By: Isabelle Lim, PharmD Candidate c/o 2024 and Justin Budz, PharmD Candidate c/o 2023

Coronavirus disease 2019 (COVID-19) is an illness caused by severe acute respiratory system coronavirus 2 (SARS-CoV-2) that primarily affects the respiratory system.¹ In order to enter human cells, the virus’ spike protein receptor-binding domain (RBD) must bind to a cell membrane-bound angiotensin-converting enzyme 2 (ACE2) before endocytosis can begin.² Once bound to its receptor, the RBD is activated by human proteases, including transmembrane serine protease 2 (TMPRSS2) and lysosomal protease cathepsins, which allows for the fusion of SARS-CoV-2 into the cell cytoplasm.² Inside the cell, the virus can enter the cell nucleus via a transport pathway mediated by the importin (IMP) α/β1 heterodimer.³ It is necessary for the virus to cross into the nucleus to replicate and further carry out its infection of the host.

Current Treatment Guidelines for COVID-19

The COVID-19 Treatment Guidelines Panel strongly recommends symptom treatment as the primary form of management in all nonhospitalized adults with mild to moderate COVID-19 who do not require supplemental oxygen. These patients are urged to utilize over-the-counter (OTC) medications to decrease the severity of typical symptoms including fever, headache, muscle pain, and cough.⁴ Nonhospitalized patients at high risk of advancing to severe COVID-19 should also receive Paxlovid (ritonavir-boosted nirmatrelvir) or Veklury® (remdesivir), with the former receiving a stronger recommendation than the latter.⁴ Alternatively, Lagevrio (molnupiravir) may be considered for use when the aforementioned medications are unavailable or inappropriate for the patient.⁴

Role of Ivermectin in Treatment of COVID-19

Since the emergence of COVID-19, medical experts have scrambled to find efficacious modes of treatment. Some focused on developing novel antivirals, while others explored the option of repurposing existing medications. Ivermectin, a well-known antiparasitic agent, rapidly became a drug product of interest in those seeking anti-COVID-19 therapy during the height of the pandemic. Oral ivermectin tablets are indicated for the treatment of strongyloidiasis of the intestinal tract as well as onchocerciasis.⁵ Ivermectin acts by selectively binding to glutamate-gated chloride ion channels found in the nerve and muscle cells of invertebrates such as nematodes. Once bound, the cell’s membrane becomes increasingly permeable to chloride ions, leading to hyperpolarization of the cell and ultimately, the paralysis and death of the parasite.⁵

Thus far, ivermectin has not been approved by the Food and Drug Administration (FDA) for the treatment of any viral disease.⁶ However, it possesses many properties holding potential for the treatment of viruses, including COVID-19. One of ivermectin’s unique antiviral mechanisms of action involves preventing SARS-CoV-2 from entering host cells by inhibiting attachment of the virus’ spike protein to cell-membrane bound ACE2.⁸ Additionally, ivermectin has shown to inhibit IMPα/β1-mediated nuclear import of viruses, and consequently, viral replication.⁷ Furthermore, it is hypothesized that those infected with COVID-19 can benefit from ivermectin’s anti-inflammatory effects.⁶

In response to the surge in demand for ivermectin based on its observed potential as an effective antiviral, many states have felt the need to increase the accessibility of the medication. To do so, some states began to allow pharmacists to dispense ivermectin without a valid prescription, despite the lack of concrete evidence supporting its use in patients with COVID-19. In March 2022, the state of New Hampshire proposed a bill which would allow pharmacists to dispense ivermectin through a standing order. The bill was approved by New Hampshire’s Senate and House of Representatives but was ultimately vetoed by Governor Sununu.⁹ New Hampshire representatives supporting the bill justified it as a way to prevent people from using inappropriate, and possibly harmful, formulations of ivermectin. One New Hampshire House Representative, Mark Pearson, stated that some individuals, after not having access to prescription ivermectin, had begun to seek alternative forms of ivermectin intended for use in livestock.¹⁰ In April 2022, Tennessee followed suit by passing a bill allowing ivermectin to be sold as an OTC medication pursuant to a collaborative agreement with a physician.¹¹ The sponsor of this bill, Senator Frank Nicelely, stated it would be much safer for patients to have access to OTC ivermectin and be able to consult a pharmacist in terms of dosing rather than having to resort to guessing “what size horse [they] are” when considering veterinary formulations.¹²

A pre-clinical trial done by Caly et al. demonstrated ivermectin’s ability to reduce the spread of infection of SARS-CoV-2, adding to the support of ivermectin as a possible treatment option for COVID-19.¹³ In this in vitro study, infected cells treated with 5 μM of ivermectin showed a 93% decrease in SARS-CoV-2 RNA levels after 24 hours and a subsequent ~5000-fold decrease after 48 hours.¹³ However, it is important to note that 5 μM of ivermectin would be equivalent to 100-times the plasma concentration of a patient on 200 mcg/kg of ivermectin, which is a standard dose used in the treatment of onchocerciasis.¹⁴ Although the ability to achieve similar plasma concentrations in humans is not possible with currently approved ivermectin dosing, this study acknowledges that ivermectin does hold activity against SARS-CoV-2 in vitro and could potentially be clinically effective. Soon after the results of Caly et al. were published, additional clinical trials were conducted to further assess the safety and efficacy of ivermectin in the treatment of COVID-19.

Literature Review: IVERCOR-COVID19 Study

The Ivermectin to Prevent Hospitalization in Patients with COVID-19 (IVERCOR-COVID19) study was a randomized, double-blind, placebo-controlled clinical trial done in Corrientes, Argentina to determine whether ivermectin would be effective in preventing the hospitalization of patients with early onset COVID-19.¹⁵ Patients over 18 years old with a positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test result within the last 48 hours were recruited to participate in the trial. Those that required supplemental oxygen or were concomitantly using hydroxychloroquine, chloroquine or other antiviral drugs were excluded from the study. Individuals who had used ivermectin within a week before randomization were also not included.¹⁵

A total of 501 patients were randomized to either the ivermectin plus standard of care (SOC) arm (n = 250) or the placebo plus SOC arm (n = 251). The ivermectin group received staggered weight-based doses of ivermectin. Those that weighed ≤ 80 kg received 12 mg (two 6 mg tablets) of oral ivermectin at the time of inclusion and then again 24 hours after, for a total of 24 mg. Similar dosing schedules were given in subsequent weight groups, with only a change in dose. The dose for those weighing 80 to 110 kg was 18 mg (three tablets), for a total of 36 mg. Lastly, those weighing ≥ 110 kg received 24 mg (four tablets), for a total dose of 48 mg. Participants in the placebo group received the corresponding number of placebo tablets to the ivermectin weight-based regimen, both at baseline and 24 hours after.¹⁵

The primary outcome of this study measured was the number of hospitalizations in patients with COVID-19.¹⁵ 14 individuals (5.60%) from the ivermectin group and 21 individuals (8.37%) from the placebo group required hospitalization within any point of the trial. The difference in hospitalization rates between ivermectin and placebo was not statistically significant (Odds Ratio [OR] 0.65; 95% Confidence Interval [CI] 0.32 to 1.31; p = 0.227), indicating that ivermectin had no significant effect in preventing hospitalization in patients with mild to moderate COVID-19.¹⁵

Literature Review: I-TECH Study

The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted across 20 public hospitals and 1 COVID-19 quarantine center all located in Malaysia.¹⁶ This study looked to determine the efficacy of ivermectin in preventing the progression to severe COVID-19 in high-risk populations with mild-to-moderate COVID-19. Participants of the study had to be at least 50 years old, have at least 1 comorbidity, and produce a positive SARS-CoV-2 RT-PCR test or antigen test within 7 days of their symptom onset.¹⁶ Individuals were excluded from the study if they required supplemental oxygen, had a pulse oximetry oxygen saturation (SpO₂) level less than 95% at rest, or had severe hepatic impairment (alanine transaminase (ALT) level greater than 10 times that of the upper limit of normal). They were also not to have a history of anti-COVID-19 drug use, including ivermectin use, in the past 7 days.¹⁶

During this trial, 500 patients were randomized in a 1:1 ratio into either the treatment group, which received 400 mcg/kg of oral ivermectin plus SOC (n = 241), or the control group, which received only SOC (n = 249). Participants in the treatment group received a dosage of ivermectin based on weight and rounded to the nearest 6 mg or 12 mg tablet, with a total treatment duration of 5 days.¹⁶

The primary outcome of this study was the proportion of patients who progressed to severe COVID-19, defined as having hypoxia and requiring supplemental oxygen to maintain a SpO₂ of 95% or greater.¹⁶ Of the 490 patients included in the primary analysis, 52 participants (21.6%) from the treatment group progressed to severe COVID-19 versus 43 participants (17.3%) from the control group (Relative Risk [RR] 1.25; 95% CI 0.87 to 1.80; p = 0.25).¹⁶ These results lacked statistical significance, but still suggest that ivermectin was not able to reduce the risk of progression to severe COVID-19 in high-risk populations.¹⁶

Literature Review: RIVET-COV Study

The Single-Dose Oral Ivermectin in Mild and Moderate COVID-19 (RIVET-COV) study was a pilot, double-blind, three-arm, placebo-controlled randomized control trial conducted at the COVID-19 facility of the National Cancer Institute in New Delhi, India.¹⁷ This study aimed to determine the safety and efficacy of ivermectin elixir in the treatment of COVID-19. Individuals over 18 years old were considered for the study if they had non-severe COVID-19, confirmed by a positive SARS-CoV-2 RT-PCR or rapid antigen test and an SpO₂ greater than 90%.¹⁷ Patients were excluded if they had a creatinine clearance (CrCl) < 30 mL/min, elevated transaminase levels (> 5 times the upper limit of normal), or any severe comorbidities.¹⁷

In this study, 157 patients were randomized in a 1:1:1 ratio to receive either 12 mg of ivermectin (n = 40), 24 mg of ivermectin (n = 40), or placebo (n = 45). Ultimately, 125 patients received a positive SARS-CoV-2 RT-PCR on the day of enrollment and were included in the modified intention-to-treat (mITT) group. Of this population, 80 patients (64%) had mild COVID-19 and 45 (36%) had moderate COVID-19.¹⁷

The two primary outcomes of this trial assessed the proportion of participants that achieved negative RT-PCR results, as well as attained a decreased viral load (VL) at day 5 of enrollment. Regarding negative RT-PCR results by day 5, 47.5% of the ivermectin 24 mg arm had tested negative on a RT-PCR test, versus 35.0% from the ivermectin 12 mg arm and 31.1% from the placebo arm. These results were found to not be statistically significant (p = 0.3).¹⁷ Upon conclusion of the study, data also demonstrated a decrease in VL by day 5 across all arms. The VL of the ivermectin 24 mg, ivermectin 12 mg, and placebo groups decreased by 3.05 (SD 2.50), 3.04 (SD 2.05), and 3.08 (SD 1.98) log₁₀ viral copies/mL between day 0 to 5, respectively. However, these results were again found to not be statistically significant (p = 0.76).¹⁷ It was determined that the use of ivermectin elixir, regardless of dosage, was unable to show significant trends in producing negative RT-PCR results and declines of SARS-CoV-2 VL in patients with mild to moderate COVID-19.¹⁷

Literature Review: COVER Study

The High-Dose Ivermectin for Early Treatment of COVID-19 (COVER) study was a randomized, investigator-initiated, double-blind, phase 2, dose-finding, proof-of-concept clinical trial conducted with adult patients that were diagnosed with COVID-19 across four sites in Italy.¹⁸ Those recruited had to confirm SARS-CoV-2 infection through a positive real-time RT-PCR test and had to be asymptomatic or oligosymptomatic, without hospitalization or the need for supplemental oxygen.¹⁸ Individuals were excluded from the study if they had any central nervous system (CNS) disease; required dialysis; or used warfarin, antiviral treatment, chloroquine, or hydroxychloroquine.¹⁸

93 participants were randomized in a 1:1:1 ratio in arms A, B, and C. Individuals in arm A (n = 32) received placebo, while those in arm B (n = 29) received 600 mcg/kg of ivermectin and placebo for 5 days, and those in arm C (n = 32) received 1200 mcg/kg of ivermectin for 5 days.¹⁸

The primary outcome of this study evaluated the number of serious adverse drug reactions (SADRs) that occurred and the mean log­­₁₀ reduction in VL on day 7 of the trial. Regarding the number of SADRs, none were reported by day 7.¹⁸ However, it is important to note that of the 14 participants who discontinued treatment, 11 of them were from the high dose ivermectin treatment arm and stated intolerability as their reason for discontinuation.¹⁸ As for change in VL by day 7, reductions of 2.0, 2.5, and 2.9 were noted in arms A, B, and C, respectively. These reductions were not significant, with results from arm C having a p-value of 0.066 and Arm B having a p-value of 0.122.¹⁸ Although this study shows that high doses of ivermectin can be considered safe, there was no clear clinical benefit observed in its administration for the treatment of COVID-19.¹⁸

Conclusion

It is imperative that pharmacists remain diligent in keeping up to date with treatment guidelines, especially in the case of COVID-19 where the treatment landscape is continuously evolving. As seen throughout the pandemic, it is easy for misinformation to spread quickly and influence the minds of many. Although ivermectin was once popularized for the belief that it could potentially cure COVID-19, the aforementioned clinical trials indicate that ivermectin has no clinical benefit in the management or treatment of COVID-19. Pharmacists should urge against the use of ivermectin and instead recommend OTC analgesics, antipyretics, and/or antitussives for the management of COVID-19 symptoms, as well as considering ritonavir-boosted nirmatrelvir, remdesivir, or molnupiravir for those at high risk of progressing to severe COVID-19.

References

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9. Cushman L. HB1022 (2022) detail. New Hampshire Liberty Alliance Bills. https://bills.nhliberty.org/bills/2022/HB1022. Published 10/29/2021. Last Updated 09/15/2022.
10. Sexton A. New Hampshire House approves Bill to allow pharmacists to dispense ivermectin for COVID-19. WMUR. https://www.wmur.com/article/new-hampshire-house-bill-pharmacists-dispense-ivermectin-covid-19/39456443. Published March 16, 2022.
11. Niceley F. SB2188. Tennessee General Assembly. https://wapp.capitol.tn.gov/apps/BillInfo/default.aspx?BillNumber=SB2188&GA=112. Published 01/31/2022. Last Updated 04/26/2022.
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15. Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis. 2021;21(1):635. Published 2021 Jul 2. doi:10.1186/s12879-021-06348-5
16. Lim SCL, Hor CP, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial [published correction appears in JAMA Intern Med. 2022 Jun 1;182(6):690]. JAMA Intern Med. 2022;182(4):426-435. doi:10.1001/jamainternmed.2022.0189
17. Mohan A, Tiwari P, Suri TM, et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. J Infect Chemother. 2021;27(12):1743-1749. doi:10.1016/j.jiac.2021.08.021
18. Buonfrate D, Chesini F, Martini D, et al. High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Int J Antimicrob Agents. 2022;59(2):106516. doi:10.1016/j.ijantimicag.2021.106516

Published by Rho Chi Post