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Clinical Infection & Immunity

Letter to the Editor

Volume 5, Number 2, June 2020, pages 51-53

Ivermectin: Is It to Be a Potent Therapeutic Option for COVID-19?

The emergence and spread of coronavirus disease 2019 (COVID-2019) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as a pandemic, has led to a new public health crisis. The whole world is now frightened and is in a constant battle to overcome this unprecedented situation through various conventional and non-conventional approaches. As the disease spreads, various pharmaceutical industries and research communities around the world are actively exploring drugs that would be potentially effective in combating COVID-19 infection to decrease the morbidity and mortality associated with this virus. However, till date there is no specific treatment available and all the management is empirical, and mostly consists of supportive therapy. There are some older drugs which are being considered and may be repurposed for this purpose. In this context, ivermectin (22,23-dihydroavermectin B), a well-known anti-helminthic which was introduced in mid-1980s, as the most broad-spectrum anti-parasite medication ever [1], is in focus for its potential activity against SARS-CoV-2. It evinced ideal in various ways, as from being broad-spectrum and highly efficacious to well-tolerated and safe with a wide therapeutic index, which could be administered easily (a single, annual oral dose). It is deployed in the treatment of various internal nematode infections, including onchocerciasis, filariasis, trichuriasis, strongyloidiasis, ascariasis, gnathostomiasis, and cutaneous larva migrans and also given as an oral treatment in case of infections with ectoparasitic, such as scabies (mite infestation) and pediculosis (lice infestation) [2].

A recent study done by Caly et al, 2020 [3] demonstrated the antiviral activity of ivermectin against the SARS-CoV-2 clinical isolate under in vitro conditions. The result shows a single dose administration of ivermectin i.e. 5 µM to infected SARS-CoV-2-Vero/hSLAM can efficiently slow down viral replication machinery within the time period of 24 - 48 h. The observed IC50 was about 2 µM, with about reduction of 99.98% in viral RNA in studied samples. Interestingly, the authors try to resolve the current pressure of treatment option in COVID-19, by bringing a hopeful fast-track drug repurposing option for ivermectin through the aim on establishment of an efficacious anti-viral for SARS-CoV-2, with assumption of limitation in viral load that could prevent the disease progressing to severe form and also could limit person-person transmission by decreasing viral replication in the infected hosts, if given to patients during early course of infection [3].

However, there are few points that need to be considered which could be hurdles in the progression of ivermectin as a new treatment option for COVID-19.

The study is very preliminary that includes antiviral activity of ivermectin in the in vitro culture system and data obtained from the study need to be validated further with more observative and validated experiments like, visualization of virus protein expression through immunofluorescence microscopy, time-of-drug-addition assays, etc, which can elucidate antiviral activity of ivermectin at distinct stages in the viral replication cycle. Moreover, it is onerous to infer the outcomes of in vitro experimentation to an in vivo system, that is, whole systems biology which offers various physiological factors like variation in temperature, pH, solutes, metabolites, immune response etc [4]. Additionally, any compound showing potent in vitro activity often loses its activity in in vivo models. This has been shown in a related study done by Ketkar et al, 2019, in which ivermectin had shown promising in vitro findings against Zika virus, but was unfortunately found to be ineffective for prevention of a lethal infection with the Senegal strain of Zika virus in Ifnar1 knockout mice, and no difference in morbidity or mortality was observed between the control and ivermectin-treated infected mice [5]. Hence, cautious observation is needed during optimization and selection that provide a vision for the utmost requirement for development and validation of various drugs in animal model for COVID-19, which can decide time course of treatment, the assessment of efficacy and safety of drug [6].

Secondly, administration of dosages and interaction with other drugs and foods must be in consideration prior its uses. Currently, ivermectin is prescribed at doses of 150 - 200 µg/kg against most filarial and Strongyloides stercoralis (S. stercoralis) infections and approved in doses of up to 400 µg/kg against infections Wuchereria bancrofti [7]. However, most of the antiviral activity of ivermectin is achieved at very high doses of ivermectin [8]. The safety of high-dose ivermectin appears to be comparable to standard doses, but at the same time there are not enough data to support a recommendation for its use in higher-than-approved doses. Apart from this, the safety issue of more clinical trials evaluating the safety of ivermectin at higher doses and in children < 15 kg and pregnant women is needed because of lack of safety data among these population groups [7].

Considering the safety of administration of ivermectin in pregnancy is an utmost priority [9]. Metanalysis of the literature available till date showed that the inadvertent use of ivermectin during pregnancy may lead to serious adverse event (congenital abnormalities, stillbirth and spontaneous abortions). This analysis failed to report any significant association between administration of ivermectin and critical clinical outcome in pregnant women because of selection bias and availability of only few published reports. However, on this basis, the authors emphasized to exclude pregnant women from the ivermectin treatment and clearly suggested for further work on reproductive toxicological studies as well as clinical trials that are in need to evaluate the safety of ivermectin in pregnancy [9, 10]. This is important as pregnant women are a high-risk group for the infection and also pose a risk for health care workers.

Moreover, ivermectin has also been potential for drug interactions. Drugs which are substrates of enzymes “cytochrome P450 3A4 (CYP3A4)” are mostly substrates of transport protein, “P-glycoprotein”, and thus it can increase the assimilation and can pass the blood-brain barrier with concomitant administration of ivermectin. A recent publication documents evidence of an in vitro interaction of ivermectin with a number of antiretroviral agents [11]. Fruit juice and alcohol are also found to interact with ivermectin and affects its bioavailability [12]. Evidence is also available where it has been observed about the alteration in the action of ivermectin due to the host immune response. This has been observed in both Onchocerca volvulus (O. volvulus) and Dirofilaria immitis (D. immitis) microfilariae, in which in vivo efficacy of ivermectin was observed at much lesser concentrations than in vitro [13], which supports the effect of function of host immune system in the activity of ivermectin [14]. Nonetheless, ivermectin is toxic to premature infants, adult epileptics and those with other central nervous system disorders, and often leads to serious neurological adverse events in population harbouring mutated MDR1 gene, which allows ivermectin penetration into the central nervous system (CNS) [15]. Therefore, safety monitoring will be important.

The study provides baseline information of ivermectin against SARS-CoV-2 action only; therefore, there is a need of extensive analysis at preclinical level regarding efficacy and safety in the treatment of COVID-19 in different group of population before moving to clinical trials and off-label use.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Not applicable.

Author Contributions

RS designed the research, and SS collected and analyzed data. SS, AS and RS wrote and approved the final paper.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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Clinical Infection and Immunity is published by Elmer Press Inc.