The Place of Ivermectin in the Management of Covid-19: State of the Evidence

Abstract

Background and aims. The covid 19 pandemic necessitated the use of old, repurposed, and new drugs, in addition to vaccines and public health measures. There are still many controversies about the efficacy and impact of some of the medications used, which need further elucidation. We review the pharmacological properties and the place of the repurposed drug, Ivermectin (IVM) in the prophylaxis and treatment of SARS - CoV- 2 (severe acute respiratory syndrome coronavirus 2.) infection or Covid 19 disease. Major findings: in-vitro, in-vivo, and human studies In vitro studies in Vero/hSlam cells caused a 99.98 % inhibition of SARS - Cov-2 (5000-fold) within 48 hours. The IC50 (half maximal inhibitory concentration) for this virucidal action was 2.8μM, which was thought unattainable in humans in-vivo. Thus, there was initial skepticism on pharmacokinetic grounds as to possible efficacy of IVM in humans with Covid 19. There are, however, a multiplicity of anti-covid 19 mechanisms, beyond mere anti-viral effects, such as blockade of ACE2 receptor viral entry, and the anti-cytokine and anti-inflammatory effects of IVM. IVM has a long half-life of 18 - 24 hours, Mean Residence Time (MRT) of 3.4 days and a preferential site of lung accumulation. In-vivo studies in Syrian Golden hamsters confirmed the symptomatic, anti-inflammatory, anti-cytokine, histopathological and survival benefit of IVM, which was more manifest in female animals. In a January 2023 meta-analysis of studies (s) in total number of patients (n) for various parameters (p), the reduction in risk relative to placebo or controls were as follows: Overall improvement (s= 95) (n= 134,554) was 62% [95%CI 54-69]. Mortality (s=48) (n=120,000) there was 51% reduction [95%CI 37-62]. Hospitalization (s=29) (n = 44, 784), there was 34% reduction [ 95% CI 20-45]. Viral clearance (s=20) (n= 3945) there was 45% reduction [95%CI 31-55]. Prophylaxis (s=17) (n=19,764) showed 82% reduction [95%CI 73-88] 6 Randomised Control Trial (RCT) studies (s= 45) (n=2173) showed a 54 % mortality reduction [95% CI 39-65] In addition, IVM has been shown in studies to cause a rapid reversal of hypoxemia (SPO2 < 94%) and a rapid increase in SPO2, an effect exhibiting a gender dichotomy. (SPO2 is the percentage of the maximum carrying capacity of the blood). This effect on SPO2 has been attributed to IVM’s reversal and prevention of SARS-CoV-2 virus induced hemagglutination. The dosage used for treatment of covid 19 varied widely within studies, but doses of 200-400 μg/kg twice weekly or daily for 5 consecutive days, caused significant viral clearance and clinical improvement, with minimal safety concerns. For prophylaxis, a dose of 200μg/kg for two consecutive days every 15 days was found effective in studies. Conclusion: This review provides powerful evidence that IVM is efficacious singly or as a part of a regimen for covid 19. IVM could potentially be combined with newer oral anti-covid 19 agents, such as Paxlovid, for effective and life-saving regimen in patients infected with covid-19. The anti-viral properties of these drugs can synergize with the anti-inflammatory and anti-cytokine properties of Ivermectin. Ivermectin is also useful prophylactically, especially where vaccines are unavailable or undesirable.