elsewhere. Such treatment would be particularly valuable if it could be used as a prophylactic against COVID-19 transmission, thereby effectively slowing spread of the disease while we await the wide availability of safe and effective vaccines. Here, we show that countries with routine mass drug administration of prophylactic chemotherapy including Ivermectin have significantly lower incidences of COVID-19. Prophylactic use of Ivermectin against parasitic infections is most common in Africa and we hence show that the reported correlation is highly significant both when compared among African nations as well as in a worldwide context. We surmise that this may be connected to Ivermectin's ability to inhibit SARS-CoV-2 replication which likely leads to lower infection rates. However, other pathways must exist to explain persistence of such inhibitory effect after serum levels of Ivermectin have declined. It is suggested that Ivermectin be evaluated for potential off-label prophylactic use in certain cases to help bridge the time until a safe and effective vaccine becomes available.

The disease COVID-19 is caused by SARS-Cov-2, a novel coronavirus that emerged in Wuhan, Hubei Province, China in December 2019 [1] and quickly spread throughout the entire world. [2] As of October 20 th 2020, approximately 41 million people were diagnosed and more than one million had died from the disease worldwide. [3] Many nations have responded by implementing strict social distancing guidelines [4] that begin to show promising results in some countries. [5] While this is in itself a positive development, a decrease in new cases is also likely to decrease adherence to protective measures or to cause authorities to lift restrictions aimed at containing the virus' spread as they consider competing economic interests. This, paired with the continued resistance to initial control measures in some nations such as the United States, [4] carries the risk of further accelerating global disease spread and, consequently, fatalities. On April 18 th , 2020, 11,265 patients died from COVID-19 in a single day worldwide. [3] While several vaccine candidates are entering clinical trial phases, it is unlikely that a safe and effective vaccine will be available to the public within the next few months. [6] In order to effectively reduce the spread of SARS-CoV-2 and especially the associated fatalities, a highly effective treatment option is needed.

As time if of the essence and the approval process for new drugs can be lengthy, [7] there have been many attempts at repurposing existing and approved drugs for treatment of SARS-CoV-2 infections. [8] This has included malaria drugs such as Hydroxychloroquine and Chloroquine, which have recently been shown to be less effective than originally thought while carrying considerable risk of sometimes fatal complications and interactions. [9] Other approaches focus on repurposing existing antiviral drugs such as Remdesivir which has been shown to significantly reduce recovery time in hospitalized patients. [10] However, there is currently no accepted treatment for patients that are not yet hospitalized. Treating patients before they need to be admitted -perhaps even prophylactically -could greatly reduce the load on hospitals, protect healthcare professionals and reduce the spread of SARS-Cov-2.

One avenue to slow viral transmission would be to inhibit the virus' replication, reducing viral load in infected individuals. Interestingly, the relatively old anti-parasitic drug Ivermectin has recently been reported to inhibit SARS-CoV-2 replication in vitro, [11] although the authors rightfully caution that additional studies will need to determine dosing for potential use in COVID 19 patients. This is particularly important as the serum levels used in their study far exceed those that would be achieved with commonly administered safe doses. While they certainly don't suggest prophylactic use of Ivermectin for SARS-CoV-2, the drug is actually widely used prophylactically in mass drug administration (MDA) campaigns against both filiariasis [12] and onchocerciasis. [13] Throughout the past few months, interest in Ivermectin as a treatment for infected patients has grown [14] and the drug has been shown to reduce mortality among hospitalized patients [15] . In contrast to most other recently explored treatments, Ivermectin has been reported as especially promising in early and mild cases of COVID 19 [16] . This strong precedent paired with Ivermectin's well understood safety profile [17] naturally raises the question whether it could also be used prophylactically against SARS-CoV-2.

In order to answer this intriguing question, we collected data from countries that routinely deploy prophylactic chemotherapy (PCT) using various drugs including Ivermectin. [18] Based on the varying MDA designs, we grouped these countries into two different categoriesthose that include Ivermectin in their PCT and those that do not. We then proceeded to compare COVID-19 proliferation between these two groups and further contrasted them against a third group of countries that do not use PCT at all. [3] 

The data used in this study was obtained from two publicly available databases. Information about PCT was extracted from the PCT databank administered by the World Health Organization (WHO) which provides current and historic data about MDA campaigns. [18] Current data on COVID-19 cases was obtained from Worldometers, a public data aggregation site usedamong others -by the COVID 19 portal published by Johns Hopkins University. [3] All data is current as of October 20 th , 2020. As in all cases involving more than one data source, there was a certain amount of missing data which we addressed by omitting any country that did not have sufficient coverage in both sources. We then extracted and aggregated the data in a standard spreadsheet format that we provide in the supplementary material.

Our statistical analysis was performed using IBM's SPSS (Version 23). We grouped countries into three different bins -countries that do not use any PCT, countries that use some PCT that does not include Ivermectin and countries that use PCT with Ivermectin. As a dependent variable we selected the incidence of COVID-19 measured in confirmed cases per 100,000 citizens.

Standard ANOVA was not an option for data analysis since the data was not normally distributed as determined by the Shapiro-Wilk test. This is primarily due to large variability within the "No PCT" group as well as the starkly different sizes of the three groups. We therefore analyzed the assembled data using a one-way non parametric Kruskal-Wallis ANOVA on ranks with incidence as the dependent variable and the three treatments as factor (PCT With Ivermectin, PCT Without Ivermectin, No PCT). Post Hoc comparisons were run using a Dunn Test. Significances were adjusted using the Bonferroni method.

Our study compared incidence among countries with different prophylactic chemotherapy campaigns and those countries in which PCT is nonexistent. It is perhaps obvious that the latter group is by far the largest. It should also not be surprising that this set of samples had a rather large variability ( Figure 1 ). However, in spite of this, the difference between nations that deploy PCT using Ivermectin and those that do not use any PCT turned out to be highly significant (Adjusted significance <0.01). These initial results were obtained on April 15 th 2020 and because at that time SARS-CoV-2 was still being detected in new countries on an almost daily basis, we chose to monitor the situation and observe whether this correlation would over time become less significant. We updated our calculations and added additional newly affected countries several times throughout the month of May and noticed that the observed association between Ivermectin MDA and lower COVID-19 incidence actually grew strictly stronger over time. By June 5 th , the adjusted significance had improved to p<0.001, actually reported by SPSS as 0.000. It has remained at that level since. As we have stated, the size of the three samples (PCT with Ivermectin, Other PCT and No PCT) vary greatly. Another important aspect to consider is the fact that much of the Ivermectin campaigns are naturally administered in African countries as the underlying parasitic infections are particularly common in these nations. As such it is important to look at the subset of African countries separately as well. Figure 2 shows a boxplot similar to Figure 1 , but containing only the African countries in our dataset. It should not be surprising that the largest difference between the two analyses can be seen in the "No PCT" group as this group contained the most non-African countries. The much smaller number of nations on the African continent and associated island groups allows us to enumerate the individual countries and to visualize them in a violin plot. Figure 3 quite clearly visualizes the strong correlation between PCT with Ivermectin and lower incidence of COVID 19. This relationship is statistically significant with p=0.017, making it only slightly less significant in Africa than among the worldwide dataset. It might be interesting to note that the percentage of the overall population that received PCT using Ivermectin mostly ranged from 30% to 90%, yet there was no significant difference in the resulting incidence of COVID-19. Even the lower treatment coverages achieved the same reductions resulting from MDA reaching nearly the entire population. The reasons for this fact are so far unexplained. There was also no detectable advantage to any one administration timeframe or interval. While individual dosages generally varied between 150 micrograms and 200 micrograms per kg of body weight, there seemed to be no notable difference in COVID-19 incidence among recipients of different dosages either. It must therefore be assumed that any pathway connecting Ivermectin administration and lower COVID-19 incidence is achieved by administration of the drug in relatively low doses far below potentially dangerous levels considered elsewhere as potentially effective for COVID 19 treatment [19] . This becomes less surprising once we consider Ivermectin's relatively short half life [20] , meaning that the added effect of any higher dose would not be prolonged. Instead, we hypothesize that there is an as of yet unknown pathway that can be triggered with lower, proven safe doses.

The fact that PCT without Ivermectin also show a strong negativealbeit not statistically significant -correlation with COVID-19 incidence suggests that other drugs used in MDA campaigns might include additional candidates for the treatment and/or prevention of COVID-19. It is, however, important to note that many of the analyzed countries that only administered these other drugs in 2018 actually have used Ivermectin in previous or following years. Hence a residual effect of an Ivermectin induced pathway cannot be ruled out although the exact nature of such a pathway would still need to be discovered. This speculation would gain further strength if experimental analysis could prove that SARS-CoV-2 replication remains inhibited after serum levels of Ivermectin decline.

It is important to note that the hypothesis that Ivermectin might have a prophylactic effect against SARS-CoV-2 is merely based on a rather strong correlation. On the other hand, this correlation has grown increasingly stronger in the worldwide dataset earlier this year and then be independently replicated within the African dataset later in the summer. Both remain highly significant suggesting that there may be a causal connection which is also suggested by other recent findings reported in literature. We therefore hope that this communication may serve as an invitation to further investigate and consider Ivermectin as a potential prophylactic against COVID-19. In addition to the obvious advantages of a potential prophylactic, more refined results could hopefully also deter the public from further dangerous self-medication with Ivermectin that has sometimes included veterinary grade products that contain additional ingredients [21] . In this sense even negative results might be very valuable to the health community and to society at large.

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