Ivermectin in COVID-19

Clinical Question

Ivermectin - Summary of COVID-related information

Key Findings

  • There are no published randomized, controlled clinical studies testing the efficacy and safety of ivermectin against COVID-19 in humans.
  • According to an international, multicenter observational study across three continents, a single dose of 150 mcg/kg of ivermectin is shown to decrease fatality rate of COVID-19 patients (7.3% vs 21.3% control) and overall death rate (1.4% vs 8.5% control, p< 0.0001).[1]
  • Caly et al demonstrated a single dose of 5μM Ivermectin used to treat SARS-CoV-2-infected cells in vitro results in a ~5000-fold reduction in viral RNA at 48 hours.[2] However, according to pharmacokinetic data analysis from clinically relevant and excessive dosing studies, the dosage is multifold higher than the therapeutic recommended dosage for ivermectin in treating parasitic infections and thus, is not achievable in humans.[3]
  • FDA issued a warning concerning possible inappropriate use of ivermectin intended for animals as an attempt to self-medicate for COVID-19.[4] It has been shown that accidental self-injection of veterinary medicinal products to result in clinical toxicity, even when using a therapeutically approved dose (~200 μg/kg).[5]

Summary of Information

What is Ivermectin?

Ivermectin originated from a lab-isolated microorganism from soil samples in Japan in the late 1970s.[6] It was first used as treatment for Onchocerciasis in 1988 and was considered a “Wonder Drug” in terms of nutrition boosts and wellness improvements in human health with its safe and broad-spectrum features.[6] This antiparasitic drug is FDA-approved for use in humans for the treatment of parasitic worms (intestinal strongyloidiasis and onchocerciasis) and topical Ivermectin is used for external parasites (head lice) and skin conditions such as rosacea. In animals, Ivermectin is used for heartworm disease and for certain internal and external parasites in animals.[7]

Ivermectin and COVID-19

Ivermectin antiviral activity against RNA/DNA viruses

SARS-CoV-2 virus is a single stranded positive sense RNA virus.[2] Studies revealed a potential role for importin (IMP) α/β1 during infection in signal-dependent nucleocytoplasmic inhibition of SARS-CoV nucleocapsid protein, which may impact host cell division.[2] Also, SARS-CoV accessory protein ORF6 has been shown to antagonize the antiviral activity of the STAT1 transcription factor by sequestering IMPα/β1 on the rough ER/Golgi membrane.[8] Given these reports, it is suggested that ivermectin’s nuclear transport inhibitory activity may be effective against SARS-CoV-2 virus.[8]

Ivermectin has been shown to inhibit nuclear import of viral proteins via the IMPα/β1 such as simian virus SV40 large tumour antigen (T-ag) and dengue virus (DENV) non-structural protein 5, and HIV-1 replication.[9][10][11][12] Ivermectin can limit infection by RNA viruses such DENV 1-4, West Nile virus, Venezuelan equine encephalitis virus (VEEV) and influenza.[13][14][15][16] Furthermore, ivermectin has also been shown to increase survival in mice infected with pseudorabies virus (PRV), a DNA virus.[17] This broad spectrum activity may be due to the fact many viral RNA strains rely on IMPα/β1 for their invasion. In Thailand, ivermectin was tested in phase III clinical trial in 2014-2017 against DENV infection where a single dose resulted in a reduction in serum levels of viral NS1 protein.[18] However, it should be noted that no change in viremia or clinical benefits was observed for this clinical trial.[18]

Ivermectin reduces SARS-CoV-2 replication in vitro

To test the antiviral activity of ivermectin against SARS-Cov-2, Caly et al. infected Vero/hSLAM cells with SARS-CoV-2 isolate (Australia/VIC01/2020) for 2 hours followed by the addition of 5 μM ivermectin.[2] At 24 hours, there was a 93% reduction of viral RNA in the supernatant of samples treated with ivermectin and a 99.8% reduction in cell-associated viral RNA with ivermectin treatment.[2] At 48 hours, there was a ~5000-fold reduction of viral RNA in ivermectin treated samples.[2] To further investigate the effectiveness of ivermectin, SARS-CoV-2-infected cells were treated with a series of dilutions of ivermectin 2 hours post infection and collected for quantitation of viral load using real-time RT-PCR at 48 hours. A >5000 reduction in viral RNA was similarly observed for cells treated with 5 μM of ivermectin.[2] Using the same approach, subsequent treatments against the cell-associated virus and supernatant using a serial dilution of ivermectin also yielded the same trend with a result of around 50% reduction in viral materials when using 2.5μM. In all experiments, no toxicity was observed. These results demonstrate that ivermectin has antiviral activity against SARS-CoV-2 in vitro with a single dose able to control viral replication in 48 hours.[2] Caly et al further hypothesized that this effect of ivermectin is likely through inhibiting IMPα/β1-mediated nuclear import of viral proteins.

Effect of Ivermectin in COVID-19 patients: Ivermectin reduces COVID-19 fatality

Ivermectin is associated with a reduction in COVID-19 fatality rate and length of hospital stay.[1] In an international, multicenter observational study, data of COVID-19 patients was collected between January 1, 2020 and March 21, 2020 from 169 hospitals across three continents (704 ivermectin-treated cases with a single dose of 150 mcg/kg of ivermectin vs 704 receiving only medical therapy without ivermectin).[1] Of the patients who required mechanical ventilators, fewer died in the ivermectin group (7.3% vs 21.3% control). The overall death rates were lower with ivermectin administered (1.4% vs 8.5% control, p< 0.0001).[1]

There are also anecdotal reports of doctors using ivermectin to treat patients with success. In a news report, Dr. Jean-Jacques Rajter, a pulmonologist, included ivermectin in his cocktail of treatment (hydroxychloroquine, azithromycin, and zinc sulfate) on COVID-19 patients at the Broward Health Medical Center.[19] According to Dr. Rajter, he has a 100% response rate if the patient’s oxygen requirements are less than 50%. If the oxygen requirement is more than 50% then the response varied, with some patients having no response. Dr. Rajter is in the process of publishing his results.

Counter to Caly et al in vitro study

From a pharmacokinetic perspective, the ivermectin dose concentration used in the in vitro study by Caly et al is not likely to be attainable in humans because it is multifold higher than the recommended therapeutic dose for ivermectin in humans.[3] The clinically relevant dose for ivermectin is 150-800 μg/kg and excessive dosing is up to 2000 μg/kg.[3] Pharmacokinetic data for ivermectin in patients with parasitic infection and healthy volunteers were pooled to derive the maximal plasma concentration levels (Cmax) in order to allow direct juxtaposition with the in vitro inhibitory concentrations presented in Caly et al. The analyzed data show that at the clinically relevant dose range of ivermectin, the published in vitro inhibitory concentrations (5 μmol/L) are not achievable in humans. The 5 μmol/L concentration is 50 times higher than the levels obtainable (700 μg/kg) and 17 times higher than the largest Cmax found in literature (247.8 ng/ml). Noted, large doses of ivermectin could have a high inhibitory effect, however, there is expected high risk of overdosing.

It should be noted that although ivermectin has shown to have antiviral activity in vitro against DENV, influenza virus, West Nile virus etc., there has not been any clinical translation of these data so far.[3] It should also be noted that not as much ivermectin may be needed to have antiviral effects. Patel 2020 preliminary study only administered one dose of 150 mcg/kg of ivermectin and has decreased fatality rate results.[3]

Clinical trials for Ivermectin used in humans

Currently, there are no published randomized, controlled clinical trials testing ivermectin’s effectiveness in preventing or treating COVID-19 in humans. There are currently seven trials registered with clinicaltrial.gov that are intended to look into ivermectin’s effect on humans.[20] Medincell, a French pharmaceutical research venture funded by the Gates Foundation, also plans to start clinical trials on ivermectin by launching a research initiative on a long-acting formulation of ivermectin which they believe to play a role in COVID-19 management.[21] Their objective is to validate the efficacy and safety of ivermectin against COVID-19 for preventive action in humans and to determine dosage requirements.[21] There is no data to date to support the use of ivermectin, thus is it recommended to heed the FDA’s warning.

Gaps in Knowledge

There is a potential to repurpose the use of ivermectin as a time-saver in this pandemic since it is an existing FDA-approved drug. However, data to support use of ivermectin in prevention or treatment of COVID-19 has not been established. Randomized, controlled clinical trials testing ivermectin’s effectiveness in preventing or treating COVID-19 are needed to confirm the effect and safety of ivermectin for human use. In order to speed up research for the development of COVID-19 treatments, FDA has recently released a new emergency program called Coronavirus Treatment Acceleration Program (CTDAP).

Author Information

Authors: Thanh Tran, BS, UC San Diego
Completed on: May 8, 2020
Last revised on: Not yet revised

Reviewed by: Marsha-Gail Davis, MD
Reviewed on: May 14, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

  1. Patel A, Desai S. Ivermectin in COVID-19 Related Critical Illness. SSRN Electronic Journal. 2020. doi:10.2139/ssrn.3570270
  2. Caly L, Druce JD, Catton MG, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.  [PMID:32251768]
  3. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view. 2020. doi:10.1101/2020.04.11.20061804
  4. FDA Letter to Stakeholders: Do Not Use Ivermectin Intended for Animals as Treatment for COVID-19 in Humans | FDA. https://www.fda.gov/animal-veterinary/product-safety-information/fda-lette.... Accessed April 10, 2020.
  5. Ivermectin (PIM 292). Inchem.org. http://www.inchem.org/documents/pims/pharm/ivermect.htm. Published 2020. Accessed May 8, 2020.
  6. Crump A, Ōmura S. Ivermectin, 'wonder drug' from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(2):13-28.  [PMID:21321478]
  7. FAQ: COVID-19 and Ivermectin Intended for Animals| FDA. https://www.fda.gov/animal-veterinary/product-safety-information/faq-covid.... Accessed May 1, 2020.
  8. Frieman M, Yount B, Heise M, et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol. 2007;81(18):9812-24.  [PMID:17596301]
  9. Kosyna FK, Nagel M, Kluxen L, et al. The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways. Biol Chem. 2015;396(12):1357-67.  [PMID:26351913]
  10. van der Watt PJ, Chi A, Stelma T, et al. Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic. Mol Cancer Ther. 2016;15(4):560-73.  [PMID:26832790]
  11. Wagstaff KM, Rawlinson SM, Hearps AC, et al. An AlphaScreen®-based assay for high-throughput screening for specific inhibitors of nuclear import. J Biomol Screen. 2011;16(2):192-200.  [PMID:21297106]
  12. Wagstaff KM, Sivakumaran H, Heaton SM, et al. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851-6.  [PMID:22417684]
  13. Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 2013;99(3):301-6.  [PMID:23769930]
  14. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 2020;177:104760.  [PMID:32135219]
  15. Lundberg L, Pinkham C, Baer A, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication. Antiviral Res. 2013;100(3):662-72.  [PMID:24161512]
  16. Götz V, Magar L, Dornfeld D, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138.  [PMID:26988202]
  17. Lv C, Liu W, Wang B, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. 2018;159:55-62.  [PMID:30266338]
  18. Yamasmith E, Mairiang D, Tanrumluk S, et al. Efficacy and safety of ivermectin against dengue infection: a phase III, randomized, double-blind, placebo-controlled trial. Internal Medicine and One Health. http://www.rcpt.org/abstractdb/media/abstract/CON2018/Best Resident27/BRA_77_Eakkawit.pdf.
  19. Local Doctor Tries New Coronavirus Drug Treatment| NBC 6 South Florida. https://www.nbcmiami.com/news/local/local-doctor-tries-new-coronavirus-dru.... Published 2020. Accessed May 8, 2020.
  20. Search of: Ivermectin: COVID-19 - List Results. Home - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results.... Accessed May 8, 2020.
  21. Invest.medincell.com. https://invest.medincell.com/wp-content/uploads/2020/04/PR_MedinCell_Adapt.... Published 2020. Accessed May 8, 2020.
Last updated: July 1, 2020