Editorial, J Infect Dis Immune Ther Vol: 5 Issue: 5

Ivermectin, a therapeutic against RNA viruses and an emerging candidate for COVID-19 patients: A Short Review

Marcos A Sanchez-Gonzalez

National Institutes of Health (NIH) Minority Programs , United States

*Corresponding author: Marcos A Sanchez-Gonzalez , Email: masanchez@larkinhospital.com

Citation: Journal of Infectious Diseases & Immune Therapies

Abstract

Keywords: RNA viruses, Immune Therapies

Introduction

Ivermectin (IVM) was first introduced commercially, for use in animals, in 1981. Apart from treating multiple livestock and other animals globally to help maintain food production and veterinary health, IVM is also used for treating various diseases in humans, such as being a key drug for the elimination of onchocerciasis (1,2). IVM, belongs to the Avermectin family, as these compounds are produced by the soil microorganism; Streptomyces avermitilis, hence called Avermectins (3). IVM also illustrates a structural similarity to macrolide antibiotics (4). IVM, an endectocide, selectively binds to the glutamate-gated chloride channels in invertebrates, causing hyperpolarization of parasite neurons and muscles by increasing chloride ion influx, ultimately resulting in the death of the parasite. It acts on endoparasites and ectoparasites by suppressing the nerve impulse conduction in intermediary neurons or nerve-muscle synapses, respectively (5,6).

To demonstrate the antiviral activity of IVM, Caly (2020) conducted an in-vitro experiment. Vero/hSLAM cells containing SARS-CoV-2 clinical isolate were treated with IVM 5 µM. After 10 minutes of centrifugation, cells were harvested at days 0-3 and analyzed by RT-PCR for SAR-COV-2 RNA replication. A 93% and 99% viral RNA reduction was observed for at 24 and 48 hours respectively for samples treated with Ivermectin. (7). These results indicate IVM’s potential as a successful antiviral drug for COVID-19, based on its already proven efficacy and safety.

Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-COV-2), is considered to have 80% genetic similarity to previously known severe acute respiratory syndrome coronavirus (SARS-CoV), but only 50 to 60% genetic similarity to other Coronaviruses (CoVs) (8). Of the three groups of CoVs (alpha, beta, gamma, and delta), SARS-COV-2 belongs to the beta family (9). The previously known Severe Acute Respiratory Syndrome virus (SARS-CoV-1) and the Middle East Respiratory Syndrome virus (MERS) also belong to the beta coronavirus family. The viral genome is made up of structural and non-structural proteins. Like all enveloped viruses, the envelope of SARS-COV-2 is also derived from the host cells, made up of several viral coded proteins, including spike protein (S), a structural protein that plays an important role in the entry of the virus in the host cell (10). The S protein of CoV-2 interacts with cell surface protein angiotensin-converting enzyme 2 (ACE2) and then it is cleaved by TMPRSS2, allowing its fusion subunit to form a hairpin which is then fused with the target cell. It may survive on various surfaces for over 24 hours and is thought to be highly mutative thus making it difficult for scientists and researchers to find a cure or vaccine. The Coronaviruses are silently present in many species but may present with respiratory infections in a few; including birds, chickens, cows, and pigs. The highly contagious SARS-CoV-2 is thought to be found in bats and can be transmitted to the human host (11). It causes mostly flu-like symptoms, including respiratory infections. The radiological findings of chest X-rays and CT scans may vary from normal to focal or patchy infiltrates in an infected person (12).

There are currently no treatment regimens approved for SARS-CoV-2. Numerous clinical trials are currently underway to fill the treatment gap. Multiple studies to explore the antiviral properties of ivermectin, yielded promising results, indicating that ivermectin has potent activity against several viruses that pose a threat to human health at large. IVM is an antiparasitic drug approved for the treatment of onchocerciasis and strongyloidiasis (13). IVM showed successful halting of viral replication owing to its inhibition of importin α/β facilitated the nuclear import of viral proteins vital for replication of the virus (14,15). Antiviral efficacy of ivermectin has been demonstrated against Human Immunodeficiency Virus (HIV), Dengue virus (DENV), Yellow Fever Virus (YFV), Chikungunya virus, West Nile Virus (WNV), Zika virus, SARS CoV2 (7,16–20), and several other RNA or DNA viruses. In-vitro antiviral properties of IVM warrant, in-vivo experiments, and trials, especially during this ongoing pandemic. Our purpose in writing this review is to gather all the information related to the antiviral properties of IVM and its efficacy in viral infections including COVID-19 and to encourage further investigation and clinical trials for use of ivermectin in COVID-19 as a potential treatment.

Efficacy of Ivermectin Against Viral Infections

Several studies revealed the effectiveness of ivermectin in microbial diseases besides parasitic infections. Fatemeh and Reza published a systematic review of the antiviral effectiveness of ivermectin summarizing approximately 50 studies. They found it effective against various RNA viruses such as the Zika virus, DENV, YFV, WNV, Venezuelan equine encephalitis, Chikungunya Virus, Avian influenza A, HIV type 1, and SARS CoV2. Besides RNA viruses, the efficacy of ivermectin has also been reported against several DNA viruses such as BK Polyomavirus, Pseudorabies virus, Bovine Herpesvirus, and Equine herpes type 1 virus (21).

In another study, Eloise Et al reported Ivermectin’s effectiveness against the flaviviruses (DENV, Zika virus, YFV, WNV, Japanese encephalitis (JEV), and Tick-borne encephalitis viruses (TBEV) (17). It is a potent flavivirus replication inhibitor that specifically targets NS3 helicase activity. Xu and his colleagues observed its activity against the dengue virus and concluded that Ivermectin can directly or indirectly inhibit DENV-2 multiplication in Aedes albopictus (18).

Dengue Virus

In a study to determine the efficacy of ivermectin in the treatment of dengue virus type 2, Aedes albopictus was fed on human blood infected with Dengue virus 2 (DENV-2) for four days and thereafter they were divided into eight groups. Seven of them were administered 0, 2, 4, 8, 16, 32, and 64 ng/ml of ivermectin respectively, while the last group served as the control group. Results showed a 49.63% reduction in infection treatment in the treatment group (18).

 Another study done to determine whether ivermectin could inhibit dengue virus (DENV) infection, showed that ivermectin almost eliminated virus production at a concentration of 50 µM and reduced virus production at 25 µM (14). Results from a study conducted on Huh- 7 cells infected with four specific serotypes of the dengue virus revealed that ivermectin showed inhibitory effects towards both DENV 1 and 2, this was achieved via NS5 interaction with its nuclear transporter importin α/β in vitro. Results also showed that it protected against infection from DENV 1-4 (16).

Zika Virus

A study done in vitro to evaluate the effects of ivermectin on various cell lines infected with the Zika virus revealed a 60% reduction in nonstructural protein 5 (NS5) which is important for viral RNA replication in the nucleus, after seven hours of treatment with 20 um of ivermectin (19). An in vitro study by Yang et al involving Vero cells infected with the zika virus. The cells were later treated with ivermectin and results from cell supernatant analyzed quantitatively after 22 hours for virus production and proliferation shows that ivermectin is a potent inhibitor of the zika virus (15).

Chikungunya Virus

A study conducted on baby hamster kidney cells infected with chikungunya virus (CHIKV) revealed that ivermectin could inhibit CHIKV replication dose-dependently. Results also revealed that it reduced the synthesis of CHIKV genomic and anti-genomic viral RNA and it also mediated downregulation of viral protein (20).

Human Immunodeficiency Virus

HIV integrase (IN) plays a vital role in the importation of viral cDNA into the nucleus. It does so by interaction with importin alpha/beta heterodimer (22). Ivermectin's potential antiviral mechanism is due to its interaction and dissociation of importin alpha/beta heterodimer. (23) Wagstaff et al demonstrated that treatment with ivermectin for 2 hours at concentrations of 25μM (minimum concentration) leads to a significant reduction in the virus production (14).

West Nile Virus

To demonstrate the efficacy of ivermectin against WNV, Yang et al infected Vero cells at a multiplicity of infection (MOI) of 1 and then administered increasing doses of ivermectin. Results showed a potential decrease in the infectious virus production and as well as viral replication, quantified by plaque assay and RT-PCR respectively (15). This demonstrates the effectiveness of ivermectin against WNV.

Efficacy of Ivermectin against SARS-CoV-2

Ivermectin has displayed broad-spectrum activity against endo/ectoparasites, as well as antiviral, antibacterial, and anticancer properties (1). The ability of Ivermectin to inhibit the importin α/β-mediated nuclear transport enables the blockage of the nuclear trafficking of viral proteins (15). This specific mechanism of action allows ivermectin to work against several RNA viruses (24) including SARS-CoV-2 (7) that depend on Impα/β1 during the infection process. SARS-CoV-2 is expected to demonstrate a similar mechanism of action. The expected anti-SARS-CoV-2 action of ivermectin is centered on the binding of ivermectin to the Impα/β1 heterodimer. This destabilizes and prevents Impα/β1 from binding to viral proteins. Therefore, the viral proteins are prevented from entering the nucleus, thereby reducing the viral replication and thus viral load. Vero-hSLAM cells were treated with 5 µM IVM two hours of post-SARS-COV-2 infection in a study by Caly et al. After 48 hours, this treatment resulted in a 5000-fold reduction in viral load (7)

Figure 1: Demonstration of the potential antiviral mechanism of Ivermectin in SARS-CoV-2 infection.

Safety & Limitations for the use of IVM

Despite ivermectin efficacy being established in humans against several parasitic illnesses, its antiviral properties are not yet utilized to their full capacity, mainly due to its complex chemical structure which cannot be easily chemically modified. The lack of appropriate formulations that could improve cellular internalization of ivermectin reduces the unfavorable effect of the drug (25). Although recent reviews and meta-analysis have indicated high dose ivermectin having comparable safety to the standard low-dose treatment, there is still not enough evidence to make conclusions about the safety profile in pregnancy (26,27). Hypersensitivity to IVM, or any of its components (13). As emphasized on by Jans et al. 2020, big scale randomized clinical trials are warranted to evaluate the efficacy of ivermectin against SARS-CoV-2(28); these clinical trials will also able to better understand the safety profile of ivermectin when given in a dosage sufficient enough to inhibit SARS-CoV-2 replication.

Conclusions

The on-going COVID-19 pandemic has challenged the human race to find a therapeutic regimen or a vaccine as a prophylactic tool against this viral illness. The current SARS-CoV-2 pandemic has affected multiple industries globally, but the healthcare industry remains the most vulnerable. With a continuous surge in COVID-19 cases, there is a need for either an effective antiviral agent or a vaccine, to minimize the magnitude of the on-going pandemic and to have a potential treatment or prevention for COVID-19. The need for this detailed review was undertaken keeping into consideration that, data regarding Ivermectin’s antiviral use, besides its antiparasitic use, is scarce and scattered. However, it has been one of the most extensively experimented and studied drugs over the past years. Hence, this review is of significant importance as it critically focuses on the compilation of various clinical trials, case series, and/or original research papers looking into Ivermectin’s role as a potent antiviral agent. Ivermectin is a cost-effective FDA approved drug with an established safety profile. Although, many studies suggest that Ivermectin is predominantly an antiparasitic agent, it has a proven mechanism of action against many viruses. It is effective against many RNA viruses and some DNA viruses. This further supports the main purpose of this review that Ivermectin is an effective antiviral agent for the treatment of various viral infections and given the fact that SARS-CoV-2 is an RNA virus, we can suggest that Ivermectin can prove to be efficacious in the treatment of COVID-19. Moreover, Ivermectin was specifically tested in vitro for its antiviral activity against the causative virus SARS-CoV-2. It was noticed that SARS-CoV-2 viral loads were reduced by “~5000-fold” at 48 h in cell culture in a single treatment with Ivermectin. This is a very strong indicator of Ivermectin’s efficacy in the treatment of COVID-19. This should be taken into consideration and is expected to encourage Ivermectin clinical trials in affected humans in light of the potential treatment for the COVID-19; based on antiviral activity, pharmacokinetics, pharmacodynamics, dosage, side effects, and most importantly the efficacy of the drug. Though the latter supports ivermectin as a candidate for COVID-19 patients, recent clinical data and literature illustrate uncertainty concerning its rapid and widespread use, owing to the detrimental side effects it may lead to due to the high doses it is administered at in COVID-19 patients.

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