Epidemiology and molecular mechanisms of anthelminthic treatment failure in Kinta

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DESCRIPTION (provided by applicant): Approximately one billion people are infected with hookworms (Necator americanus and Ancylostoma duodenal) which are a major global cause of anemia and malnutrition. Sub-Saharan Africa has the highest prevalence (29%) of global hookworm infection. Infections are responsible for sublime morbidity including impairment of both cognitive ability and growth observed in affected children. Vulnerable groups also include pregnant women. Evidence also suggests that chronic low intensity hookworm infection may impair the ability to control other tropical diseases, including HIV, tuberculosis, and malaria. Current global programs to control soil-transmitted nematodes rely primarily on mass drug administration (MDA) with anthelminthic drugs to either reduce or prevent morbidity - preventive chemotherapy - in endemic populations. We conducted pilot studies of the epidemiology of hookworm infection in communities in Kintampo North Municipality (KNM), Ghana in 2007 and found a high prevalence of hookworm infection (45%) that correlated with poor nutritional status in adults, as well as a high rate of treatment failure (39%) following administration of single dos albendazole (400mg). A follow-up study in 2010 confirmed the high prevalence of hookworm (39%) in school age children, and 56% albendazole treatment failure. These studies confirm the limited effectiveness of albendazole in the study population, the mechanisms of which remain to be elucidated. In another preliminary study we interrogated the ?-tubulin gene as a potential benzimidazole resistance marker in human hookworms isolated from the same sites and have identified mutations that are potential markers of resistance. The specific aims of this proposed research will further define the epidemiology of hookworm infection and the specific host factors associated with albendazole treatment failure in KNM and also establish methods to detect in vitro benzimidazole resistance and corresponding gene polymorphisms for use in sentinel sites throughout Ghana. We predict that host factors, including overall nutritional status and specific dietary intake influence response to albendazole therapy and susceptibility to re-infection with hookworm and that genetically mediated resistance of hookworms to anthelminthics will emerge in communities characterized by high coincident rates of treatment failure and malnutrition. PUBLIC HEALTH RELEVANCE: Hookworm infections affect approximately a billion people globally and are responsible for morbidity including anemia, reduced growth, and impaired cognitive development. Current control strategy relies primarily on mass drug administration to all at-risk populations raising the specter of resistance to commonly used anthelminthic agents. This study will provide evidence of nutritional factors that influence treatment failures and re-infection, and identify diagnostic markers for use in monitoring and surveillance of resistance in NTD control programs. The long term goal of this work is to establish a sustainable laboratory and field based hookworm research program in order to provide expert monitoring and disease surveillance for emerging anthelminthic resistance.