Understanding the Global Dynamics of Pyrethroid Resistance-related kdr mutations in Aedes (Stegomyia) aegypti (Linnaeus, 1762) (Diptera: Culicidae).

Among the mechanisms of insecticide resistance, knockdown resistance (kdr), causes alterations in the functioning of the voltage-gated sodium channel (Nav), which is the target site for pyrethroids (PYs) and dichloro diphenyl chloroethane (DDT). In Aedes aegypti, 13 kdr mutations associated with PYs resistance have been identified, with V₄₁₀L, V₁₀₁₆I, V₁₀₁₆G, and F₁₅₃₄C being the most reported mutations in the literature. To assess global and temporal trends in the allelic frequencies of these V₄₁₀L, V₁₀₁₆I/G and F₁₅₃₄C mutations, a PRISMA-guided systematic review was conducted to analyzed their distribution and frequency, incorporating new genotyping data from five southeastern Brazilian populations. Genotyping in these populations was performed using allele-specific PCR (AS-PCR), thereby complementing the findings of the review. The results revealed that, out of a total of 187 studies, the F₁₅₃₄C mutation is the most studied (144 studies) and has the widest geographical distribution (47 countries, 4 continents), followed by the V₄₁₀L, V₁₀₁₆I, and V₁₀₁₆G mutations. In southeast Brazil, resistant alleles were detected both individually and in co-occurrence (e.g., V₄₁₀L + V₁₀₁₆I + F₁₅₃₄C), and were associated with PY resistance. These mutations alter Nav, reducing insecticide binding affinity and leading to high-level resistance-particularly when specific genotypic combinations are present. Their global spread poses a significant threat to A. aegypti control efforts, as PYs remain a cornerstone of public health interventions. Urgent, systematic monitoring of kdr allele frequencies and their synergistic effects is essential to optimize insecticide rotation strategies and prevent operational failures. This calls for coordinated international efforts to develop adaptive control strategies.