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Awad, H.;  Hassan, B.;  Dweek, S.;  Aboelata, Y.;  Rawas-Qalaji, M.;  Ahmed, I.S. Ivermectin for the Treatment and/or Prophylaxis of COVID-19. Encyclopedia. Available online: https://encyclopedia.pub/entry/31859 (accessed on 19 June 2024).
Awad H,  Hassan B,  Dweek S,  Aboelata Y,  Rawas-Qalaji M,  Ahmed IS. Ivermectin for the Treatment and/or Prophylaxis of COVID-19. Encyclopedia. Available at: https://encyclopedia.pub/entry/31859. Accessed June 19, 2024.
Awad, Hoda, Basmala Hassan, Sara Dweek, Yasmeen Aboelata, Mutasem Rawas-Qalaji, Iman Saad Ahmed. "Ivermectin for the Treatment and/or Prophylaxis of COVID-19" Encyclopedia, https://encyclopedia.pub/entry/31859 (accessed June 19, 2024).
Awad, H.,  Hassan, B.,  Dweek, S.,  Aboelata, Y.,  Rawas-Qalaji, M., & Ahmed, I.S. (2022, October 29). Ivermectin for the Treatment and/or Prophylaxis of COVID-19. In Encyclopedia. https://encyclopedia.pub/entry/31859
Awad, Hoda, et al. "Ivermectin for the Treatment and/or Prophylaxis of COVID-19." Encyclopedia. Web. 29 October, 2022.
Ivermectin for the Treatment and/or Prophylaxis of COVID-19
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The pathogenesis of Coronavirus Disease 2019 (COVID-19) is initiated by viral entry through the angiotensin-converting enzyme 2 (ACE-2) receptor in the host cell. After entry, RNA is translated into viral proteins upon its release in the cytoplasm. The resulting symptoms and clinical manifestations include fever, headache, myalgia, and respiratory symptoms. Several drugs have been and continue to be repurposed for the prophylaxis and treatment of COVID-19. Ivermectin (IVM) belongs to the naturally occurring family of avermectins produced by the bacterium Streptomyces avermitilis. Its broad antiparasitic spectrum is achieved through the hyperpolarization of the invertebrate’s cell membrane, with subsequent parasite paralysis. It was tested and confirmed for its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Trials have put IVM to test for both the treatment and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the targeted delivery of IVM was studied in animals and COVID-19 patients.

ivermectin COVID-19 SARS-CoV-2 coronavirus drug repurposing

1. Ivermectin Role in the Treatment of COVID-19

1.1. Therapeutic Benefit

Many trials were conducted in different countries with the aim of exploiting the therapeutic benefit of IVM in COVID-19 cases. In a randomized, controlled, double-blinded study between May and November 2020, Babalola et al. selected 62 mild-to-moderate COVID-19 patients at the Lagos University Teaching Hospital, Lagos, Nigeria, and divided them into 3 treatment groups. Over the duration of two weeks, Group A received 6 mg intravenous IVM twice a week, Group B received 12 mg intravenous IVM twice a week, and Group C received oral lopinavir/ritonavir daily and a placebo (control group). All patients showed mild symptoms, such as cough, headache, and fever. No patients were on mechanical ventilation. Group A showed a negative polymerase chain reaction (PCR) result 3.15 days prior to the control group, while group B showed a negative PCR result 4.5 days prior to the control group (p = 0.0066). It was concluded that 12 mg of intravenous IVM is significantly effective, as it showed a shortened duration of treatment. No adverse side effects were documented during this trial despite using a high dose of IVM [1].
In another study, similar outcomes on PCR negativity were reported. Mohan et al. conducted a double blinded, randomized controlled study on 125 hospitalized patients with mild-to-moderate COVID-19 in the All India Institute of Medical Sciences (New Delhi, India) between July and September 2020. Forty patients received 24 mg IVM, forty patients received 12 mg IVM, and forty-five patients received a placebo. IVM oral elixir formulation was used. No serious adverse events were recorded. Although the PCR negativity at the 5th day was high in both IVM groups (47.5% for 24 mg group, 35.0% for 12 mg group) compared to the placebo group (31.1%), these results were statistically insignificant (p = 0.30) [2].

1.2. Viral Clearance/Load

The IVM effect on the viral clearance/load of the COVID-19 patients was also studied. A pilot, randomized, controlled, outcome-assessor blinded trial by Krolewiecki et al. was conducted in 4 hospitals in Buenos Aires, Argentina, between May and September 2020. The study included 30 patients receiving 600 μg/kg/day IVM via oral tablet for 5 days and 15 patients serving as the control group. Both groups also received the standard of care which at that time included the hospitalization of all symptomatic patients. The viral load was not found to be different between the two groups; however, patients with higher IVM plasma levels exhibited significant viral load reduction (72%) compared to the control group (42%, p = 0.004). The high dose of IVM was well tolerated [3].
Another randomized controlled trial by Samaha et al. conducted between September and November 2020 involved 100 asymptomatic COVID-19 patients in Lebanon. Fifty participants received a single oral dose of IVM based on their body weight (participants with body weight of 45–64 kg, 65–84 kg, and ≥85 kg received 9 mg, 12 mg or 150 μg/kg, respectively), and fifty participants were in the control group. Both groups also received zinc and vitamin C supplements. Viral load was measured utilizing the cycle threshold indicator (Ct-values) in which a value of 30 or higher indicates an insignificant viral load. At 72 h after starting the regimen, it was found that Ct-values in the IVM group reached 30.14 ± 6.22, compared to the control group, reaching 18.96 ± 3.26 (p < 0.001). Additionally, the development of clinical symptoms was more evident in the control group [4].
Another study reported an insignificant effect on the viral load, but a significant impact on the recovery speed. In Barcelona, Spain, a double-blinded randomized control trial by Chaccour et al. was designed to test the efficacy of a single maximum dose of IVM in reducing COVID-19 transmission. Patients of Clinica Universidad de Navarra with non-severe COVID-19 participated in the trial between July and September 2020. The participants were divided randomly into two equal groups (1:1). One group (n = 12) received a single oral dose of IVM (400 μg/kg), and the second group (n = 12) received a placebo within 72 h of fever or cough onset. The viral load, infectivity, as well as the number of patients with positive PCR on day 7, were the main outcomes compared between the two groups. On day 7, there was no difference in the proportion of positive PCR patients between the two groups (12/12 and 12/12). The viral loads of the IVM group for gene E and gene N on day 4 and day 7 were lower, though the difference was non-significant compared to the placebo group (p > 0.1 for all). IgG titers in the IVM group were also non-significantly lower (p = 0.24) compared to the placebo group. However, the IVM group had a faster recovery from hyposmia/anosmia (76 patient-days) compared to the placebo group (158 patient-days) (p < 0.001). Patient-days is the unit used to measure the number of patients occupying beds in a healthcare facility for the period for which an assessment is being conducted [5].
Earlier viral clearance was also reported by some studies. In November 2020, Ahmed et al. published a randomized, double-blinded, placebo-controlled trial in Dhaka, Bangladesh, to study the efficacy and safety of oral IVM in the management of COVID-19. Seventy-two hospitalized patients were divided equally into three treatment groups. Group 1 received 12 mg of oral IVM once daily for the duration of 5 days. Group 2 received 12 mg of oral IVM as a single dose with 200 mg doxycycline on day 1 followed by doxycycline 100 mg every 12 h for 4 days. Group 3 was the placebo group. The results of the trial showed no statistically significant difference between the three groups in the recession of clinical symptoms, including fever, sore throat, and cough. However, this was not the case with the viral clearance. Groups 1 and 2 experienced earlier viral clearance (9.7 days and 11.5 days respectively), compared to Group 3 (12.7 days). The number of days for viral clearance was significantly lower in Group 1 compared to Group 3 (p = 0.02), unlike Group 2 (p = 0.27). Overall, the five-day course of IVM showed faster viral clearance, which suggests the potential role of IVM in the management of COVID-19 [6].

1.3. Symptoms Resolution/Hospitalization Length

On the other hand, some studies concluded that IVM has an insignificant role in COVID-19 treatment when it comes to clinical manifestations and health state. In Mexico, Gonzalez et al. conducted a randomized, controlled, double-blinded trial measuring the length of hospitalization in severe COVID-19 patients between April and August 2020. This trial involved 106 participants who were divided into 3 groups: IVM, HCQ, and a placebo group. Group 1 was treated with oral IVM (12 mg in patients weighing <80 kg and 18 mg in those >80 kg), group 2 received HCQ 400 mg every 12 h on the 1st day, followed by 200 mg every 12 h for four days, and group 3 received a placebo. This research concluded that there was no significant difference between the three groups in the duration of hospitalization, with an average of 7 days for HCQ group, 6 days for IVM group, and 5 days for the placebo. There was also no significant difference between the three groups in the respiratory deterioration or death [7].
Another trial that took place between March and October 2020 by Abd-Elsalam et al. tested the antiviral potential of IVM compared to standard care in mild to moderate COVID-19 patients hosted in Tanta and Assiut University Hospitals, Egypt. The trial used a 1:1 randomized, open-label parallel-group design. The IVM group (82 participants) received a single oral dose of IVM tablets (12 mg/day) for 3 days, after which the Egyptian standard protocol care was added, while the control group (82 participants) received the Egyptian standard protocol care alone for 14 days. The Egyptian standard protocol included an empiric antibiotic, oseltamivir (if needed), paracetamol, oxygen, and mechanical ventilation in case of PaO2 (partial pressure of oxygen in arterial blood) less than 60 mmHg. The results showed a shorter hospital stay for the IVM group (8.82 ± 4.94 days) in comparison with the control group (10.97 ± 5.28 days). However, these results lacked statistical significance (p = 0.085). In both groups, three patients needed mechanical ventilation. The mortality rates in both groups were not significantly different with 3.7% in the IVM group, compared to 4.9% in the control group (p = 1.00). Overall, despite the outcomes bearing no significant difference, the study did observe a pattern of shortened hospitalization periods in the IVM group [8].
Similarly, López-Medina conducted a double-blinded randomized trial in Cali, Colombia, on 400 patients with mild COVID-19 between July and December 2020. One group of 200 patients received 300 μg/kg of oral IVM (as a solution) per day for 5 days, and 200 patients received a placebo. The difference in time to symptoms resolution was statistically insignificant between both groups (10 days in the IVM group compared to 12 days in the placebo group) [9].
Lastly, in Corrientes, Argentina, during the period between August 2020 and February 2021, Vallejos et al. carried out a randomized, double-blinded, placebo-controlled trial to determine whether the use of IVM can help with hospitalization prevention in patients with early COVID-19. The study was conducted on 501 patients. Two hundred and fifty of these patients were randomized into a weight-based dose of oral IVM for 2 days (participants with body weight of ≤80 kg, >80 to ≤110 kg, and >110 kg received 12 mg, 18 mg, or 24 mg, respectively) and the rest took placebo treatment. The results showed no significant difference in hospitalization prevention with 14 patients (5.6%) of the IVM group requiring hospitalization compared to 21 patients (8.4%) in the control group. However, hospitalized patients that used IVM required invasive mechanical ventilation earlier compared to those on placebo. Therefore, the authors concluded that there was no significant effect of IVM on hospitalization prevention in COVID-19 patients [10]. A summary of the reviewed studies on the role of IVM in the COVID-19 treatment is included in Table 1.

2. Ivermectin Role in the Prophylaxis against COVID-19

Treating COVID-19 with IVM was not the only question of interest in the conducted research. Many studies were conducted and continue to investigate the potential role of IVM as a chemoprophylactic agent in COVID-19. A clinical randomized open label-controlled trial was conducted by Shoumann et al. at the University of Zagazig, Egypt, to investigate the use of IVM as prophylactic therapy in COVID-19 during June and July 2020. Three hundred four asymptomatic participants were enrolled. All the participants were in close contact with confirmed COVID-19 family members. The participants were divided into two groups. The IVM group included 203 asymptomatic participants who received the first dose of oral IVM ranging between 200 and 300 μg/kg on the enrollment day and an equal second dose on the third day. In the non-intervention group, no treatment was provided to 101 asymptomatic participants. The groups were followed-up for a 2-week period for the common symptoms, complete blood count (CBC), and C-reactive protein (CRP). PCR tests were conducted after the follow-up period and showed that 59 participants (58.4%) tested positive for COVID-19 in the non-intervention group. On the other hand, only 15 participants (7.4%) tested positive in the IVM group. This research reported that there was a 2-day delay in symptoms development in the IVM group, compared to the control group. IVM protection was more noticeable in participants less than 60 years old. Differences between the two groups in terms of outcomes were highly significant (p = 0.001) [11].
A protection program in Itajaí, Brazil, reported by Kerr et al., investigated the role of IVM in COVID-19 prophylaxis during January 2022. This was an observational prospective study that included 159,561 citizens. They were divided into two major groups: the IVM group and the control group. The IVM group included 113,845 participants who received a dose of 200 μg/kg of IVM as a prophylactic treatment for 2 consecutive days. The control group consisted of 45,716 participants who did not receive any prophylactic agents. After 15 days of taking IVM, only 4311 (3.9%) tested positive for COVID-19, while 3034 (6.6%) were reported positive from the control group. According to the findings of this research, there was an observed reduction in the infection rate by 44%, the mortality rate by 68%, and the hospitalization rate by 67% in the IVM prophylaxis group, compared to the control group (p < 0.0001 for all). After this research and considering the benefit and risk analysis, the authors are waiting for the approval of using IVM by agencies throughout the world, such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA) [12].
Apart from the aforementioned trials, studies investigating the prophylactic role of IVM were mostly conducted in a retrospective manner. A trial was conducted in Africa investigating COVID-19 infection rates among countries which have either participated in the earlier African Program for Onchocerciasis Control (APOC) and those which did not (non-APOC). APOC was a mass onchocerciasis prevention program which began in 1989 and continued until 2015. The program distributed IVM to a total of 19 countries and treated 90 million individuals annually. The study demonstrated significantly lower COVID-19 infection rates, as well as significantly lower mortality in APOC countries, compared to non-APOC [13].
Similarly, in the period between June and July 2020, Morgenstern et al. conducted an observational retrospective cohort study in Punta Cana, Dominican Republic, to evaluate the pre-exposure prophylactic effect of IVM in 271 healthcare personnel who adhered to a weekly oral dose of 200 μg/kg of IVM versus a control group of another 271 healthcare personnel who did not adhere to such regimen. After 28 days of follow-up, the IVM exposed group showed statistically significant prophylaxis against the infection with only 1.8% of the personnel developing COVID-19 compared to 6.6% in the control group (p = 0.006). The results suggest that the preventive use of a weekly oral IVM dose could be an option for healthcare workers and as an adjunct to immunization [14].
Additionally, a hospital-based matched case-control study in AIIMS Bhubaneswar, India, conducted by Behera et al. from September to October 2020 on 372 individuals, showed that two oral doses of 300 μg/kg IVM, 72 h apart, taken as a prophylactic agent reduced the COVID-19 infection by 73% in healthcare workers within the subsequent month [15].
Another study by Hellwig and Maia in October 2020 explored the impact on COVID-19 patients associated with the prophylactic administration of IVM. They gathered data from countries that utilize IVM as part of their prophylactic chemotherapy (PCT) campaign and countries which do not include IVM in the PCT and compared both to countries that do not deploy PCT at all. The incidence of COVID-19 was significantly lower (p < 0.001) in populations that previously received IVM compared to populations without PCT, while it showed lower but statistically insignificant incidence in populations receiving PCT without IVM [16]. A summary of the reviewed studies on the role of IVM in the prophylaxis against COVID-19 is included in Table 2.

References

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