Background We have previously shown that ivermectin used as prophylaxis for coronavirus disease 2019 (COVID-19), regardless of regularity, in a tightly controlled city program in southern Brazil (Itajaí, Brazil), was associated with reductions in COVID-19 infection, hospitalization and death rates. In this study, we aimed to determine whether regular use of ivermectin affected the level of protection against COVID-19 and related outcomes, strengthening the efficacy of ivermectin by demonstrating a dose-response effect .
Methods This exploratory analysis of a prospective observational study involved a program using ivermectin at a dose of 0.2 mg/kg/day for two consecutive days every 15 days for 150 days. The definitions of regularity 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 nonusers (subjects who did not use ivermectin) and regular and irregular users after multivariate adjustments. The full city database was used to calculate and compare the risk of COVID-19 infection and death from COVID-19. We used the COVID-19 database and used propensity score matching (PSM) for hospitalization and mortality rates.
Results Among the 223,128 subjects in the city of Itajaí, 159,560 were 18 years of age or older and were not infected by COVID-19 until July 7, 2020, of which 45,716 (28.7%) did not use ivermectin and 113,844 ( 71.3%). Among ivermectin users, 33,971 (29.8%) use irregularly (up to 60 mg) and 8,325 (7.3%) use regularly (more than 180 mg). The remaining 71,548 participants were not included in the analysis. The rate of COVID-19 infection was 49% lower for regular users (3.40%) than for non-users (6.64%) (risk ratio (RR): 0.51; CI 95%: 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 for non-users (RR: 0.68; 95% CI: 0.64–0.73; p < 0.0001). Among the COVID-19 participants, regular users were older and had a higher prevalence of type 2 diabetes and hypertension than irregular and non-users. After PSM, the comparative analysis included 283 subjects in each group of non-users and regular users, between regular users and irregular users, and 1542 subjects between non-users and irregular users.
The hospitalization rate was reduced by 100% in regular users compared to both irregular users and nonusers (p < 0.0001), and by 29% among irregular users compared to nonusers (RR : 0.781, 95% CI: 0.49-1.05). ; p = 0.099). The death rate was 92% lower in regular users than in non-users (RR: 0.08; 95% CI: 0.02-0.35; p = 0.0008) and 84% lower than in 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 users (RR: 0.67; 95% CI: 0.40-0.99; p = 0.049). The risk of dying from COVID-19 was 86% lower among regular users than nonusers (RR: 0.14; 95% CI: 0.03–0.57; p = 0.006) and 72% higher 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 the death rate and a seven-fold increase in the risk of dying from COVID-19 compared with usual use of ivermectin. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.
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