Ivermectin and COVID-19

Emerging evidence about the use of this antiparasitic medicine to treat COVID-19

Ivermectin and COVID-19

Please note: Information, evidence and advice relating to COVID-19 is constantly changing. The information in this article was correct at the time of writing.

In response to international interest in the use of ivermectin for the prevention and treatment of COVID-19, the disease caused by the virus SARS-CoV-2, we look at emerging evidence, current guidelines and whether ivermectin is a potential ‘cure’ as has been claimed.

This article is for health professionals.

Find information for consumers about ivermectin

 

What is ivermectin?

Ivermectin is an antiparasitic medicine. In Australia, oral ivermectin is indicated for the treatment of:1

  • onchocerciasis (river blindness)
  • intestinal strongyloidiasis
  • crusted scabies (in conjunction with topical therapy)
  • human sarcoptic scabies when prior topical treatment has failed or is contraindicated.

For information about the PBS-listed indications for ivermectin, see the PBS website.

Ivermectin is also available as a cream, indicated for topical treatment of inflammatory lesions of rosacea (papulo-pustular) in adults over the age of 18.2

Ivermectin was identified in the late 1970s and first approved for use in animals in 1981, with potential use in humans confirmed a few years later. When taken orally, it has a good safety profile with low adverse effects.3

Table 1. Usual therapeutic doses of oral ivermectin for adults with indicated conditions

Condition

Dose

Onchocerciasis

150 micrograms/kg as a single dose1

Scabies

200 micrograms/kg

Classic/typical scabies: two doses (day 1 and second dose between day 8 and day 15)

Crusted scabies (ivermectin in combination with a topical scabicide): two doses for mild cases (day 1 and second dose between day 8 and day 15)

Moderate to severe cases may require more than three doses.1

Strongyloidiasis

200 micrograms/kg as a single dose1

 

How does it work?

Ivermectin works by binding to glutamate-gated chloride ion channels to alter chloride channel function, and acting as a gamma-aminobutyric acid (GABA) agonist in the parasite. This leads to parasite paralysis and death.4

In recent years, ivermectin has shown anti-viral activity against a broad range of viruses in vitro. It has been hypothesised that ivermectin may exert its anti-viral activity against SARS-CoV-2 by inhibiting IMPα/β1-mediated nuclear import of viral proteins.5 IMPα is part of the Imp (importin) superfamily of proteins, which play a role in the movement of proteins between the nucleus and cytoplasm of the cell, essential in key cellular processes (such as differentiation and development), as well as being critical to disease states such as viral disease and oncogenesis.6

 

What are the adverse effects?

Patients receiving ivermectin for onchocerciasis may experience more frequent or severe adverse effects (arthralgia, lymphadenopathy, itch, oedema, rash, fever, tachycardia, hypotension and temporary worsening of ocular symptoms) due to allergic or inflammatory responses resulting from the death of the parasite (Mazzotti reaction). They occur in approximately one-third of patients and are most severe if there is a high microfilariae count and lessen with repeated courses.4

Common adverse effects (occurring in more than 1% of patients who receive ivermectin) include diarrhoea, nausea, dizziness and somnolence.4

 

Is there any evidence for using ivermectin against COVID-19?

Currently there are limited data to support the use of ivermectin for the treatment of COVID-19. There are currently no known published data from randomised, controlled clinical trials on the efficacy or safety of ivermectin for treatment of COVID-19.7

In vitro studies

While the results of a preclinical study suggest some evidence of benefit, further research is required.

A study published on 3 April 2020 by the Monash Biomedicine Discovery Institute (BDI) has shown that ivermectin produced a 99.8% reduction in cell-associated viral RNA in Vero/hSLAM cells (non-human cell line) infected with SARS-CoV-2 after 48 hours, compared to control samples. This indicated that ivermectin treatment resulted in the loss of nearly all viral material within 48 hours, with no toxicity observed at any timepoints.5

A study by Momekov et al, published on 23 May 2020, analysed the in vitro antiviral activity end-points of the Monash BDI study from a pharmacokinetic perspective. They stated that the cells infected with SARS-CoV-2 were continuously exposed to concentrations of ivermectin that are virtually unattainable, even with excessive dosing of the drug. They concluded that the experimental design is based on clinically irrelevant drug levels, with inhibitory concentrations which may be difficult to target in a clinical trial.8

On 15 July 2020, the Australian Commission on Safety and Quality in Health Care identified that while ivermectin has a well-documented safety profile, the investigators of the Monash BDI study cautioned that a safe dosage in humans needs to be established before considering treatment of patients with COVID-19.9

While this may discourage follow-up with clinical trials, Chaccour et al state that some in vivo effect may still be possible, even if efficacious in vitro concentrations are unattainable.10

Observational studies

Some evidence of a positive benefit has been described by small observational studies. However, heterogeneity among the trial designs and methodologies limits any conclusions about the utility of this medicine to date.

Note: Some of these are currently only pre-prints and have not been peer reviewed, therefore the implications of the findings may be subject to change upon review. They are summarised in the table below.

Table 2: Observational studies of patients with COVID-19 treated with ivermectin

Reference

Type of study Country

Main results

Comments

Gorial et al11

(pre-print)

Pilot observational study

Iraq

Hospitalised patients (n = 16) with mild to moderate COVID-19 received a single dose of ivermectin 200 micrograms/kg on admission day as add-on treatment to hydroxychloroquine (HCQ) daily and azithromycin (AZT). The control group (n = 71) received HCQ and AZT only.

All patients in the ivermectin group were cured compared to the controls (100% vs 97.2%). The mean time of hospital stay was significantly lower in the ivermectin group (7.62 ± 2.75 vs 13.22 ± 5.90 days, p = 0.00005).

The primary outcome was percentage of cured patients within 23 days. ‘Cured’ was defined by assessing the proportion of patients who were symptom-free and able to be discharged from hospital, with a normal body temperature for longer than 3 days, improvement of respiratory symptoms and two consecutive negative PCR test results from nasopharyngeal swabs at least 24 hours apart.

Rajter et al12

(pre-print)

Retrospective cohort study

United States

Patients with confirmed SARS-CoV-2 infection who received at least one oral dose of ivermectin 200 micrograms/kg (n = 173) at any time during hospitalisation were compared to those who received usual care (n = 107).

Univariate analysis showed lower mortality in the ivermectin group (15% vs 25.2%, OR 0.52, 95% CI 0.29-0.96, p = 0.03). Mortality was also lower in patients (n = 75) with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%, OR 0.15, CI 0.05-0.47, p = 0.001) but there was no significant difference in successful extubation rates (36.1% vs 15.4%, OR 3.11 (0.88-11.00), p = 0.07).

The primary outcome was all-cause in-hospital mortality. Patients were considered to be ‘survivors’ if they were discharged from hospital or if their status in hospital changed from active care to awaiting transfer to a skilled nursing facility. The latter outcome required that two consecutive nasopharyngeal swab specimens were negative for SARS-CoV-2, collected equal to or greater than 24 hours apart.

The effect of ivermectin on viral load was not evaluated and any impact of confounding patient factors (eg. time from diagnosis to initiation of treatment, differences in medicines used for standard care) is unknown.7

Alam et al13

Observational/cross-sectional study

Bangladesh

Patients with RT-PCR confirmed cases of SARS-CoV-2 (n = 100) were given a combination of ivermectin 200 mcg/kg as a single dose and doxycycline 100 mg daily for 10 days. After starting treatment, 50% of patients with mild to moderate cases showed symptomatic improvement between day 3 and 5. All 7 patients with severe symptoms had a reduction in their symptoms by 50% by the seventh day of treatment. Retesting was completed between 4 to 18 days after starting treatment and all patients tested negative.

There was no control group in this study.

Randomised trial

A pre-print of a randomised trial from Bangladesh by Chowdhury et al compared ivermectin and doxycycline vs HCQ and AZT in patients with mild to moderate COVID-19 infection who had tested positive for SARS-CoV-2 using RT PCR. Patients (n = 116) were randomly assigned to receive either:14

  • ivermectin 200 micrograms/kg as a single dose plus doxycycline 100 mg twice daily for 10 days (Group A), or
  • HCQ 400 mg on day one then 200 mg twice daily for 9 days, then azithromycin 500 mg daily for 5 days (Group B).

In Group A (n = 60), the recovery to negative PCR was 100% with a mean recovery duration of 8.93 days. In Group B (n = 56), the recovery rate was 96.36% with a mean recovery duration of 9.33 days. The difference between these groups was not statistically significant (p = 0.231).14

Withdrawal of studies

A pre-print study was recently deleted from the pre-print server after there were concerns about the data used by the authors of the study. The study derived data from the Surgisphere database, an analytics company who claimed to have assembled large and detailed databases that included real-time medical records from many hospitals around the world. The authors claimed that this data showed that ivermectin use in patients with COVID-19 was accompanied by a reduction in mortality.15,16

Several other articles on treatments for COVID-19 published in the New England Journal of Medicine and The Lancet were also retracted, after co-authors of the studies could not verify the validity of COVID-19 patient data extracted from Surgisphere. Investigations by The Scientist and the Guardian identified discrepancies in Surgisphere’s claims going back years. The company website has now been taken offline.17

However, despite the withdrawal of the paper discussing ivermectin, there has been a surge in the popularity of ivermectin in South America. In one example, ivermectin has now been included in the national therapeutic guidelines for COVID-19 in Peru.17

For more information around the impact of this study on ivermectin usage in South America, see The Scientist.

 

What's next?

Randomised controlled trials are needed to investigate further.

Details of ongoing and completed clinical trials related to COVID-19 that have been listed on the World Health Organization’s (WHO) International Clinical Trials Registry Platform can be found on the US Clinical Trials website.

 

What do Australian guidelines say?

The Australian guidelines for the clinical care of people with COVID-19 are maintained by the National COVID-19 Clinical Evidence Task Force.

They do not currently have any recommendations on the use of ivermectin for treatment of patients with COVID-19 infection.

The Therapeutic Goods Administration (TGA) are currently investigating ‘promotion’ of an ivermectin-based regimen for COVID-19, by gastroenterologist Professor Thomas Borody. Professor Borody, who developed triple-therapy for Helicobacter pylori infection, has recommended that GPs prescribe a triple therapy protocol using ivermectin, doxycycline and zinc. However, some of his comments are being investigated by the TGA as they potentially breach the ban on advertising COVID-19 treatments.18

 

What about international guidelines?

World Health Organization (WHO)

WHO has excluded ivermectin from its co-sponsored Solidarity Trial for COVID-19 treatments.19

The Pan American Health Organisation (PAHO), the WHO regional office for the Americas, have advised against using ivermectin for any purposes other than for those for which use is authorised.19

United States

The US Food and Drug Administration (FDA) has released a consumer FAQ about COVID-19 and ivermectin in response to concerns that consumers may be self-medicating by taking ivermectin intended for animals, as a substitute for ivermectin intended for humans. The FDA have stated that additional testing is required for use of ivermectin in patients with COVID-19.20

 

Is ivermectin recommended by doctors in Australia?

The Royal Australian College of General Practitioners (RACGP) has stated there is insufficient evidence to support ivermectin as a treatment for COVID-19.21

 

References

  1. Merck Sharp & Dohme (Australia) Pty Ltd. Ivermectin (Stromectol) product information. South Granville, NSW: MSD (Australia) Pty Ltd, 2013 (accessed 20 August 2020).
  2. Galderma Australia Pty Ltd. Ivermectin (Soolantra) cream product information. Belrose, NSW: Galderma Australia Pty Ltd, 2020 (accessed 26 August 2020).
  3. Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot 2020;73:593-602.
  4. Australian Medicines Handbook. Ivermectin. Adelaide: AMH Pty Ltd, 2020 (accessed 20 August 2020).
  5. 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.
  6. 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;443:851-6.
  7. American Society of Health-System Pharmacists. Assessment of evidence for COVID-19-related treatments: Updated 8/13/2020. United States: ASHP, 2020 (accessed 20 August 2020).
  8. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens. Biotechnology & Biotechnological Equipment 2020;34:469-74.
  9. Australian Commission on Safety and Quality in Health Care. Potential medicines to treat COVID-19. Sydney: ACSQHC, 2020 (accessed 26 August 2020).
  10. Chaccour C, Hammann F, Ramón-García S, et al. Ivermectin and COVID-19: Keeping rigor in times of urgency. Am J Trop Med Hyg 2020;102:1156-7.
  11. Gorial FI, Mashhadani S, Sayaly HM, et al. Effectiveness of ivermectin as add-on therapy in COVID-19 management (pilot trial). medRxiv 2020:2020.07.07.20145979.
  12. Rajter JC, Sherman M, Fatteh N, et al. ICON (Ivermectin in COvid Nineteen) study: Use of ivermectin is associated with lower mortality in hospitalized patients with COVID19. medRxiv 2020:2020.06.06.20124461.
  13. Alam M, Murshed R, Bhiuyan E, et al. A case sries of 100 COVID-19 positive patients treated with combination of ivermectin and doxycycline. 2020;38.
  14. Chowdhury A, Shahbaz M, Karim M, et al. A randomized trial of ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID19 patients. Bangladesh, 2020 (accessed 20 August 2020).
  15. Ledford H, Van Noorden R. High-profile coronavirus retractions raise concerns about data oversight. Nature, 2020 (accessed 26 August 2020).
  16. Packer M. Critical lessons From last week's retraction of two COVID-19 papers. United States: Medpage Today, 2020 (accessed 20 August 2020).
  17. Offord C. Surgisphere sows confusion about another unproven COVID-19 drug. The Scientist, 2020 (accessed 26 August 2020).
  18. Scholefield A. TGA launches probe as GPs urged to prescribe ivermectin 'COVID cure'. Pyrmont, NSW: AusDoc, 2020 (accessed 26 August 2020).
  19. Pan American Health Organization. Recommendation regarding the use of ivermectin as a treatment for COVID-19. USA: PAHO, 2020 (accessed 26 August 2020).
  20. US Food and Drug Administration. FDA letter to stakeholders: Do not use ivermectin intended for animals as treatment for COVID-19 in humans. USA: FDA, 2020 (accessed 26 August 2020).
  21. Lewin E. Insufficient evidence to support ivermectin as COVID-19 treatment. East Melbourne: RACGP, 2020 (accessed 20 August 2020).