Review of emerging evidences demonstrate efficacy of Ivermectin in treating COVID-19 cases.
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.
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 ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including 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.
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 “ivermectin distribution” campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.
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 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.
According to American Journal of Therapeutics, 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 corticosteroids 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. 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. 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, including 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 servers, a now standard practice for both rapid dissemination and adoption of new therapeutics throughout the pandemic. Following is a comprehensive review of the available efficacy data as of December 12, 2020, taken from in vitro, animal, clinical, and real-world studies all showing the above impacts of ivermectin in COVID-19.
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 polygyrus. 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. 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. 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 eliminated the world of two of its most disfiguring and devastating diseases. The unprecedented partnership between Merck & Co. Inc, and the Kitasato Institute combined with the aid of international health care organizations 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.
Ivermectin’s impacts in controlling onchocerciasis and lymphatic 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 inclusion on the World Health Organization’s (WHO) “List of Essential Medicines.” Furthermore, it has also been used to successfully overcome several other human diseases and new uses for it are continually being found.
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. Insights into the mechanisms of action by which ivermectin both interferes with the entrance and replication of SARS-CoV-2 within human cells are mounting. Caly et al 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 massive doses of ivermectin. 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 synergistically with a therapeutic agent, such as ivermectin.
Furthermore, prolonged durations of exposure to a drug likely would require a fraction of the dosing in short-term cell model exposure. Furthermore, multiple coexisting 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. 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 mechanism by which viral antibodies, in particular, those generated by the Pfizer and Moderna vaccines contain the SARS-CoV-2 virus. The high binding activity of ivermectin 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. Ivermectin has also been shown to bind to or interfere with multiple essential structural and nonstructural proteins required by the virus to replicate. Finally, ivermectin also binds to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication.
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 μg/kg of ivermectin versus placebo.31 The study included 40 infected mice, with 20 treated with ivermectin, 20 with phosphate-buffered saline, and then 16 uninfected control mice that were also given phosphate-buffered saline. At day 5, all the mice were killed to obtain tissues for examination 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 showing histopathological damage such that the differences between the livers from the uninfected control mice were not statistically significant.
Dias De Melo et al recently posted the results of a study they did with golden hamsters that were intranasally inoculated with SARS-CoV-2 virus, and at the time of the infection, the animals also received a single subcutaneous 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 = 0.03), which was also sex dependent in that the male hamsters exhibited a reduction in clinical score while the treated female hamsters 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 further in vitro and animal studies should be undertaken to better define not only these mechanisms but also to further 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, the most likely pathophysiologic mechanism is that identified by Li et al 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 overwhelming 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 inflammation are far more clinically potent than previously recognized. The growing list of studies demonstrating the anti-inflammatory properties of ivermectin include its ability to inhibit cytokine production after lipopolysaccharide exposure, downregulate transcription of NF-kB, and limit the production of both nitric oxide and prostaglandin E2.
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 trials (OCTs) with 4 of the 8 (2 of them RCTs) published in peer-reviewed journals.
Elgazzar and colleagues at Benha University in Egypt randomized 200 health care and household contacts of patients with COVID-19 where the intervention group consisted of 100 patients given a high dose of 0.4 mg/kg on day 1 and a second dose on day 7 in addition to wearing personal protective equipment, whereas the control group of 100 contacts wore personal 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. 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. 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. 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 group that included 1195 health care workers, they found that over a 3-month period there were no infections 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. 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 intervention group that took 12 mg once weekly, only 3.4% contracted COVID-19 versus 21.4% of controls, P < .0001.
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 intervention group (n = 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. Then, in a large retrospective observational case–control study from India, Behera et al reported that among 186 case–control pairs (n = 372) of health care workers, they identified 169 participants who had taken some form of prophylaxis, with 115 participants that had taken ivermectin. After matched pair analysis, they reported that in the workers who had taken 2 dose ivermectin prophylaxis, 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 prophylaxis 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, 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 International Journal of Antimicrobial agents where a group of researchers analyzed data using the prophylactic chemotherapy databank administered by the WHO along with case counts obtained by Worldometers, a public data aggregation site used by among others, the Johns Hopkins University. 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.
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