A current initiative to eliminate lymphatic filariasis (LF), headed by the World Health Organization, aims to interrupt transmission of the disease through yearly community-wide treatment with the broad spectrum anthelmintic albendazole (ABZ), in combination with ivermectin (IVM) or diethylcarbamazine (DEC). Over the years, the use of both ABZ and IVM in the treatment of veterinary parasites has led to widespread anthelmintic resistance against these drugs. In this study, we genotyped microfilaria of Wuchereria bancrofti, a causative agent of LF, in order to detect the presence of mutations which confer ABZ resistance in other parasites, and we identified such mutations in worms obtained from untreated patients in Ghana and Burkina Faso, West Africa. Microfilaria from patients who had been treated with ABZ + IVM, had a significantly higher frequency of the resistant genotype, and this frequency was even higher in worms from patients that had received two rounds of treatment. In addition, the untreated population of microfilaria had an excess of homozygotes in the population. This excess homozygosity was equivalent to a Wright's Inbreeding Statistic of FIT= 0.44, and we found that the population was significantly subdivided between patients. In order to better understand the mechanisms and factors involved in the potential spread of ABZ resistance, caused by such mutations, through a population of Culex-transmitted W. bancrofti, we developed a deterministic model that incorporates genotype structure into the epidemiological model EPIFIL. This model predicts that the combination of ABZ + DEC leads to stronger selection for the resistant genotype than ABZ + IVM, and that drug efficacy assumptions are an important factor affecting the spread of drug resistance. Treatment coverage, non-random mating, initial allele frequency and number of treatments also had substantial impact on the speed and magnitude of the spread of ABZ resistance. When we expanded this model to include potential IVM-resistance alleles we found that, under ABZ + IVM treatment, selection for resistance to either drug is enhanced by the presence of resistance against the second drug. Similarly, excess homozygosity caused by parasite non-random mating may increase selection for a dominant IVM resistance allele through enhancing the spread of a recessive ABZ resistance allele. Resistence developed more slowly when it was inherited as a polygenic trait. Results from this study suggest that resistance monitoring is crucial, as resistance may not be apparent until treatment is stopped, recrudescence occurs and treatment is reapplied.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103006 |
| Date | January 2007 |
| Creators | Schwab, Anne Elisabeth. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Institute of Parasitology.) |
| Rights | © Anne Elisabeth Schwab, 2007 |
| Relation | alephsysno: 002600949, proquestno: AAINR32238, Theses scanned by UMI/ProQuest. |
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