Prospects for the Control of Neglected Tropical Diseases by Mass Drug Administration

Henk L. Smits

Disclosures

Expert Rev Anti Infect Ther. 2009;7(1):37-56. 

In This Article

Lymphatic Filariasis

Etiology of LF

The causative agents of LF are W. bancrofti, Brugia malayi and B. timori and disease is induced by the presence of adult worms living in the lymphatic system and by secondary infections. After mating, the female worm produces thousands of larvae or microfilariae (mf), which appear in the peripheral blood at times that coincide with the biting activity of mosquito vectors that include several genera of mosquitoes. The mosquito Culex quinquefasciatus, which breeds in stagnant and organically polluted water, is globally the most important vector for W. bancrofti and is an important target for vector control. Infection often occurs already at very young age.[91] Infection may be asymptomatic or may present with one or more acute manifestations.[92,93] Chronic complications include lymphoedema or elephantiasis of the limbs, damage of the genital organs (testicular hydrocele in males) and damage of the kidneys and the lymphatic system. As an effective macrofilaricide is not available, the prime target of MDA are mf, which are sensitive to a number of drugs.[94] Combinations of drugs have demonstrated to be more effective than single agents[95] and MDA for LF is based on single-dose annual treatment with DEC (6 mg/kg) plus ALB (400 mg).[96] In most of sub-Saharan Africa, IVM is used instead of DEC. As DEC, and also IVM, may cause severe adverse effects and risk of encephalopathy in patients with high-level Loa loa infection, MDA can not be provided in certain areas where onchocerciasis or loiasis (caused by L. loa infection) are coendemic and surveys for the presence of loiasis should be carried before MDA can be instigated.[97] MDA is administered to all eligible individuals of the entire at-risk population. Management of existing cases is an important part of the MDA program.

MDA for Lymphatic Filariasis

Of the drugs, DEC has some direct or indirect macrofilaricidal activity, through increased vulnerability to the host immune defence system, while IVM presumably has not.[98,99,100,101] However, all three drugs have an effect on the production of mf, although it is not clear whether this is due to killing of the adult worms or to killing of mf already being produced in the female worm.[92,102,103] While a single dose of DEC and IVM is effective in killing mf, multiple doses are needed to exert an optimal effect on macrofilariae. When tested separately, these drugs have been demonstrated to be highly effective[104] but, while in some areas transmission was apparently interrupted,[105] elimination was not achieved in others, in spite of the very long duration of preventive chemotherapy.[106,107] IVM administration has demonstrated to be highly effective in parts of Latin America, presumably due to a greater sensitivity of the parasite.[108] Mathematical modeling has demonstrated that, of the two-drug combinations, IVM–ALB has the greatest effect on the mf levels (an average of almost 100% reduction in treated patients vs 83% loss for DEC–ALB), and DEC–ALB has the greatest effect on mf productivity (100% vs 96% for IVM–ALB).[109]

In spite of the success of ongoing MDA programs, mathematical modeling has confirmed that interruption of transmission may be hard to achieve within the proposed time-frame of 6 years, in particular in areas with a high precontrol prevalence.[110,111,112] Models predict that MDA for 6 years at 80% coverage eliminates transmission if the target threshold is 0.5% with a baseline prevalence at the start of the treatment of up to 10%. Thus, the typical coverage of 65% for MDA programs[113] is considered too low to be fully effective, and at least 2 more years with two additional rounds of treatment would be desirable. Modeling has demonstrated that, in low-prevalence areas, vector control would increase the effect of MDA, and this is in accordance with the experience in China where drug treatment in combination with vector control has resulted in an interruption of the filarial transmission without resurgence.[114,115] MDA programs for LF have been quite successful in different countries, including countries in Africa, for example, Egypt. A sufficiently high coverage is of prime importance and this may be achieved by promotion of the program using appropriate health education messages and methods.[16,116]

Drug Resistance

The risk of developing drug resistance has been considered low because a combination of two drugs is used and the transmission cycle is relatively long. Investigation of possible drug resistance for DEC and IVM, however, is hampered by the fact that the mechanism of action of these two drugs has not been clarified in detail. DEC presumably acts by blocking enzymes involved in arachidonic acid metabolism.[117] IVM is likely to act on P-glycoprotein and on several ATP-binding cassettes (ABC) transporter genes, transmembrane proteins that transport a variety of molecules, including drugs, across the cell membrane and that regulate a variety of parasite functions, including locomotion and reproducibility.[63] Resistance to IVM has been described for a number of helminths of veterinary importance, but not for LF. Of concern is the possible development of resistance to ALB. The resistant genotype represented by a single amino acid change from phenylalanine to tyrosine in the parasite β-tubulin gene at position 200 has been observed in worms isolated in Burkina Faso and Ghana, and the percentage of worms with the resistant genotype increased considerably after one or two rounds of MDA.[66] Resistant genotypes were not detected in worms from different parts of India, and it is assumed that the existence of resistant genotypes on the African continent could be due to previous antihelminthic therapy for intestinal nematodes.[118] If the increased detection of these mutant genotypes indeed reflects the appearance of drug-resistant worms, and if this is the result of MDA with ALB for intestinal helminths, this underlines the risks involved with single-drug mass treatment.[119] Owing to the problems in reaching a high coverage, application of vector control measures could be crucial as it may help to reduce the time needed for the interruption of LF transmission, thereby reducing the small risk of the development of drug resistance.[120]

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