Ivermectin for the Treatment and Prophylaxis of Covid-19: Does it Work?

By Mayuri Ramnarain MBChB IV and Kaylee Stella Harris MBChB III

Figure 1 ⁽¹⁾

The anti-parasitic drug ivermectin has divided the medical community in South Africa, with some medical practitioners arguing that it can prevent and treat Covid-19 while others refute this. As South Africa’s vaccination rollout progresses, the Covid-19 pandemic continues. Ivermectin is a cheap drug (retailed at about R57.00 for a pack of 10 pills before the drug was propounded to treat Covid-19)(2),it was widely used, and approved, for the past 50 years in animals and humans against diseases like lymphatic filariasis and onchocerciasis. Proponents of the drug maintain that ivermectin has a long history of safe use in humans. Moreover, largely anecdotal evidence regarding its efficacy has been referred to as the basis for administration.(3)

Proposed Mechanism of Action

Reports from in vitro studies propose that ivermectin inhibits the patient’s importin alpha (IMP alpha) and beta-1 nuclear transport proteins. These transport proteins are used in an intracellular process which SARS-CoV-2 takes over to augment infection by suppressing the patient’s antiviral immune response. Furthermore, ivermectin may block the attachment of the SARS-CoV-2 spike protein to the patient’s cell membrane. Ivermectin has also been studied in vitro against viruses such as Zika, HIV and yellow fever. Even though ivermectin has broad-spectrum activity in vitro against these viruses, no clinical trials have reported any clinical benefit in these patients. Some studies have also indicated that ivermectin has potential anti-inflammatory properties, which could be beneficial in helping Covid-19 patients fight off the viral infection.(4)

Figure 2: Ivermectin inhibits SARS-CoV-2 protein transport to the nucleus⁽⁵⁾

Dosage and Side Effects

In April 2020 Caly et al. reported that ivermectin has the ability to inhibit the replication of SARS-CoV-2 in vitro⁽⁶⁾. However, pharmacokinetic and pharmacodynamic studies suggest that in order to achieve the plasma concentrations necessary for the antiviral efficacy detected in vitro, ivermectin doses up to 100 times higher than those currently approved for human use would be required. Even though ivermectin seems to accumulate within the lung, the predicted plasma and lung tissue concentrations are significantly lower than 2µM (which is the half-maximal inhibitory concentration against SARS-CoV-2 in vitro). On the down side, the side effects of ivermectin include nausea, emesis, diarrhoea, abdominal pain, oedema, neurologic adverse events, hypotension, hepatitis and severe skin rash which could require hospitalisation.⁽⁴⁾

The State of Research

Several trials have been conducted. Specific examples include that of Caly et al (discussed above)⁽⁶⁾. Furthermore, in a preprint published in February 2021, Beltran- Gonzalez et al. stated that “In non-critical hospitalised patients with Covid-19 pneumonia, neither ivermectin nor hydroxychloroquine decreases the number of in-hospital days, respiratory deterioration, or deaths”⁽⁷⁾. One of the most recent randomised controlled trials, published in the Journal of the American Medical Association (JAMA), reports that ivermectin does not decrease the recovery time in people with mild cases of Covid-19. This study by López-Medina et al. indicated that Covid-19 symptoms lasted an average of 10 days in patients who received ivermectin, compared with 12 days among those who received the placebo, a statistically insignificant difference.⁽⁸⁾ A notable question, not answered by this trial, is whether hospitalisation or death could be prevented by ivermectin, especially in medically vulnerable populations much as the elderly or those with comorbidities. Despite several trials being conducted, the key issue is that many studies contain incomplete information and significant methodological limitations. These limitations include sample size being too small, different doses used, neither participants nor investigators being blinded, the simultaneous use of other medications, the severity of Covid-19 not being well described and outcomes not clearly defined⁽⁴⁾. This has greatly hindered the ability of medical approval bodies to satisfactorily review and conclude whether ivermectin is indeed effective for the prophylaxis and treatment of Covid-19.

Figure 3: Summary of findings for the study by López-Medina et al ⁽⁸⁾

1. Recommendations by Medical Regulatory BodiesEuropean Medicines Agency (EMA)

The EMA determined that the available data does not support its use for Covid-19 outside well-designed clinical trials. Ivermectin is therefore not authorised for use in Covid-19 in the European Union.⁽⁹⁾

2. US National Institutes of Health (NIH)

The NIH established that there is inadequate data to recommend for or against the use of ivermectin for the treatment of Covid-19. Results from larger scale, well-designed, and well-conducted clinical trials are needed to provide evidence-based guidance.⁽⁴⁾

3. South African Health Products Regulatory Authority (SAHPRA)

SAHPRA has stated that there is inadequate evidence to recommend for or against the use of ivermectin in the prevention or treatment of Covid-19. Furthermore, the regulatory bodies with which SAHPRA is aligned have not recommended the use of ivermectin in the management of Covid-19. In the meantime, SAHPRA has implemented a compassionate use access program so that medical practitioners may apply for approval of access to unregistered ivermectin for individual patients. This program will also be used to collect data on the use of ivermectin for Covid-19 via the COVI-VIG reporting platform, therefore increasing the amount of available data to determine whether ivermectin is effective in treating Covid-19 or not.⁽¹⁰⁾ In spite of the recommendations of these medical regulatory bodies, the price of ivermectin has risen from R57.00 to an alarming R350.00 per 10 pill pack as South Africa’s animal ivermectin supply is bought up.^{(2, 11)}

In conclusion, larger scale and more robust clinical trials are needed to determine the effect of ivermectin for the prophylaxis and treatment of Covid-19. In the meantime, and in the absence of widespread access to vaccines, proven epidemiological tools such as large-scale track and tracing and strengthening of public health measures regarding the prevention of Covid-19, mask wearing, hand washing and social distancing remain our first line of defence. Currently, there is no drug to effectively replace these measures.

Use the following University of Pretoria library link to read the full article:

https://UnivofPretoria.on.worldcat.org/oclc/8570931877

References

1. Susan J. Don’t Stop Taking ‘Immunosuppressive’ Medication During the COVID-19 Pandemic: A Plea from Doctors Who Are Studying COVID-19 in Inflammatory Diseases: Creaky Joints; 2021 [Available from: https://creakyjoints.org/living-with-arthritis/coronavirus/treatments/dont-stop-disease-modifying-immunosuppressive-medication-covid-19-pandemic/.
2. Ivermectin: South African medics using unproven worm drug to treat Covid-19. BBC News [Internet]. 2021 Mar 27 [cited 2021 Mar 27]; Available from: https://www.bbc.com/news/world-africa-56526632
3. Fihlani P. Ivermectin: South African medics using unproven worm drug to treat Covid-19: BBC; 2021 [Available from: https://www.bbc.com/news/world-africa-56526632.
4. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed 6 May 2021.
5. Mudatsir M, Yufika A, Nainu F, Frediansyah A, Megawati D, Pranata A, et al. Antiviral Activity of Ivermectin Against SARS-CoV-2: An Old-Fashioned Dog with a New Trick—A Literature Review. Scientia Pharmaceutica. 2020;88(3):36.
6. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral research. 2020;178:104787.
7. Gonzalez JLB, González Gámez M, Enciso EAM, Maldonado RJE, Hernández Palacios D, Dueñas Campos S, et al. Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial. medRxiv. 2021:2021.02.18.21252037.
8. López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021.
9. EMA advises against use of ivermectin for the prevention or treatment of COVID-19 outside randomised clinical trials 2021 [Available from: https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-19-outside-randomised-clinical-trials.
10. SAHPRA Update on the use of Ivermectin in the Prevention or Treatment of Covid-19 2021 [Available from: https://www.sahpra.org.za/press-releases/update-on-the-use-of-ivermectin-in-the-prevention-or-treatment-of-covid-19/.
11. Dealers are “standing by” with R35 ivermectin tablets, as SA’s animal supplies dry up [Internet]. BusinessInsider. 2021 [cited 2021 May 12]. Available from: https://www.businessinsider.co.za/ivermectin-for-human-use-can-be-sold-very-soon-supplies-say-as-regulators-okay-very-limited-use-2021-1