RESUMO
Introduction In 2020, nations hastened to contain an emerging COVID-19 pandemic by deploying diverse public health approaches, but conclusive appraisals of the efficacy of these approaches are elusive in most cases. One of the medicines deployed, ivermectin (IVM), a macrocyclic lactone having biochemical activity against SARS-CoV-2 through competitive binding to its spike protein, has yielded mixed results in randomized clinical trials (RCTs) for COVID-19 treatments. In Peru, an opportunity to track the efficacy of IVM with a close consideration of confounding factors was provided through data for excess deaths as correlated with IVM use in 2020, under semi-autonomous policies in its 25 states. Methods To evaluate possible IVM treatment effects, excess deaths as determined from Peruvian national health data were analyzed by state for ages ≥60 in Peru's 25 states. These data were compared with monthly summary data for excess deaths in Peru for the period 2020-2021 as published by the WHO in 2022. To identify potential confounding factors, Google mobility data, population densities, SARS-CoV-2 genetic variations, and seropositivity rates were also examined. Results Reductions in excess deaths over a period of 30 days after peak deaths averaged 74% in the 10 states with the most intensive IVM use. As determined across all 25 states, these reductions in excess deaths correlated closely with the extent of IVM use (p<0.002). During four months of IVM use in 2020, before a new president of Peru restricted its use, there was a 14-fold reduction in nationwide excess deaths and then a 13-fold increase in the two months following the restriction of IVM use. Notably, these trends in nationwide excess deaths align with WHO summary data for the same period in Peru. Conclusions The natural experiment that was put into motion with the authorization of IVM use for COVID-19 in Peru in May 2020, as analyzed using data on excess deaths by locality and by state from Peruvian national health sources, resulted in strong evidence for the drug's effectiveness. Several potential confounding factors, including effects of a social isolation mandate imposed in May 2020, variations in the genetic makeup of the SARS-CoV-2 virus, and differences in seropositivity rates and population densities across the 25 states, were considered but did not appear to have significantly influenced these outcomes.
RESUMO
Background We have previously demonstrated that ivermectin used as prophylaxis for coronavirus disease 2019 (COVID-19), irrespective of the regularity, in a strictly controlled citywide program in Southern Brazil (Itajaí, Brazil), was associated with reductions in COVID-19 infection, hospitalization, and mortality rates. In this study, our objective was to determine if the regular use of ivermectin impacted the level of protection from COVID-19 and related outcomes, reinforcing the efficacy of ivermectin through the demonstration of a dose-response effect. Methods This exploratory analysis of a prospective observational study involved a program that used ivermectin at a dose of 0.2 mg/kg/day for two consecutive days, every 15 days, for 150 days. Regularity definitions were as follows: regular users had 180 mg or more of ivermectin and irregular users had up to 60 mg, in total, throughout the program. Comparisons were made between non-users (subjects who did not use ivermectin), and regular and irregular users after multivariate adjustments. The full city database was used to calculate and compare COVID-19 infection and the risk of dying from COVID-19. The COVID-19 database was used and propensity score matching (PSM) was employed for hospitalization and mortality rates. Results Among 223,128 subjects from the city of Itajaí, 159,560 were 18 years old or up and were not infected by COVID-19 until July 7, 2020, from which 45,716 (28.7%) did not use and 113,844 (71.3%) used ivermectin. Among ivermectin users, 33,971 (29.8%) used irregularly (up to 60 mg) and 8,325 (7.3%) used regularly (more than 180 mg). The remaining 71,548 participants were not included in the analysis. COVID-19 infection rate was 49% lower for regular users (3.40%) than non-users (6.64%) (risk rate (RR): 0.51; 95% CI: 0.45-0.58; p < 0.0001), and 25% lower than irregular users (4.54%) (RR: 0.75; 95% CI: 0.66-0.85; p < 0.0001). The infection rate was 32% lower for irregular users than non-users (RR: 0.68; 95% CI: 0.64-0.73; p < 0.0001). Among COVID-19 participants, regularusers were older and had a higher prevalence of type 2 diabetes and hypertension than irregular and non-users. After PSM, the matched analysis contained 283 subjects in each group of non-users and regular users, between regular users and irregular users, and 1,542 subjects between non-users and irregular users. The hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p < 0.0001), and by 29% among irregular users compared to non-users (RR: 0.781; 95% CI: 0.49-1.05; p = 0.099). Mortality rate was 92% lower in regular users than non-users (RR: 0.08; 95% CI: 0.02-0.35; p = 0.0008) and 84% lower than irregular users (RR: 0.16; 95% CI: 0.04-0.71; p = 0.016), while irregular users had a 37% lower mortality rate reduction than non-users (RR: 0.67; 95% CI: 0.40-0.99; p = 0.049). Risk of dying from COVID-19 was 86% lower among regular users than non-users (RR: 0.14; 95% CI: 0.03-0.57; p = 0.006), and 72% lower than irregular users (RR: 0.28; 95% CI: 0.07-1.18; p = 0.083), while irregular users had a 51% reduction compared to non-users (RR: 0.49; 95% CI: 0.32-0.76; p = 0.001). Conclusion Non-use of ivermectin was associated with a 12.5-fold increase in mortality rate and a seven-fold increased risk of dying from COVID-19 compared to the regular use of ivermectin. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.
