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An analysis of the population genetics of potential multi-drug resistance in Wuchereria bancrofti due to combination chemotherapy

SUMMARY Currently, annual mass treatments with albendazole (ABZ) plus ivermectin (IVM) or diethylcarbamazine (DEC) are administered under the Global Programme to Eliminate Lymphatic Filariasis (GPELF). Drug resistance against both ABZ and IVM is prevalent in nematodes of veterinary importance, raising awareness that if anthelmintic resistance were to develop among Wuchereria bancrofti populations, this would jeopardize GPELF's goals. Genetic structure was incorporated into an existing transmission dynamics model for lymphatic filariasis (LF) to investigate the potential development of concurrent resistance to ABZ and IVM. The resultant models explore the impact of different inheritance modes of resistance to ABZ and IVM on the likely risk of treatment failure under our model assumptions. Results indicate that under ABZ+IVM combination, selection for resistance to one drug is enhanced if resistance to the other drug is already present. Excess parasite homozygosity may increase selection for dominant IVM resistance via enhancing the frequency of recessive ABZ resistance. The model predicts that if multiple resistance genes are associated with different efficacy properties of a drug combination, then examining changes at single loci may be misleading. Sampling schemes in genetic epidemiological surveys investigating the frequency of an allele under selection should consider host age, as individuals of different ages may acquire parasites at different rates.