Population genetics of concurrent selection with albendazole and ivermectin or diethylcarbamazine on the possible spread of albendazole resistance in Wuchereria bancrofti A. E. SCHWAB 1 , T. S. CHURCHER 2 , A. J. SCHWAB 3 , M.-G. BASA ´ N ˜ EZ 2 and R. K. PRICHARD 1 * 1 Institute of Parasitology, McGill University, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9 2 Department of Infectious Disease Epidemiology, St Mary’s Campus, Imperial College London, Norfolk Place, London W2 1PG, UK 3 Research Institute of the McGill University, Health Centre General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada, H3G 1A4 (Received 5 April 2006; revised 23 May 2006; accepted 24 May 2006; first published online 12 July 2006) SUMMARY The Global Program for the Elimination of Lymphatic Filariasis (GPELF) intends to achieve its aims through yearly mass treatments with albendazole (ABZ) combined with ivermectin (IVM) or diethylcarbamazine (DEC). The use of ABZ and IVM separately to combat parasites of veterinary importance has, on many occasions, resulted in widespread drug resistance. In order to help predict the spread of potential ABZ resistance alleles through a population of Wuchereria bancrofti, we have developed a mathematical model that incorporates population genetics into EPIFIL, a model which examines the transmission dynamics of the parasite. Our model considers the effect of the combined treatments on the frequency of a recessive allele, which confers ABZ resistance. The model predicts that after 10 yearly treatments with ALB and DEC, 85% coverage and an initial resistance allele frequency of 5%, the frequency of the resistance genotype will increase from 0 . 25 to 12 . 7%. If non-random mating is assumed, the initial genotype frequency will be 2 . 34% and will increase to 62 . 7 %. ABZ and IVM combination treatment may lead to weaker selection for this genotype. Treatment coverage, initial allele frequencies and number of treatments also affect the rate of selection. Key words: Wuchereria bancrofti, drug resistance, mathematical model, population genetics, albendazole. INTRODUCTION Lymphatic filariasis (LF) is a disease caused by a group of lymphatic-dwelling filarial nematodes transmitted by mosquito vectors which infect ap- proximately 120 million people in over 90 countries, and whose disease sequelae impose a severe economic and social burden on affected communities and in- dividuals (Michael and Bundy, 1997 ; Ramaiah et al. 1999 ; Zagaria and Savioli, 2002). Currently, a global public-private partnership, under the auspices of the World Health Organization (the Global Alliance for the Elimination of Lymphatic Filariasis), aims to eliminate this disease as a public health problem within the next 20 years. It is hoped that this will be achieved by community-wide yearly mass treatment with the broad spectrum anthelmintic albendazole (ABZ) in combination with the well-known micro- filaricide diethylcarbamazine (DEC) or ivermectin (IVM) (Dean, 2002; Maher and Ottesen, 2000; Ottesen, 2000, 2002 ; Zagaria and Savioli, 2002). Benzimidazoles and avermectins have been used extensively in veterinary medicine for over 2 decades, and this has led to the development of drug resistance to both types of compounds by many helminth parasites affecting livestock (Prichard et al. 1980; Prichard, 1990 ; Wolstenholme et al. 2004). Conse- quently, there is concern that lymphatic filarial nematodes in humans may also develop such drug resistance, as this could severely hamper the control programmes. There have already been some reports of tolerance to DEC by filarial parasites (Eberhard et al. 1988, 1991). Recently, we have shown that a mutation at position 200 of the beta-tubulin gene, from phenylalanine to tyrosine (TYR200), known to cause benzimidazole resistance in veterinary para- sites is present in populations of Wuchereria bancrofti from West Africa, and is significantly higher in treated than in non-treated populations (Schwab et al. 2005). Thus, selection for albendazole resist- ance may already be occurring. Mathematical models can be invaluable in helping to understand parasite population dynamics and * Corresponding author : Institute of Parasitology, McGill University, 21111 Lakeshore road, Ste-Anne-de-Bellevue, Quebec, Canada, H9X 3V9. Tel: +514 398 7729. Fax : +514 398 7857. E-mail : roger.prichard@mcgill.ca 589 Parasitology (2006), 133, 589–601. f 2006 Cambridge University Press doi:10.1017/S003118200600076X Printed in the United Kingdom