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The successful eradication of smallpox and the significant worldwide advances in control of several vaccine-preventable viral infections including polio and measles have given cause for optimism that a number of other infectious diseases can be controlled, if not eliminated. Lymphatic filariasis has been identified as one such disease amenable to elimination.1 As no vaccine is available, and vector control does not result in a sustained effect apart from in a small number of locations, the elimination of lymphatic filariasis relies on mass drug administration (MDA) using the three drugs currently available for treatment: diethylcarbamazine (DEC), albendazole, and ivermectin.2 The eradication of lymphatic filariasis from much of the People’s Republic of China using DEC alone has demonstrated the feasibility of this approach.
The vulnerability of parasite control programs that rely on MDA to the development of drug resistance is well known. This phenomenon is illustrated in humans by the spread of resistance to antimalarial drugs including chloroquine and pyrimethamine-sulfadoxine and in livestock by widespread anthelmintic resistance of parasitic nematodes.3 The issue of resistance to anthelmintics used in humans has assumed increasing importance as the global program to eliminate lymphatic filariasis is implemented in larger population groups and the duration of the program increases. Factors that have been considered to mitigate against the development of drug resistance in lymphatic filariasis include the combined use of drugs with different modes of action and the long and complex lifecycle of filariae.
DEC is the oldest of the three drugs used for control of lymphatic filariasis. It is the antifilarial drug with the best activity in single dose against the lymphatic-dwelling adult worm and microfilariae, the life-cycle stage residing in the blood that is taken up by the mosquito vector. Of note, the drug is not 100% effective against adult worms, with clinical and ultrasound studies demonstrating a variable response, and even refractory infection.4,5 However, detailed study of resistance to DEC has been hampered by a poor understanding of its mechanism of action. The activity of ivermectin is largely confined to immature stages of the parasite, including embryos in the uterus of the adult female and microfilariae. It is only deployed in the program to eliminate lymphatic filariasis in certain areas of West Africa where Loa loa or onchocerciasis are co-endemic. Despite more than a decade of use in the Onchocerciasis Control Program, ivermectin resistance has not been an apparent issue until recently when resistance of adult female worms to ivermectin was reported.6
Albendazole, a member of the benzimidazole (BZ) class of drugs, is one of the most important anthelmintics in human medicine. It possesses clinically important activity against a wide range of nematode and cestode parasites and even some protozoa such as Giardia sp. Although single-dose albendazole has little effect on microfilariae, when used as part of a combined single-dose regimen with either ivermectin or DEC, synergistic activity is observed, presumably by an effect on adult worm viability. As noted above, widespread resistance to BZ drugs is present in a number of nematodes of veterinary importance, where specific mutations in the gene encoding ß-tubulin, the target of these drugs, have been associated with drug resistance. A single nucleic acid polymorphism at amino acid codon 200 results in an amino acid change from phenylalanine to tyrosine and is the polymorphism most commonly associated with BZ resistance.3 Of note, this polymorphism appears to be present at low levels in unselected veterinary parasite populations and increases in frequency with drug selection.
The presence of drug-resistant alleles in untreated populations of Wuchereria bancrofti has now been demonstrated by a study published in this issue of the Journal by Schwab and others7 where the investigators collected and genotyped microfilariae from human subjects in Ghana and Burkina Faso. Among the Ghanaian study subjects, the frequency of the Y200 genotype in microfilariae collected 1 week after the first cycle of ivermectin-albendazole chemotherapy ranged from 0.33% to 2.7%, whereas in Burkina Faso this genotype was significantly more common at baseline (26.6%). The authors speculate about the possible role of previous anthelmintic therapy for intestinal nematodes as an explanation of the difference in gene frequency between the two sites. Genotyping of microfilariae collected from 17 study subjects from Burkina Faso several days after the second cycle of albendazole-ivermectin chemotherapy revealed that 86.2% of microfilariae were now homozygous for the Y200 allele associated with BZ resistance and that none were homozygous for the drug-sensitive genotype. Although drug response data and parasite genotype before and after treatment from individual study subjects are not presented in this study, the finding of the study raises concern. As the initial clearance of microfilaraemia is likely to have been mediated by the ivermectin component of the antifilarial chemotherapy, the effect of this genetic change on the clinical efficacy of the chemotherapy may not be evident by evaluation for clearance of microfilaraemia soon after treatment. However, it would represent the genotype of the adult female worms present in the human host. The pharmacodynamic interaction of albendazole with ivermectin and the as yet unreported effect on the DEC-albendazole combination on parasite genotype are likely to be critical determinants of the sustainability of the program to eliminate lymphatic filariasis.
A widely recognized secondary benefit of MDA for lymphatic filariasis is the likely health benefit that would accrue from the reduction of the burden of intestinal nematode infections (ascariasis, hookworm, and whipworm). However, the issue of promotion of drug resistance among intestinal nematodes by way of the MDA for filariasis is of equal concern. Collateral damage, in the form of BZ resistance in intestinal nematodes, would represent a significant price to pay for the elimination of filariasis given that few other broad-spectrum anthelmintics are available. Two reports of BZ resistance8,9 in human hookworm serve to underline this problem. In the one recently published study in which the relationship between anthelmintic resistance in hookworms and genetic polymorphism in the ß-tubulin was studied, no association between specific alleles and resistance was observed.9 The possibility of an alternate mechanism for BZ resistance is also suggested by veterinary experience where high-level drug resistance has been observed without the fixation of the Y200 allele in the population.10 To better understand the magnitude of the threat of anthelmintic resistance and to combat it, approaches involving a range of techniques will be necessary. These should include prospective detailed studies of clinical efficacy, the development and validation of bioassays for detecting anthelmintic resistance, as well as further studies of the genetic basis for anthelmintic resistance.
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