by Lucy Kerr, Flavio A. Cadegiani, Fernando Baldi, Raysildo B. Lobo, Washington Luiz O. Assagra, Fernando Carlos Proença, Pierre Kory, Jennifer A. Hibberd, Juan J. Chamie-Quintero
Background: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itajaí, a southern city in Brazil in the state of Santa Catarina. The objective of this study was to evaluate the impact of regular ivermectin use on subsequent COVID-19 infection and mortality rates.
Materials and methods: We analyzed data from a prospective, observational study of the citywide COVID-19 prevention with ivermectin program, which was conducted between July 2020 and December 2020 in Itajaí, Brazil. Study design, institutional review board approval, and analysis of registry data occurred after completion of the program. The program consisted of inviting the entire population of Itajaí to a medical visit to enroll in the program and to compile baseline, personal, demographic, and medical information. In the absence of contraindications, ivermectin was offered as an optional treatment to be taken for two consecutive days every 15 days at a dose of 0.2 mg/kg/day. In cases where a participating citizen of Itajaí became ill with COVID-19, they were recommended not to use ivermectin or any other medication in early outpatient treatment. Clinical outcomes of infection, hospitalization, and death were automatically reported and entered into the registry in real time. Study analysis consisted of comparing ivermectin users with non-users using cohorts of infected patients propensity score-matched by age, sex, and comorbidities. COVID-19 infection and mortality rates were analyzed with and without the use of propensity score matching (PSM).
Results: Of the 223,128 citizens of Itajaí considered for the study, a total of 159,561 subjects were included in the analysis: 113,845 (71.3%) regular ivermectin users and 45,716 (23.3%) non-users. Of these, 4,311 ivermectin users were infected, among which 4,197 were from the city of Itajaí (3.7% infection rate), and 3,034 non-users (from Itajaí) were infected (6.6% infection rate), with a 44% reduction in COVID-19 infection rate (risk ratio [RR], 0.56; 95% confidence interval (95% CI), 0.53-0.58; p < 0.0001). Using PSM, two cohorts of 3,034 subjects suffering from COVID-19 infection were compared. The regular use of ivermectin led to a 68% reduction in COVID-19 mortality (25 [0.8%] versus 79 [2.6%] among ivermectin non-users; RR, 0.32; 95% CI, 0.20-0.49; p < 0.0001). When adjusted for residual variables, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001). There was a 56% reduction in hospitalization rate (44 versus 99 hospitalizations among ivermectin users and non-users, respectively; RR, 0.44; 95% CI, 0.31-0.63; p < 0.0001). After adjustment for residual variables, reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001).
Conclusion: In this large PSM study, regular use of ivermectin as a prophylactic agent was associated with significantly reduced COVID-19 infection, hospitalization, and mortality rates.
Ivermectin has been demonstrated to have not only extensive anti-parasitic actions [1,2], but also anti-viral, anti-bacterial, and anti-protozoan properties. Ivermectin has been long proposed for use as a repurposed antiviral agent [3-6]. Indeed, antiviral effects of ivermectin have been reported against both RNA and DNA types of viruses, including HIV-1, yellow fever, Japanese encephalitis, tick-borne encephalitis, West Nile, Zika, dengue fever, chikungunya, Venezuelan equine encephalitis, and the pseudorabies virus [3,5,7,8], as well as functioning in regulation of proteins involved in antiviral responses .
Additional actions of ivermectin described include agonism activity to the liver X receptor (LXR) and farnesoid X receptor (FXR), with multiple potential metabolic benefits [9,10]; neuronal regeneration [11,12], prevention of muscle hypoxia , and actions on specific sites, including interferon (INF) , nuclear factor-κB (NF-κB), lipopolysaccharide (LPS) , and Janus kinase/signal transducer and activator of transcription (JAK-STAT) and PAI-1 pathway [16,17]; generation of P21 activated kinase 1 (PAK-1) [18,19]; reduction of interleukin-6 (IL-6) levels ; allosteric modulation of P2X4 receptor ; inhibition of high mobility group box 1 (HMGB1) [21,22]; and suppression of mucus hypersecretion, diminished recruitment of immune cells, and production of cytokines in the lung . Ivermectin is also described to induce T helper 1 cell (Th1)-type immune response against protozoan infections , and anti-coagulant action through binding to the S protein of some viruses .
The hypothesis that ivermectin could be protective against coronavirus disease 2019 (COVID-19) is substantiated by its multi-pathway, anti-inflammatory effects [15,26], and multi-antiviral mechanisms. COVID-19 pathogenesis is largely understood as an inflammation-mediated hemagglutinating infection disrupting pulmonary, vascular, and endothelial systems, leading to a multi-systemic disease. In vitro and in silico, ivermectin has demonstrated anti-severe acute respiratory syndrome coronavirus 2 activity through more than 20 direct and indirect mechanisms [2,27,28].
Ivermectin has demonstrated preliminary protective effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in terms of reducing times to clinical recovery and rates of disease progression and mortality [2,29,30]. However, more robust studies with larger sample sizes are still recommended to confirm the possible beneficial effects of ivermectin in COVID-19.
Since the onset of the COVID-19 pandemic, the use of inexpensive options based on a consistently beneficial signal of efficacy, a well-established safety profile, and favorable cost-effectiveness, ivermectin is a highly attractive intervention for the patient-centered medicine practiced by frontline clinicians, with use aligning strongly with the bioethical principles for medical practice outlined in Article 36 of the Declaration of Helsinki .
However, despite this favorable risk/benefit profile and absence of therapeutic alternatives, ivermectin is yet to be approved for prophylaxis and treatment of COVID-19 by agencies throughout the world, including FDA (USA), European Medicines Agency (EMA; Europe), and ANVISA (Agência Nacional de Vigilância Sanitária – Brazilian Health Regulatory Agency; Brazil).
The ability to prescribe ivermectin or any other off-label drug for COVID-19 has long been at the discretion of frontline physicians once all risks, uncertainties, potential benefits, and patients’ rights are exposed, and informed consent has been obtained. Of particular note, in Brazil, this follows the medical autonomy to determine the best therapeutic strategies for individuals, as per the Medical Code of Ethics of the Brazilian Board of Medical Doctors, the Federal Council of Medicine – Conselho Federal de Medicina (CFM), that determines the obligations and rights of medical doctors in Brazil .
Since vaccines for COVID-19 were not available in Brazil until 2021, and because of the lack of prophylactic alternatives in the absence of vaccines, Itajaí, a city in the southern Brazilian state of Santa Catarina, initiated a population-wide government program for COVID-19 prophylaxis. The medical-focused decision parameters established are based on the distribution of ivermectin to whole populations in different countries. To ensure the safety of the population, a well-controlled computer program was developed to compile and maintain all relevant demographic and clinical data (detailed in the Materials & Methods section). The use of ivermectin was optional and based on patients’ preferences, given its benefits as a preventative agent was unproven.
This study’s objective is to assess the impact on important clinical outcomes when ivermectin is used as prophylaxis for COVID-19. The prophylaxis program occurred in addition to the standard non-pharmacological strategies of masking and social distancing, as part of a citywide program conducted in outpatient settings.