Global plan for insecticide resistance management in malaria vectors

The practical issues in implementation of IRM strategies requirefurther investigation, for example:• Overall: What additional challenges are involved – andwhat additional activities are needed – to change fromone vector control intervention to another and to changeinsecticides for IRS (including political acceptance, donorflexibility, training and supervision, and communityeducation)?• Rotations: What are the challenges to timely procurementof multiple insecticides, and how can they be overcome?• Mixtures: In what conditions could insecticide formulationsbe mixed, in the factory or during applications, as inagriculture? What would be the implications for cost,registration, training and chemical safety? Some arguethat insecticides for use in public health must be properlyformulated at the factory, and not mixed during application.Can mixture formulations be devised so that differentcomponents decay over time at exactly the same rate?Further understanding is required regarding the applicability ofdifferent IRM strategies under varying circumstances, as wellas the decision criteria used to select among different options.Specialized technical support should be provided on the selectionof alternative IRM strategies.Many of these questions cannot be evaluated before theinterventions are implemented on a large scale. More empiricalevidence is needed to strengthen confidence that the IRM strategyof using combinations, synergists, or mixtures can work. Moreevidence can be accumulated on a smaller scale, by testing theseIRM strategies in experimental huts and monitoring the effect onmosquitoes entering and leaving the huts. Evidence for the efficacyof rotations can be accumulated only by testing on a larger scale,in a village or several villages.Trends: Resistance should be monitored over time to identifytrends in its evolution, with the aim of providing guidance on whento respond to resistanceMetabolic resistance.Background: The understanding of metabolic resistance isrelatively limited. This is a concern, given the increasing reports ofmetabolic resistance and the widely accepted hypothesis that it isa stronger resistance mechanism, and that it could potentially havegreater operational impact.Research agenda: The research agenda should focus on threeelements. Firstly, the genetic mutations responsible for metabolicresistance to pyrethroids in different geographical settings need tobe identified, and their relative importance should be studied. Thetask is more challenging than for most resistance mechanismsin mosquitoes, because the cytochrome-oxidase enzymes arecoded by a large gene family scattered throughout the genome.In addition, the mutations associated with resistance appearto be located in promoter or regulator sequences that are notnecessarily genetically linked to the resistance gene itself and aremuch harder to locate.Secondly, identification of these resistance genes, preferablywith high-throughput DNA-based methods, will be essential forunderstanding the fundamental genetic processes of the spreadof resistance, for developing new methods to assess the impactof resistance on malaria transmission, and as proxy indicators ofselection for resistance. Experts hope that such methods will beavailable within 3 years. High-throughput methods are alreadyavailable for kdr resistance, which has allowed researchers tostudy its spread more closely and understand its importanceand impact more clearly. The current inability to track metabolicresistance in this way is a significant obstacle to the design ofrational, evidence-based resistance management strategies.Thirdly, a range of vector strains resistant to different insecticidesshould be colonized in different locations in order to understandtheir resistance mechanisms and to determine the probableeffectiveness of new resistance management products and activeingredients as they appear.Genetics.Background: With limited genetic information on resistancegenes, it is difficult to track and anticipate the course of resistance,and understand which IRM strategies would be most effective.The evolution of resistance and the possibility of reducing andeven reversing resistance cannot be predicted because of limitedinformation on factors such as baseline frequency (mutationrates), fitness cost, genetic mode of inheritance and the selectionpressure due to different uses of insecticides in agriculture andpublic health. Inability to track resistance genetically makes theconsequences of insecticide resistance more difficult to anticipate;it is also difficult to measure the efficacy of IRM strategies.Research agenda: The genes that confer metabolic resistancemust be identified in order to answer several important researchquestions. Outputs from this research agenda would haveimmediate practical implications for decisions on resistancemanagement taken in national malaria control programmes. Thetopics for research should include genetic dominance, fitnesscost, cross-resistance, linkage disequilibrium, drivers of selectionpressure and behavioural resistance. See Annex 10 for moredetails of the genetic research agenda.69