Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

American Journal of Therapeutics 28, e299–e318 (2021)

Pierre Kory, MD,1* Gianfranco Umberto Meduri, MD,2 Joseph Varon, MD,3 Jose Iglesias, DO,4 and Paul E. Marik, MD5

Background: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials.

Areas of Uncertainty: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent iver- mectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups includ- ing Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses.

Data Sources: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribu- tion campaigns.

Therapeutic Advances: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large “natural experiments” occurred in regions that initiated “iver- mectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.

Conclusions: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID- 19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly

1Front-Line Covid-19 Critical Care Alliance, Madison, WI; 2Memphis VA Medical Center—University of Tennessee Health Science Center, Pulmonary, Critical Care, and Research Services, Memphis, TN; 3University of Texas Health Science Center, Critical Care Service, Houston, TX; 4Department of Medicine, Hackensack School of Medicine, Seton Hall, NJ; and 5Eastern Virginia Medical School, Division of Pulmonary and Critical Care, Norfolk, VA.

G. U. Meduri’s contribution is the result of work supported with the resources and use of facilities at the Memphis VA Medical Center. The contents of this commentary do not represent the views of the US Department of Veterans Affairs or the US Government.
The authors have no conflicts of interest to declare.
P. Kory and G. U. Meduri have contributed equally to this work.

Study conception and design: P. Kory and G. . Meduri. Acquisition of data: Paul Marik and Jose Iglesias. Analysis and interpretation of data: Paul Marik, P. Kory, and Jose Iglesias. Drafting of manuscript: P. Kory. Critical revision: G. U. Meduri and Joseph Varon.
Off-Label Use: This manuscript includes discussion of off-label use in COVID-19 of the FDA-approved medication ivermectin.
*Address for correspondence: Pierre Kory, MD, MPA, Front-Line Covid-19 Critical Care, 2002 L St NW, Suite 500, Washington, D.C 20036. E-mail: pkory@flccc.net

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4. 0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

Keywords: ivermectin, COVID-19, infectious disease, pulmonary infection, respiratory failure

INTRODUCTION

In early 2020, on the onset of the spreading pandemic, many providers and institutions began to continuously review the rapidly emerging basic science, translational, and clinical data to identify potentially effective treatment options for COVID-19. Although there is now a small and increasing number of therapeutics showing some efficacy in important clinical outcomes, chief of which are cortico- steroids in moderate to severe illness, the world continues to suffer from a worsening crisis with the potential of again overwhelming hospitals and intensive care units (ICU). As of February 21, 2020, the number of deaths attributed to COVID-19 in the United States reached 510,248 with more than 9.3 million active cases, the highest number to date. In addition, multiple European countries have imposed new rounds of restrictions and lockdowns.

Further compounding these alarming developments was a wave of recently published results from therapeutic randomized controlled trials conducted on medicines believed effective for COVID-19 that found a lack of impact on mortality in hospitalized patients with the use of remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, and monoclonal antibody therapy.1–4 One year into the pandemic, the only therapy considered “proven” as a life-saving treatment in COVID- 19 is the use of corticosteroids in patients with moderate to severe illness.5,6 Similarly, most concerning is the fact that no agent has yet proven effective in outpatients to prevent disease progression to prevent hospitalization.

More recently, trial results of ivermectin, a widely used antiparasitic medicine with known antiviral and anti- inflammatory properties, have been showing benefits in multiple important clinical and virologic outcomes, includ- ing mortality. Although growing numbers of the studies supporting this conclusion have passed through peer review, approximately half of the remaining trials data are from manuscripts uploaded to medical preprint serv- ers, a now standard practice for both rapid dissemination and adoption of new therapeutics throughout the pan- demic. Following is a comprehensive review of the avail- able efficacy data as of December 12, 2020, taken from in vitro, animal, clinical, and real-world studies all show- ing the above impacts of ivermectin in COVID-19.

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History of ivermectin

In 1975, Professor Satoshi Omura at the Kitsato institute in Japan isolated an unusual Streptomyces bacterium from the soil near a golf course along the southeast coast of Honshu, Japan. Omura, along with William Campbell, found that the bacterial culture could cure mice infected with the roundworm Heligmosomoides pol- ygyrus. Campbell isolated the active compounds from the bacterial culture, naming them “avermectins” and the bacterium S. avermitilis for the compounds’ ability to clear mice of worms.7 Despite decades of searching around the world, the Japanese microorganism remains the only source of avermectin ever found. Ivermectin, a derivative of avermectin, then proved revolutionary. Originally introduced as a veterinary drug, it soon made historic impacts in human health, improving the nutrition, general health, and well-being of billions of people worldwide ever since it was first used to treat onchocerciasis (river blindness) in humans in 1988. It proved ideal in many ways, given that it was highly effective, broad-spectrum, safe, well tolerated, and could be easily administered.7 Although it was used to treat a variety of internal nematode infections, it was most known as the essential mainstay of 2 global disease elimination campaigns that has nearly elimi- nated the world of two of its most disfiguring and dev- astating diseases. The unprecedented partnership between Merck & Co. Inc, and the Kitasato Institute combined with the aid of international health care orga- nizations has been recognized by many experts as one of the greatest medical accomplishments of the 20th century. One example was the decision by Merck & Co to donate ivermectin doses to support the Mectizan Donation Program that then provided more than 570 million treatments in its first 20 years alone.8 Ivermec- tin’s impacts in controlling onchocerciasis and lym- phatic filariasis, diseases which blighted the lives of billions of the poor and disadvantaged throughout the tropics, is why its discoverers were awarded the Nobel Prize in Medicine in 2015 and the reason for its inclu- sion on the World Health Organization’s (WHO) “List of Essential Medicines.” Furthermore, it has also been used to successfully overcome several other human dis- eases and new uses for it are continually being found.7

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Preclinical studies of Ivermectin’s activity against SARS-CoV-2

Since 2012, a growing number of cellular studies have demonstrated that ivermectin has antiviral properties against an increasing number of RNA viruses, including influenza, Zika, HIV, Dengue, and most importantly, SARS-CoV-2.9–17 Insights into the mechanisms of action by which ivermectin both interferes with the entrance and replication of SARS-CoV-2 within human cells are mount- ing. Caly et al18 first reported that ivermectin significantly inhibits SARS-CoV-2 replication in a cell culture model, observing the near absence of all viral material 48 hours after exposure to ivermectin. However, some questioned whether this observation is generalizable clinically given the inability to achieve similar tissue concentrations used in their experimental model using standard or even mas- sive doses of ivermectin.19,20 It should be noted that the concentrations required for an effect in cell culture models bear little resemblance to human physiology given the absence of an active immune system working synergisti- cally with a therapeutic agent, such as ivermectin. Fur- thermore, prolonged durations of exposure to a drug likely would require a fraction of the dosing in short- term cell model exposure. Furthermore, multiple coexist- ing or alternate mechanisms of action likely explain the clinical effects observed, such as the competitive binding of ivermectin with the host receptor-binding region of SARS-CoV-2 spike protein, as proposed in 6 molecular modeling studies.21–26 In 4 of the studies, ivermectin was identified as having the highest or among the highest of binding affinities to spike protein S1 binding domains of SARS-CoV-2 among hundreds of molecules collectively examined, with ivermectin not being the particular focus of study in 4 of these studies.27 This is the same mecha- nism by which viral antibodies, in particular, those gen- erated by the Pfizer and Moderna vaccines contain the SARS-CoV-2 virus. The high binding activity of ivermec- tin to the SARS-CoV-2 spike protein could limit binding to either the ACE-2 receptor or sialic acid receptors, respectively, either preventing cellular entry of the virus or preventing hemagglutination, a recently proposed pathologic mechanism in COVID-19.21,22,26–28 Ivermectin has also been shown to bind to or interfere with multiple essential structural and nonstructural proteins required by the virus to replicate.26,29 Finally, ivermectin also binds to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication.30

Arevalo et al investigated in a murine model infected with a type 2 family RNA coronavirus similar to SARS- CoV-2, (mouse hepatitis virus), the response to 500 mg/kg of ivermectin versus placebo.31 The study included 40 in- fected mice, with 20 treated with ivermectin, 20 with phosphate-buffered saline, and then 16 uninfected control

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mice that were also given phosphate-buffered saline. At day 5, all the mice were killed to obtain tissues for exam- ination and viral load assessment. The 20 nonivermectin- treated infected mice all showed severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158), whereas in the ivermectin-treated mice a much lower viral load was measured (23,192; P , 0.05), with only few livers in the ivermectin-treated mice show- ing histopathological damage such that the differences between the livers from the uninfected control mice were not statistically significant.

Dias De Melo et al32 recently posted the results of a study they did with golden hamsters that were intrana- sally inoculated with SARS-CoV-2 virus, and at the time of the infection, the animals also received a single sub- cutaneous injection of ivermectin at a dose of 0.4 mg/kg on day 1. Control animals received only the physiologic solution. They found the following among the ivermectin-treated hamsters: a dramatic reduction in anosmia (33.3% vs. 83.3%, P 5 0.03), which was also sex dependent in that the male hamsters exhibited a reduction in clinical score while the treated female ham- sters failed to show any sign of anosmia. They also found significant reductions in cytokine concentrations in the nasal turbinates and lungs of the treated animals, despite the lack of apparent differences in viral titers.

Despite these mounting insights into the existing and potential mechanisms of action of ivermectin both as a prophylactic and treatment agent, it must be emphasized that significant research gaps remain and that many fur- ther in vitro and animal studies should be undertaken to better define not only these mechanisms but also to fur- ther support ivermectin’s role as a prophylactic agent, especially in the optimal dose and frequency required.

Preclinical studies of ivermectin’s anti-inflammatory properties

Given that little viral replication occurs in the later phases of COVID-19, nor can virus be cultured, and only in a minority of autopsies can viral cytopathic changes be found,33–35 the most likely pathophysio- logic mechanism is that identified by Li et al36 where they showed that the nonviable RNA fragments of SARS-CoV-2 lead to a high mortality and morbidity in COVID-19 through the provocation of an over- whelming and injurious inflammatory response. Based on these insights and the clinical benefits of ivermectin in the late phase of disease to be reviewed below, it seems that the increasingly well-described in vitro properties of ivermectin as an inhibitor of inflamma- tion are far more clinically potent than previously rec- ognized. The growing list of studies demonstrating the anti-inflammatory properties of ivermectin include its

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ability to inhibit cytokine production after lipopolysac- charide exposure, downregulate transcription of NF- kB, and limit the production of both nitric oxide and prostaglandin E2.37–39

Exposure prophylaxis studies of ivermectin’s ability to prevent transmission of COVID-19

Data are also now available showing large and statistically significant decreases in the transmission of COVID-19 among human subjects based on data from 3 randomized controlled trials (RCTs) and 5 observational controlled tri- als (OCTs) with 4 of the 8 (2 of them RCTs) published in peer-reviewed journals.40–46

Elgazzar and colleagues45 at Benha University in Egypt randomized 200 health care and household con- tacts of patients with COVID-19 where the interven- tion group consisted of 100 patients given a high dose of0.4mg/kgonday1andaseconddoseonday7in addition to wearing personal protective equipment, whereas the control group of 100 contacts wore per- sonal protective equipment alone. They reported a large and statistically significant reduction in contacts testing positive by Reverse Transcriptase Polymerase Chain Reaction (PCR) when treated with ivermectin versus controls, 2% versus 10%, P , 0.05.

Shouman conducted an RCT at Zagazig University in Egypt, including 340 (228 treated and 112 control) family members of patients positive for SARS-CoV-2 through PCR.44 Ivermectin (approximately 0.25 mg/kg) was administered twice, on the day of the positive test and 72 hours later. After a two-week follow-up, a large and statistically significant decrease in COVID-19 symptoms among household members treated with ivermectin was found, 7.4% versus 58.4%, P , 0.001.

Recently, Alam et al from Bangladesh performed a prospective observational study of 118 patients who were evenly split into those who volunteered for either the treatment or control arms, described as a persuasive approach. Although this method, along with the study being unblinded, likely led to confounders, the difference between the 2 groups was so large (6.7% vs. 73.3%, P ,0.001) and similar to the other prophylaxis trial results that confounders alone are unlikely to explain such a result.47 Carvallo et al also performed a prospective observational trial where they gave healthy volunteers ivermectin and carrageenan daily for 28 days and matched them to similarly healthy controls who did not take the medicines.40 Of the 229 study subjects, 131 were treated with 0.2 mg of ivermectin drops taken by mouth 5 times per day. After 28 days, none of those receiving ivermectin in the prophylaxis group had tested positive for SARS-COV-2 versus 11.2% of patients in the control arm (P , 0.001). In a much larger follow-up prospective, observational controlled trial by the same

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group that included 1195 health care workers, they found that over a 3-month period there were no infec- tions recorded among the 788 workers who took weekly ivermectin prophylaxis, whereas 58% of the 407 controls had become ill with COVID-19. This study demonstrates that remarkable protection against transmission can be achieved among high-risk health care workers by taking 12 mg once weekly.40 The Carvallo IVERCAR protocol was also separately tested in a prospective RCT by the Health Ministry of Tucuman, Argentina, where they found that among 234 health care workers, the interven- tion group that took 12 mg once weekly, only 3.4% con- tracted COVID-19 versus 21.4% of controls, P , .0001.46

The need for weekly dosing in the Carvallo study over a 4-month period may not have been necessary given that, in a recent RCT from Dhaka, Bangladesh, the inter- vention group (n 5 58) took 12 mg once monthly for a similar 4-month period and also reported a large and statistically significant decrease in infections compared with controls, 6.9% versus 73.3%, P , 0.05.47 Then, in a large retrospective observational case–control study from India, Behera et al41 reported that among 186 case– control pairs (n 5 372) of health care workers, they identified 169 participants who had taken some form of prophylaxis, with 115 participants that had taken iver- mectin. After matched pair analysis, they reported that in the workers who had taken 2 dose ivermectin pro- phylaxis, the odds ratio for contracting COVID-19 was markedly decreased (0.27, 95% confidence interval (CI) 0.15–0.51). Notably, one dose prophylaxis was not found to be protective in this study. Based on both their study finding and the Egyptian prophylaxis study, the All India Institute of Medical Sciences instituted a pro- phylaxis protocol for their health care workers where they now take two 0.3 mg/kg doses of ivermectin 72 hours apart and repeat the dose monthly.

Data that further illuminates the potential protective role of ivermectin against COVID-19 come from a study of nursing home residents in France which reported that in a facility that suffered a scabies outbreak where all 69 residents and 52 staff were treated with ivermectin,41 they found that during the period surrounding this event, 7 of the 69 residents fell ill with COVID-19 (10.1%). In this group with an average age of 90 years, only one resident required oxygen support and no resident died. In a matched control group of residents from surrounding facilities, they found 22.6% of residents fell ill and 4.9% died.

Further evidence supporting the efficacy of ivermectin as a prophylaxis agent was published recently in the Inter- national Journal of Antimicrobial agents where a group of researchers analyzed data using the prophylactic chemo- therapy databank administered by the WHO along with case counts obtained by Worldometers, a public data

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FIGURE 1. Meta-analysis of ivermectin prophylaxis trials in COVID-19. OBS, observational study; RCT, randomized controlled trial. Symbols: Squares: Indicate treatment effect of an individual study. Large diamond: Reflect summary of study design immediately above. Size of each symbol correlates with the size of the confidence interval around the point estimate of treatment effect with larger sizes indicating a more precise confidence interval.

aggregation site used by among others, the Johns Hopkins University.42 When they compared the data from countries with active ivermectin mass drug administration programs for the prevention of parasite infections, they discovered that the COVID-19 case counts were significantly lower in the countries with recently active programs, to a high degree of statistical significance, P , 0.001.

Figure 1 presents a meta-analysis performed by the study authors of the controlled ivermectin prophylaxis trials in COVID-19.

Further data supporting a role of ivermectin in decreasing transmission rates can be found from South American countries where, in retrospect, large “natural experiments” seem to have occurred. For instance, begin- ning as early as May, various regional health ministries and governmental authorities within Peru, Brazil, and Paraguay initiated “ivermectin distribution” campaigns to their citizen populations.48 In one such example from Brazil, the cities of Itajai, Macapa, and Natal distributed massive amounts of ivermectin doses to their city’s

population, where in the case of Natal, 1 million doses were distributed. The distribution campaign of Itajai began in mid-July, in Natal they began on June 30th, and in Macapa, the capital city of Amapa and others nearby, they incorporated ivermectin into their treatment protocols in late May after they were particularly hard hit in April. The data in Table 1 were obtained from the official Brazilian government site and the national press consortium and show large decreases in case counts in the 3 cities soon after distribution began compared with their neighboring cities without such campaigns.

The decreases in case counts among the 3 Brazilian cities given in Table 1 were also associated with reduced mortality rates as summarized in Table 2.

Clinical studies on the efficacy of ivermectin in treating mildly ill outpatients

Currently, 7 trials that include a total of more than 3000 patients with mild outpatient illness have been completed, a set composed of 7 RCTs and 4 case series.49–60

Table 1. Comparison of case count decreases among Brazilian cities with and without ivermectin distribution campaigns.

Region South

North North East

New cases

Itajaı ́

Chapeco ́

Macapa ́

Ananindeua

Natal

June July August

2123 2854 998

1760 1754 1405

7966 2481 2370

1520 1521 1014

9009 7554 1590

Population 2020 (1000)

223

224

503

535

890

% Decline in new cases between June and August 2020

– 53%

– 20%

– 70%

– 30%

– 82%

– 43%

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Joa ̃o Pessoa
Bolded cities distributed ivermectin, neighboring regional city below did not. http://www.americantherapeutics.com

9437 7963 5384

817

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Table 2. Change in death rates among neighboring regions in Brazil.

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% Change in average deaths/week compared with 2 weeks before

–36%

Region South

North

North East

State

Santa Catarina

PARANA ́
Rio Grande do Sul
Amapa ́ –75% AMAZONAS –42% Para ́ +13% Rio Grande do Norte –65% CEARA ́ +62% Paraı ́ba –30%

–3% –5%

Bolded regions contained a major city that distributed ivermectin to its citizens, the other regions did not.

The largest, a double-blinded RCT by Mahmud49 was conducted in Dhaka, Bangladesh, and targeted 400 patients with 363 patients completing the study. In this study, as in many other of the clinical studies to be re- viewed, either a tetracycline (doxycycline) or macrolide antibiotic (azithromycin) was included as part of the treat- ment. The importance of including antibiotics such as doxycycline or azithromycin is unclear; however, both tetracycline and macrolide antibiotics have recognized anti-inflammatory, immunomodulatory, and even antivi- ral effects (58–61). Although the posted data from this study does not specify the amount of mildly ill outpatients versus hospitalized patients treated, important clinical outcomes were profoundly affected, with increased rates of early improvement (60.7% vs. 44.4% P , 0.03) and decreased rates of clinical deterioration (8.7% vs. 17.8%, P , 0.02). Given that mildly ill outpatients mainly com- prised the study cohort, only 2 deaths were observed (both in the control group).

Ravikirti performed a double-blinded RCT of 115 patients, and although the primary outcome of PCR positivity on day 6 was no different, the secondary out- come of mortality was 0% versus 6.9%, P 5 .019.60 Ba- balola in Nigeria also performed a double-blinded RCT of 62 patients, and in contrast to Ravikirti, they found a significant difference in viral clearance between both the low-dose and high-dose treatment groups and con- trols in a dose dependent fashion, P 5 .006.59

Another RCT by Hashim et al53 in Baghdad, Iraq, included 140 patients equally divided; the control group received standard care, and the treated group included a combination of both outpatient and hospitalized patients. In the 96 patients with mild-to-moderate outpatient ill- ness, they treated 48 patients with a combination of ivermectin/doxycycline and standard of care and com- pared outcomes with the 48 patients treated with stan- dard of care alone. The standard of care in this trial

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included medicines such as dexamethasone 6 mg/d or methylprednisolone 40 mg twice per day if needed, vita- min C 1000 mg twice/day, zinc 75–125 mg/d, vitamin D3 5000 IU/day, azithromycin 250 mg/d for 5 days, and acetaminophen 500 mg as needed. Although no patients in either group progressed or died, the time to recovery was significantly shorter in the ivermectin-treated group (6.3 days vs. 13.7 days, P , 0.0001).

Chaccour et al conducted a small, double-blinded RCT in Spain where they randomized 24 patients to ivermectin versus placebo, and although they found no difference in PCR positivity at day 7, they did find statistically significant decreases in viral loads, patient days of anosmia (76 vs. 158, P , 0.05), and patient days with cough (68 vs. 98, P , 0.05).57

Another RCT of ivermectin treatment in 116 outpatients was performed by Chowdhury et al in Bangladesh where they compared a group of 60 patients treated with the combination of ivermectin/doxycycline to a group of 60 patients treated with hydroxychloroquine/doxycycline with a primary outcome of time to negative PCR.54 Although they found no difference in this outcome, in the treatment group, the time to symptomatic recovery approached statistical significance (5.9 days vs. 7.0 days, P 5 0.07). In another smaller RCT of 62 patients by Pod- der et al, they also found a shorter time to symptomatic recovery that approached statistical significance (10.1 days vs. 11.5 days, P . 0.05, 95% CI, 0.86–3.67).55

A medical group in the Dominican Republic reported a case series of 2688 consecutive symptomatic outpatients seeking treatment in the emergency department, most whom were diagnosed using a clinical algorithm. The patients were treated with a high-dose ivermectin of 0.4 mg/kg for one dose along with 5 days of azithromycin. Remarkably, only 16 of the 2688 patients (0.59%) required subsequent hospitalization with only a single death recorded.61

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In another case series of 100 patients in Bangladesh, all treated with a combination of 0.2 mg/kg ivermectin and doxycycline, they found that no patient required hospitalization nor died, and all patients’ symptoms improved within 72 hours.62

A case series from Argentina reported on a combi- nation protocol that used ivermectin, aspirin, dexa- methasone, and enoxaparin. In the 135 mild illness patients, all survived.50 Similarly, a case series from Mexico of 28 consecutively treated patients with iver- mectin, all were reported to have recovered with an average time to full recovery of only 3.6 days.58

Clinical studies of the efficacy of ivermectin in hospitalized patients

Studies of ivermectin among more severely ill hospi- talized patients include 6 RCTs, 5 OCTs, and a data- base analysis study.45,51–53,63–70

The largest RCT in hospitalized patients was performed concurrent with the prophylaxis study reviewed above by Elgazzar et al.45 Four hundred patients were randomized among 4 treatment groups of 100 patients each. Groups 1 and 2 included mild/moderate illness patients alone, with group 1 treated with one dose 0.4 mg/kg ivermectin plus standard of care (SOC) and group 2 received hydroxy- chloroquine 400 mg twice on day 1 then 200 mg twice daily for 5 days plus standard of care. There was a statis- tically significant lower rate of progression in the ivermectin-treated group (1% vs. 22%, P , 0.001), with no deaths and 4 deaths, respectively. Groups 3 and 4 included only severely ill patients, with group 3 again treated with a single dose of 0.4 mg/kg plus SOC, whereas group 4 received hydroxychloroquine plus SOC. In this severely ill subgroup, the differences in out- comes were even larger, with lower rates of progression 4% versus 30% and mortality 2% versus 20% (P , 0.001).

The one largely outpatient RCT conducted by Hashim reviewed above also included 22 hospitalized patients in each group. In the ivermectin/doxycycline-treated group, there were 11 severely ill patients and 11 critically ill patients, whereas in the standard of care group, only severely ill patients (n 5 22) were included because of their ethical concerns of including critically ill patients in the control group (45). This decision led to a marked imbalance in the severity of illness between these hospi- talized patient groups. However, despite the mismatched severity of illness between groups and the small number of patients included, beneficial differences in outcomes were seen, but not all reached statistical significance. For instance, there was a large reduction in the rate of pro- gression of illness (9% vs. 31.8%, P 5 0.15) and, most importantly, there was a large difference in mortality among the severely ill groups that reached a borderline statistical significance (0% vs. 27.3%, P 50.052). Another

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important finding was the relatively low mortality rate of 18% found among the subset of critically ill patients, all of whom were treated with ivermectin.

A recent RCT from Iran found a dramatic reduction in mortality with ivermectin use.65 Among multiple ivermectin treatment arms (different ivermectin dosing strategies were used in the intervention arms), the average mortality was reported as 3.3%, whereas the average mortality within the standard care and pla- cebo arms was 18.8%, with an odds ratio (OR) of 0.18 (95% CI 0.06–0.55, P , 0.05).

Spoorthi64 and Sasanak performed a prospective trial of 100 hospitalized patients whereby they treated 50 with ivermectin and doxycycline, whereas the 50 controls were given a placebo consisting of vitamin B6. Although no deaths were reported in either group, the ivermectin treat- ment group had a statistically significant shorter hospital length of stay (LOS) 3.7 days versus 4.7 days, P 5 0.03, and shorter time to complete resolution of symptoms, 6.7 days versus 7.9 days, P 5 0.01.

The largest OCT (n 5 280) in hospitalized patients was conducted by Rajter et al at Broward Health Hospitals in Florida and was recently published in the major medical journal Chest (43). They performed a retrospective OCT using a propensity-matched design on 280 consecutive treated patients and compared those treated with iver- mectin to those without. One hundred seventy-three patients were treated with ivermectin (160 received a sin- gle dose and 13 received a second dose at day 7) while 107 were not.63 In both unmatched and propensity-matched cohort comparisons, similar, large, and statistically signif- icant lower mortality was found among ivermectin- treated patients (15.0% vs. 25.2%, P 50.03). Furthermore, in the subgroup of patients with severe pulmonary involvement, mortality was profoundly reduced when treated with ivermectin (38.8% vs. 80.7%, P 50.001).

Another large OCT in Bangladesh compared 115 patients treated with ivermectin to a standard care cohort consisting of 133 patients.51 Despite a signifi- cantly higher proportion of patients in the ivermectin group being men (ie, with well-described, lower sur- vival rates in COVID), the groups were otherwise well matched, yet the mortality decrease was statistically significant (0.9% vs. 6.8%, P , 0.05). The largest OCT is a study from Brazil, published as a letter to the editor and included almost 1500 patients.66 Although the pri- mary data were not provided, they reported that in 704 hospitalized patients treated with a single dose of 0.15 mg/kg ivermectin, compared with 704 controls, overall mortality was reduced (1.4% vs. 8.5%, HR 0.2, 95% CI 0.12–0.37, P , 0.0001). Similarly, in the patients on mechanical ventilation, mortality was also reduced (1.3% vs. 7.3%). A small study from Baghdad, Iraq, compared 16 ivermectin-treated patients with 71

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FIGURE 2. Meta-analysis of the outcome of time to clinical recovery from controlled trials of ivermectin treatment in COVID-19. OBS, observational study; RCT, randomized controlled trial. Symbols: Squares: Indicate treatment effect of an individual study. Large diamond: Reflect summary of study design immediately above. Small diamond: Sum effect of all trial designs. Size of each symbol correlates with the size of the confidence interval around the point estimate of treatment effect with larger sizes indicating a more precise confidence interval.

controls.52 This study also reported a significant reduc- tion in length of hospital stay (7.6 days vs. 13.2 days, P , 0.001) in the ivermectin group. In a study reporting on the first 1000 patients treated in a hospital in India, they found that in the 34 patients treated with ivermec- tin alone, all recovered and were discharged, whereas in more than 900 patients treated with other agents, there was an overall mortality of 11.1%.70

Meta-analyses of the above controlled treatment tri- als were performed by the study authors focused on

the 2 important clinical outcomes: time to clinical recovery and mortality (Figures 2 and 3). The consis- tent and reproducible signals leading to large overall statistically significant benefits from within both study designs are remarkable, especially given that in several of the studies treatment was initiated late in the dis- ease course.

Details of the prophylaxis, early, and late treatment trials of ivermectin in COVID-19 can be found in Table 3.

FIGURE 3. Meta-analysis of the outcome of mortality from controlled trials of ivermectin treatment in COVID-19. OBS, observational study; RCT, randomized controlled trial. Symbols: Squares: Indicate treatment effect of an individual study. Large diamond: Reflect summary of study design immediately above. Small diamond: Sum effect of all trial designs. Size of each symbol correlates with the size of the confidence interval around the point estimate of treatment effect with larger sizes indicating a more precise confidence interval.

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Table 3. Clinical studies assessing the efficacy of ivermectin in the prophylaxis and treatment of COVID-19.

Prophylaxis Trials Author, Country, source

Study design, size

Study subjects

Ivermectin dose 40–60 kg: 15 mg, 60–

Dose frequency

Clinical outcomes reported

Prophylaxis trials Shouman W, Egypt http://www.clinicaltrials.gov

RCT N5340

Household members of pts with +COVID-19 PCR test

80 kg: 18 mg, and . 80 kg: 24 mg

Two doses, 72 hours apart

7.4% versus 58.4% developed COVID-19 symptoms, P , 0.001

NCT04422561 Elgazzar A, Egypt

RCT N5200

Health care and household contacts of pts with +COVID-19 PCR test

0.4 mg/kg

Two doses, day 1 and day 7

2% versus 10% tested positive for COVID-19 P , 0.05

ResearchSquare doi.org/10.21203/rs.3.rs-100956/v1

Chala R, Argentina NCT04701710 Clinicaltrials.gov

RCT N5234

Health care workers

12 mg

Every 7 d

3.4% versus 21.4%, P 5 0.0001.

Carvallo H, Argentina

OCT N5229

Healthy patients negative for COVID-19 PCR test

0.2 mg drops

1 drop 5 times a d x 28 d

0.0% versus 11.2% contracted COVID-19 P , 0.001

Journal of Biochemical Research and Investigation doi.org/10.31546/2633–8653.1007

Alam MT, Bangladesh

OCT N5118

Health care workers

12 mg

Monthly

6.9% versus 73.3%, P , 0.05

European J Med Hlth Sciences

10.24018/ejmed.2020.2.6.599 Carvallo H, Argentina

OCT
N 5 1195

Health care workers

12 mg

Once weekly for up to 10 wk

0.0% of the 788 workers taking ivermectin versus 58% of the 407 controls contracted COVID-19.

Journal of Biochemical Research and Investigation doi.org/10.31546/2633–8653.1007

Behera P, India

OCT
N 5 186

Health care workers

0.3 mg/kg

Day 1 and day 4

2 doses reduced odds of contracting COVID-19 (OR 0.27 95% CI 0.16– 0.53)

medRxiv

doi.org/10.1101/2020.10.29.20222661 Bernigaud C, France

case control pairs
OCT
N 5 69 case control pairs

Nursing home residents

0.2 mg/kg

Once

10.1% versus 22.6% residents contracted COVID-19 0.0% versus 4.9% mortality

Annales de Dermatologie et de Venereologi

doi.org/10.1016/j.annder.2020.09.231 Hellwig M, USA

OCT

Countries with and without IVM prophylaxis programs

Unknown

Variable

Significantly lower-case incidence of COVID-19 in African countries with IVM prophylaxis programs P , 0.001

J Antimicrobial Agents

N 5 52 countries

doi.org/10.1016/j.ijantimicag.2020.106,248

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Clinical trials–Outpatients

% Ivermectin versus % Controls

Study Prophylaxis Trials Author, design,

Country, source size Mahmud R, Bangladesh DB-RCT

Study subjects

Ivermectin dose 12 mg + doxycycline

Dose frequency

Clinical outcomes reported Early improvement 60.7%

http://www.clinicaltrials.gov NCT0452383 N5 363

Outpatients and hospitalized

Once, within 3 days

versus 44.4%, P , 0.03, deterioration 8.7% versus 17.8%, P , 0.02

Chowdhury A, Bangladesh RCT Research Square N5 116 doi.org/10.21203/rs.3.rs-38896/v1
Ravikirti, India DB-RCT medRxiv N5115 doi.org/10.1101/2021.01.05.21249310

Outpatients

0.2 mg//kg + doxycycline

of PCR+ test Once

Recovery time 5.9 versus 9.3 days (P 5 0.07)

Babalola OE, Nigeria DB-RCT medRxiv N5 62 doi.org/10.1101/2021.01.05.21249131

Mild–moderate illness

6 mg and 12 mg

Every 48 hours 3 2 wk

Time to viral clearance:
4.6 days high dose versus 6.0 days low dose versus 9.1 days control (P 5 0.006)

Podder CS, Bangladesh RCT IMC J Med Sci 2020;14(2) N5 62

Outpatients

0.2 mg/kg

Once

Recovery time 10.1 versus 11.5 days (NS), average time 5.3 versus 6.3 (NS)

Chaccour C. Spain DB-RCT Research Square N 5 24 doi.org/10.21203/rs.3.rs-116547/v1

Outpatients

0.4 mg/kg

Once

No diff in PCR+ day 7, lower viral load d 4 and 7, (P , 0.05), 76 versus 158 pts. d of anosmia (P , 0.05), 68 versus 98 pts. d of cough (P , 0.05)

Morgenstern J, Dominican Case

Outpatients and hospitalized

Outpatients: 0.4 mg/kg hospital patients: 0.3 mg/kg

Outpatients:
0.3 mg/kg
3 1 dose Inpatients:
0.3 mg/kg,
days 1,2,6, and 7

Mortality 5 0.03% in 2688 outpatients, 1% in 300 non- ICU hospital patients, and 30.6% in 111 ICU patients

Republic series medRxiv N 5 3099 doi.org/10.1101/2020.10.29.20222505

Carvallo H, Argentina Case

medRxiv

doi.org/10.1101/2020.09.10.20191619 N 5 167 Alam A, Banglades Case

Outpatients

0.2 mg/kg/kg + doxycycline

Once

All improved within 72 h

series Surg, 2020; 38:10-15 N 5 100

J of Bangladesh College Phys and

doi.org/10.3329/jbcps.v38i0.47512

Mild–moderate illness

12 mg

Daily for 2 d

No diff in day 6 PCR + 0% versus 6.9% mortality, P 5 0.019

Outpatients and series hospitalized

24 mg 5 mild, 36 mg 5 moderate, and 48 mg 5 severe

Days 0 and 7

All 135 with mild illness survived, 1/32 (3.1% of hospitalized) patients died

(Continued on next page)

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Table 3. (Continued) Clinical studies Clinical trials–Outpatients

assessing the efficacy of ivermectin in the prophylaxis and treatment of COVID-19.
% Ivermectin versus % Controls

Prophylaxis Trials Author, Country, source

Study design, size

Study subjects Outpatients

Ivermectin dose 6 mg

Dose frequency Days 1,2, 7, and 8

Clinical outcomes reported

Espatia-Hernandez G, Mexico

Case series

All pts recovered average recovery time 3.6 d

Biomedical Research

http://www.biomedres.info/biomedi..- proof-of-concept-study-14435.html

N 5 28

Clinical trials–Hospitalized patients

% Ivermectin versus % Controls

Prophylaxis Trials Author, Country, source

Study design, size

Study subjects

Ivermectin dose 0.4 mg/kg

Dose frequency Daily for 4 days

Clinical outcomes reported Moderately ill: worsened 1%

Elgazzar A, Egypt ResearchSquare doi.org/10.21203/rs.3.rs-100956/v1

OL-RCT N 5 400

Hospitalized patients

versus 22%, P,0.001. Severely ill: worsened 4% versus 30% mortality 2% versus 20% both with P , 0.001

Niaee S. M, Research Square doi.org/10.21203/rs.3.rs-109670/v1

DB-RCT

Hospitalized patients

0.2, 0.3, and 0.4 mg/kg (3 dosing strategies)

Once versus Days 1,3,5

Mortality 3.3% versus 18.3%. OR 0.18, (0.06–0.55, P , 0.05)

Hashim H, Iraq medRxiv doi.org/10.1101/2020.10.26.20219345

SB-RCT N5140

2/3 outpatients and 1/3 hospital pts

0.2 mg/kg + doxycycline

Daily for 2–3 d

Recovery time 6.3 versus 13.6 days (P,0.001), 0% versus 27.3% mortality in severely ill (P 5 0.052)

Spoorthi S, India
AIAM, 2020; 7(10):177-182

PCT
N 5 100

Hospitalized patients

0.2 mg/kg+ doxycycline

Once

Shorter hospital LOS, 3.7 versus 4.7 days, P 5 0.03, faster resolution of symptoms, 6.7 versus

Ahmed S. Dhaka, Bangladesh International journal of Infectious disease doi.org/10.1016/j.ijid.2020.11.191 Chachar AZK, Pakistan

DB-RCT N 5 72

Hospitalized patients

12 mg

Daily for 5 d

7.9 days, P 5 0.01
Faster viral clearance 9.7 versus

Int J Sciences doi.org/10.18483/ijSci.2378 Portman-Baracco A, Brazil

OCT

0.15 mg/kg

Once

N 5 180

DB-RCT N 5 50

Hospitalized patients-mild

12 mg

Two doses day 1 and one dose day 2

64% versus 60% asymptomatic by day 7

12.7 days, P 5 0.02

(Continued on next page)

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Table 3. (Continued) Clinical studies Clinical trials–Hospitalized patients

assessing the efficacy of ivermectin in the prophylaxis and treatment of COVID-19.
% Ivermectin versus % Controls

Prophylaxis Trials Author, Country, source

Study design, size

Study subjects

Ivermectin dose

Dose frequency

Clinical outcomes reported

Arch Bronconeumol. 2020 doi.org/10.1016/j.arbres.2020.06.011

N 5 1408 OCT

Hospitalized patients

Overall mortality 1.4% versus 8.5%, HR 0.2, 95% CI 0.12– 0.37, P , 0.0001

Rajter JC, Florida
Chest 2020 doi.org/10.1016/j.chest.2020.10.009

N5280 OCT

Hospitalized patients

0.2 mg/kg + azithromycin

Day 1 and day 7 if needed

Overall mortality 15.0% versus 25.2%, P 5 0.03, severe illness mortality 38.8% versus 80.7%, P 5 0.001

Khan X, Bangladesh
Arch Bronconeumol. 2020 doi.org/10.1016/j.arbres.2020.08.007 Gorial FI, Iraq
medRxiv doi.org/10.1101/2020.07.07.20145979 Budiraja S. India
medRxiv doi.org/10.1101/2020.11.16.20232223

Hospitalized patients

12 mg

Once on admission

Mortality 0.9% versus 6.8%, P , 0.05, LOS 9 versus 15 days, P , 0.001

N 5 248 OCT

Hospitalized patients

0.2 mg/kg + HCQ and azithromycin

Once on admission

LOS 7.6 versus 13.2 days, P , 0.001, 0/15 versus 2/71 died

N 5 87 OCT

Hospitalized patients

n/a

100% IVM pts recovered 11.1% mortality in non-IVM-treated pts

N 5 1000 IVM534

DB-RCT, double-blinded randomized controlled trial; HCQ, hydroxychloroquine; IVM, ivermectin; LOS, length of stay; NS, nonstatistically significant, P . .05; OCT, observational controlled trial; OL, open label; PCR, polymerase chain reaction; RCT, randomized controlled trial; SB-RCT, single blinded randomized controlled trial.

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Ivermectin in post-COVID-19 syndrome

Increasing reports of persistent, vexing, and even dis- abling symptoms after recovery from acute COVID-19 have been reported and that many have termed the con- dition as “Long COVID” and patients as “long haulers,” estimated to occur in approximately 10%–30% of cases.71–73 Generally considered as a postviral syndrome consisting of a chronic and sometimes disabling constel- lation of symptoms which include, in order, fatigue, shortness of breath, joint pains, and chest pain. Many patients describe their most disabling symptom as impaired memory and concentration, often with extreme fatigue, described as “brain fog,” and is highly sugges- tive of the condition myalgic encephalomyelitis/chronic fatigue syndrome, a condition well reported to begin after viral infections, in particular with Epstein–Barr virus. Although no specific treatments have been iden- tified for Long COVID, a recent manuscript by Aguirre- Chang et al from the National University of San Marcos in Peru reported on their experience with ivermectin in such patients.74 They treated 33 patients who were between 4 and 12 weeks from the onset of symptoms with escalating doses of ivermectin; 0.2 mg/kg for 2 days if mild and 0.4 mg/kg for 2 days if moderate, with doses extended if symptoms persisted. They found that in 87.9% of the patients, resolution of all symptoms was observed after 2 doses with an additional 7% reporting complete resolution after additional doses. Their experi- ence suggests the need for controlled studies to better test efficacy in this vexing syndrome.

Epidemiological data showing impacts of widespread ivermectin use on population case counts and case fatality rates

Similar to the individual cities in Brazil that measured large decreases in case counts soon after distributing iver- mectin in comparison to neighboring cities without such campaigns, in Peru, the government approved the use of ivermectin by decree on May 8, 2020, solely based on the in vitro study by Caly et al from Australia.48 Soon after, multiple state health ministries initiated ivermectin distri- bution campaigns in an effort to decrease what was at that time some of the highest COVID-19 morbidity and mortality rates in the world. Juan Chamie,48 a data ana- lyst and member of the FLCCC Alliance, recently posted an article based on 2 critical sets of data that he compiled and compared; first, he identified the timing and magni- tude of each region’s ivermectin interventions through a review of official communications, press releases, and the Peruvian Situation Room database to confirm the dates of effective delivery, and second, he extracted data on the total all-cause deaths from the region along with COVID-19 case counts in selected age groups over time

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from the registry of the National Computer System of Deaths (SINADEF) and from the National Institute of Statistics and Informatics.48 It should be noted that he restricted his analyses to only those citizens older than 60 years to avoid the confounding of rises in the numbers of infected younger patients. With these data, he was then able to compare the timing of major decreases in this age group of both total COVID-19 cases and total excess deaths per 1000,000 people among 8 states in Peru with the initiation dates of their respective ivermectin distri- bution campaigns as shown in Figure 4.

Figure 5 from the same study presents data on the case fatality rates in patients older than 60 years, again among the 8 states in Peru. Note the dramatically decreased case fatality rates among older patients diagnosed with COVID-19 after ivermectin became widely distributed in those areas, a result which cannot be explained by changes in mask-wearing or lock-downs.

In an even more telling example, Chamie compared the case counts and fatality rates of the 8 states above with the city of Lima, where ivermectin was not dis- tributed nor widely used in treatment during the same period. Figure 6 compares the lack of significant or sustained reductions in case counts or fatalities in Lima with the dramatic reductions in both outcomes among the 8 states with widespread ivermectin distribution.

Another example can be seen from the data compiled from Paraguay, again by Chamie who noted that the government of the state of Alto Parana had launched an ivermectin distribution campaign in early September. Although the campaign was officially described as a “deworming” program, this was interpreted as a guise by the regions’ governor to avoid reprimand or conflict with the National Ministry of Health that recommen- ded against the use of ivermectin to treat COVID-19 in Paraguay. The program began with a distribution of 30,000 boxes of ivermectin, and by October 15, the gov- ernor declared that there were very few cases left in the state as can be seen in Figure 7.

The evidence base for ivermectin against COVID-19

To date, the efficacy of ivermectin in COVID-19 has been supported by the following:

1. Since 2012, multiple in vitro studies have demon- strated that Ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue, and others.9–17

2. Ivermectin inhibits SARS-CoV-2 replication and binding to host tissue through several observed and proposed mechanisms.18

3. Ivermectin has potent anti-inflammatory proper- ties with in vitro data demonstrating profound
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FIGURE 4. Decrease in total case incidences and total deaths/population of COVID-19 in the over 60 population among 8 Peruvian states after deploying mass ivermectin distribution campaigns.

FIGURE 5. Daily total deaths, case fatalities, and case incidence for COVID-19 in populations of patients aged 60 and older for 8 states in Peru deploying early mass ivermectin treatments versus the state of Lima, including the capital city, where ivermectin treatment was applied months later.

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FIGURE 6. Covid-19 case fatalities and total deaths with and without mass ivermectin in different states of Peru.

inhibition of both cytokine production and tran- scription of nuclear factor-kB (NF-kB), the most potent mediator of inflammation.37–39

4. Ivermectin significantly diminishes viral load and protects against organ damage in multiple animal

models when infected with SARS-CoV-2 or sim-

ilar coronaviruses.31,32
5. Ivermectin prevents transmission and develop-

ment of COVID-19 disease in those exposed to infected patients.40–45

FIGURE 7. Paraguay – COVID-19 case counts and deaths in Alto Parana (bolded blue line) after ivermectin distribution began compared to other regions.

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6. Ivermectin hastens recovery and prevents deteri- oration in patients with mild to moderate disease treated early after symptoms.45,49–52,61,62

7. Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized
patients.45,51,53,63–66

8. Ivermectin reduces mortality in critically ill patients with COVID-19.45,53,63

9. Ivermectin leads to temporally associated reduc- tions in case fatality rates in regions after iver- mectin distribution campaigns.48

10. The safety, availability, and cost of ivermectin are nearly unparalleled given its low incidence of important drug interactions along with only mild and rare side effects observed in almost 40 years of use and billions of doses administered.75

11. The World Health Organization has long included ivermectin on its “List of Essential Medicines.”

A summary of the statistically significant results from the above controlled trials are as follows:

Controlled trials in the prophylaxis of COVID-19 (8 studies)

1. All 8 available controlled trial results show statis- tically significant reductions in transmission.

2. Three RCTs with large statistically significant reduc- tions in transmission rates, N 5 774 patients.44–46

3. Five OCTs with large statistically significant reduc- tions in transmission rates, N 5 2052 patients.40–43,47

Controlled trials in the treatment of COVID-19 (19 studies)

1. Five RCTs with statistically significant impacts in time to recovery or hospital length of stay.45,49,53,64,65

2. One RCT with a near statistically significant decrease in time to recovery, P 5 0.07, N 5 130.54

3. One RCT with a large, statistically significant reduction in the rate of deterioration or hospital-
ization, N 5 363.49

4. Two RCTs with a statistically significant decrease
in viral load, days of anosmia, and cough, N 5 85.57,60

5. Three RCTs with large, statistically significant reductions in mortality (N 5 695).45,60,65

6. One RCT with a near statistically significant reduction in mortality, P 5 0.052 (N 5 140).53

7. Three OCTs with large, statistically significant
reductions in mortality (N 5 1688).51,63,66

Safety of ivermectin

Numerous studies report low rates of adverse events, with the majority mild, transient, and largely attributed to the body’s inflammatory response to the death of the parasites

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and include itching, rash, swollen lymph nodes, joint paints, fever, and headache.75 In a study that combined results from trials including more than 50,000 patients, seri- ous events occurred in less than 1% and largely associated with administration in Loa loa.76 Furthermore, according to the pharmaceutical reference standard Lexicomp, the only medications contraindicated for use with ivermectin are the concurrent administration of antituberculosis and cholera vaccines while the anticoagulant warfarin would require dose monitoring. Another special caution is that immuno- suppressed or organ transplant patients who are on calci- neurin inhibitors, such as tacrolimus or cyclosporine, or the immunosuppressant sirolimus should have close monitor- ing of drug levels when on ivermectin given that interac- tions exist that can affect these levels. A longer list of drug interactions can be found on the drugs.com database, with nearly all interactions leading to a possibility of either increased or decreased blood levels of ivermectin. Given studies showing tolerance and lack of adverse effects in human subjects given escalating high doses of ivermectin, toxicity is unlikely, although a reduced efficacy because of decreased levels may be a concern.77

Concerns of safety in the setting of liver disease are unfounded given that, to the best of our knowledge, only 2 cases of liver injury have ever been reported in associa- tion with ivermectin, with both cases rapidly resolved without need for treatment.78,79 Furthermore, no dose adjustments are required in patients with liver disease. Some have described ivermectin as potentially neurotoxic, yet one study performed a search of a global pharmaceu- tical database and found only 28 cases among almost 4 billion doses with serious neurological adverse events, such as ataxia, altered consciousness, seizure, or tremor.80 Poten- tial explanations included the effects of concomitantly administered drugs that increase absorption past the blood–brain barrier or polymorphisms in the mdr-1 gene. However, the total number of reported cases suggests that such events are exceedingly rare. Finally, ivermectin has been used safely in pregnant women, children, and infants.

DISCUSSION

Currently, as of December 14, 2020, there is accumu- lating evidence that demonstrates both the safety and efficacy of ivermectin in the prevention and treatment of COVID-19. Large-scale epidemiologic analyses val- idate the findings of in vitro, animal, prophylaxis, and clinical studies. Epidemiologic data from regions of the world with widespread ivermectin use have demon- strated a temporally associated reduction in case counts, hospitalizations, and fatality rates.

In the context of ivermectin’s long-standing safety record, low cost, and wide availability along with the

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consistent, reproducible, large magnitude of findings on transmission rates, need for hospitalization, and mortality, widespread deployment in both prevention and treatment has been proposed. Although a subset of trials are of an observational design, it must be recognized that in the case of ivermectin (1) half of the trials used a randomized controlled trial design (12 of the 24 reviewed above) and (2) observational and randomized trial designs reach equivalent conclusions on average as reported in a large Cochrane review of the topic from 2014.81 In particular, OCTs that use propensity-matching techniques (as in the Rajter study from Florida) find near identical conclusions to later-conducted RCTs in many different disease states, including coronary syndromes, critical illness, and sur- gery.82–84 Similarly, as evidenced in the prophylaxis (Fig- ure 1) and treatment trial (Figures 2 and 3) meta-analyses as well as the summary trials table (Table 3), the entirety of the benefits found in both OCT and RCT trial designs aligns in both direction and magnitude of benefit. Such a consistency of benefit among numerous trials of varying sizes designs from multiple different countries and centers around the world is unique and provides strong, addi- tional support.

The continued challenges faced by health care pro- viders in deciding on appropriate therapeutic interven- tions in patients with COVID-19 would be greatly eased if more updated and commensurate evidence-based guidance came from the leading governmental health care agencies. Currently, in the United States, the treat- ment guidelines for COVID-19 are issued by the National Institutes of Health. Their most recent recom- mendation on the use of ivermectin in patients with COVID-19 was last updated on February 11, 2021, where they found that “there was insufficient evidence to recommend for or against ivermectin in COVID-19.” For a more definitive recommendation to be issued by major leading public health agencies (PHA), it is appar- ent that even more data on both the quality and quan- tity of trials are needed, even during a global health care emergency, and in consideration of a safe, oral, low-cost, widely available and deployable intervention such as ivermectin.

Fortunately, large teams sponsored by 2 different orga- nizations have embarked on this effort. One team, spon- sored by the Unitaid/WHO’s ACT Accelerator Program and led by the University of Liverpool Senior Research Fellow Dr. Andrew Hill, is performing a systematic review and meta-analysis focused solely on ivermectin treatment RCTs in COVID-19. Although a preliminary meta-analysis of 17 RCTs was posted to a preprint server in February, it is expected that by March 19, 2021, results from approximately 27–29 RCTs including almost 4500 patients will be presented to the WHO Guidelines Com- mittee and that the epidemiologic studies reviewed above

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by Chamie et al were already presented to the committee in early March (personal communication with Dr. An- drew Hill). It is important to note that on February 5, the WHO Guidelines Committee announced that they had begun a review of the accumulating ivermectin data and expected to arrive at their own formal treatment recommendation within 4–6 weeks. If the above benefits in clinical outcomes continue to be reported in the re- maining trials, it is hoped that this almost doubling of the current supportive evidence base would merit a rec- ommendation for use by the WHO, NIH, and other PHA’s would be forthcoming.

Because of the urgency of the pandemic, and in response to the surprising persistent inaction by the leading PHA’s, the British Ivermectin Recommendation Development Panel was recently coordinated by the Evidence-Based Medicine Consultancy Ltd to more rap- idly formulate an ivermectin treatment guideline using the standard guideline development process followed by the WHO. Made up of long-time research consul- tants to numerous national and international public health organizations including the WHO, they con- vened both a steering committee and a technical work- ing group that then performed a systematic review and meta-analysis. On February 12, 2021, a meeting was held that included an international consortium of 75 practitioners, researchers, specialists, and patient repre- sentatives representing 16 countries and most regions of the world. This Recommendation Development Panel was presented the results of the meta-analysis of 18 treatment RCTs and 3 prophylaxis RCTs including more than 2500 patients along with a summary of the observational trials and the epidemiologic analyses related to regional ivermectin use. After a discussion period, a vote was held on multiple aspects of the data on ivermectin, according to standard WHO guideline development processes. The Panel found the certainty of evidence for ivermectin’s effects on survival to be strong and they recommended unconditional adoption for use in the pro- phylaxis and treatment of COVID-19.

In summary, based on the totality of the trials and epidemiologic evidence presented in this review along with the preliminary findings of the Unitaid/WHO meta-analysis of treatment RCTs and the guideline rec- ommendation from the international BIRD conference, ivermectin should be globally and systematically de- ployed in the prevention and treatment of COVID-19.

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