Ivermectin Resistance in Onchocerca volvulus: Toward a Genetic Basis

Onchocerciasis (river blindness) is a human disease caused by the filarial worm Onchocerca volvulus. Adult worms can live for over a decade in skin nodules of affected humans, releasing millions of microfilariae that cause debilitating itching and blindness [1]. An estimated 37 million people are infected [2], and there are 46,000 new cases of blindness annually (http://www.apoc.bf/). International programs supported by the World Health Organization and many other groups have worked to control the impact of onchocerciasis using vector control with insecticides beginning in 1974 and mass drug administration (MDA) with ivermectin (IVM, brand name Mectizan) beginning in 1987 (Figure 1) [3]. IVM is a highly effective microfilaricide and inhibits female worm microfilarial production for several months. Annual IVM MDA reduces morbidity [4,5] and lowers transmission [6,7]. From 1974 to 2002, the Onchocerciasis Control Programme (OCP) in West Africa greatly decreased O. volvulus transmission in the 11 OCP countries and prevented 600,000 cases of blindness [8–10]. IVM without vector control has been the principal tool for the Onchocerciasis Elimination Program of the Americas (1992– present) [9] and the African Programme for Onchocerciasis Control (1995–present). In the Americas, where O. volvulus is less common, the Onchocerciasis Elimination Program has substantially reduced transmission and is on track to eliminate the disease [9]. The African Programme for Onchocerciasis Control has extended treatment to 19 countries beyond those originally included in the OCP through sustainable community-directed IVM treatment [1,11]. By the end of 2005, 400 million treatments had been supplied in Africa by Merck’s Mectizan Donation Program, with an estimated 40 million people treated by nearly 300,000 community distributors (http://www.apoc.bf/). Nevertheless, the ecology of the disease in Africa, including the broad geographic range of O. volvulus and its blackfly vector, leads to the estimation that IVM treatment of at least 65% of the population for 25 or more years will be necessary to eliminate infection [9,12]. There are significant logistical obstacles to achieving such broad-ranging and prolonged treatment, and there is also concern that O. volvulus resistance to IVM will emerge. IVM resistance has become widespread in many parasitic nematodes of livestock [13,14]. At present there are no alternative drugs for IVM for use in the Onchocerca MDA programs that reduce microfilariae or kill adult worms, which can live up to 15 years in the human host. The emergence of drug-resistant O. volvulus has been suggested by reports of patients failing to respond to IVM treatment [15,16]. A recent report from Ghana has provided the first proof of IVM resistance in O. volvulus: Mike Osei-Atweneboana and colleagues showed that the ability of IVM to suppress skin microfilariae repopulation was reduced in some communities that had received 6–18 years of IVM MDA [17]. The authors predict that a high rate of repopulation of skin with microfilariae will allow continued parasite transmission, possibly with IVM-resistant O. volvulus leading to disease recrudescence. Additionally, studies have associated IVM resistance with genetic markers [18–25], particularly the b-tubulin gene in human O. volvulus and the livestock nematode parasite Haemonchus contortus [22,26]. However, previous O. volvulus genotyping studies were non-longitudinal, using worms collected from different IVM-naı̈ve and treated individuals.