Chronology of Dichlorodiphenyltrichloroethane and pyrethroid resistance and the associated mutations in Anopheles stephensi: Insights from areas where the vector is native and invasive

Anopheles stephensi (Diptera: Culicidae), a primary malaria vector native to south Asia and the Arabian peninsula, has recently spread to Sri Lanka and the Horn of Africa (HOA). Its arrival poses a serious challenge to malaria control initiatives, particularly in the rapidly urbanized African settings because it can transmit both Plasmodium falciparum (Haemosporida: Plasmodidae) and Plasmodium vivax (Haemosporida: Plasmodidae). This threat is compounded by the vector's growing resistance to insecticides, particularly pyrethroids, the backbone of indoor residual spraying (IRS) and insecticide-treated nets (ITNs). The use of dichlorodiphenyltrichloroethane (DDT), which exhibits a comparable mode of action to pyrethroids, significantly increases the likelihood of cross-resistance development. This review presents the first regionally integrated synthesis of An. stephensi susceptibility to pyrethroids and DDT. The analysis encompasses phenotypic resistance and underlying molecular mechanisms across the World Health Organization (WHO) Eastern Mediterranean Region, the Indian subcontinent and the HOA regions where the species is either native or invasive. Twenty-one studies published over the past two decades were identified through searches in five electronic databases. The findings revealed confirmed resistance to multiple pyrethroid compounds such as permethrin, deltamethrin, lambdacyhalothrin, alpha-cypermethrin, and cyfluthrin, as well as DDT, while susceptibility to etofenprox varied by location. Geographic variability was observed in intensity of resistance and allele distribution across Iranian sites. Mechanistically, resistance was linked to both target-site knockdown resistance (kdr) mutations (L1014F and L1014S) and metabolic detoxification pathways involving cytochrome P450s, glutathione S-transferases (GSTs), and esterases. These findings underscore the escalating menace that insecticide resistance poses to malaria vector control, particularly in newly invaded regions characterized by inadequate surveillance infrastructure and pronounced reliance on pyrethroid-based interventions. This review advocates for the establishment of comprehensive global monitoring frameworks and the formulation of evidence-based resistance management strategies tailored to local vector ecologies and resistance mechanisms.