Abstract
Background: We have previously demonstrated that ivermectin used as prophylaxis for COVID-19, irrespective of the regularity or the level of monitoring, in a strictly controlled city-wide program in Southern Brazil (Itajaí, SC, 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 showed an impact on the level of protection from COVID-19 and related outcomes, reinforcing the efficacy of ivermectin through the demonstration of a dose-response effect.
Materials and methods: This exploratory analysis of a prospective observational study involved a program that used ivermectin at a dose of 0.2mg/kg/day for two consecutive days, every 15 days. Data was gathered over a 150-day period.
Regularity definitions were as follows: regular users had 180mg or more of ivermectin; irregular users had up to 60mg, in total, throughout the period of the program. Comparisons were made between non-users (subjects who did not use ivermectin), regular and irregular users from the city of Itajaí after multivariate adjustments.
The full city database was used to calculate and compare COVID-19 infection and risk of dying from COVID-19. The COVID-19 database was used, propensity score matching (PSM) was evened for intervals of age and comorbidities for hospitalization and mortality rates, and then adjusted for remaining variables (doubly adjusted). Risk of dying from COVID-19 was determined by the number of COVID-19 deaths in a certain population exposed to COVID-19.
Results: Among 223,128 subjects analyzed from the city of Itajaí, 159,560 had 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% of users) used irregularly (up to 60mg) and 8,325 (7.3%) used regularly (more than 180mg). The remaining 71,548 participants (62.9%) used intermediate dioses (between 60mg and 180mg) and were not included for analysis.
A total of COVID-19 infection rate was 49% lower for regular users (3.40% rate) than non-users (6.64% rate) [risk rate (RR), 0.51; 95% confidence interval (95%CI), 0.45–0.58; p<0.0001], and 25% lower than irregular users (4.54% rate) (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, regular users were older and had higher a 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, and between regular users and irregular users, and 1,542 subjects between non-users and irregular users.
Hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p<0.0001 for both), 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, 06.7; 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 seven-fold increased risk of dying from COVID-19 compared to the regular use of ivermectin in a PSM comparison of a strictly controlled population. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.
NOTE: This is the new version of the manuscript that analyzed the efficacy of ivermectin according to the regularity of its use. Due to the substantial changes, a new page has been created.