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

Onchocerciasis

Etiology of Onchocerciasis

Onchocerciasis is caused by infection with the nematode filarial Onchocerca volvulus .[121] Onchocerciasis is also called 'river blindness' because eye lesions may lead to serious visual impairment and blindness, and the larvae of the black fly (genus Simulium) vector live in fast-running streams. The adult worms, which in the human body live in fibrous, subcutaneous nodules, produce millions of mf that migrate under the skin and through the eyes, giving rise to a variety of dermal and ocular abnormalities. The onset of symptoms usually occurs one or several years after infection, when the adult female worms start to produce mf. Symptoms include, apart from lesions of the eye, dermal abnormalities, such as popular skin lesions, subcutaneous nodules, lymphadenitis and general debilitation.[122]

MDA for Onchocerciasis

Control programs for onchocerciasis, together with those for LF, belong to the most successful and are among the longest running programs to control an infectious disease in developing countries. The current strategy is to treat the entire population of meso- and hyperendemic communities where the prevalence of positive skin snips is at least 40% or the prevalence of palpable nodules is at least 20%. Treatment consists of an oral dose of IVM (150 µg/kg bodyweight) administered annually to all eligible individuals and, ideally, is accompanied with vector control and monitoring for recrudescence. The strategy has proven to be highly effective in reducing transmission intensity, prevalence and mf load.[123,124,125,126,127] Programs in Latin America have been most successful, presumably owing to a lower efficacy of the vector.[128] Programs in Africa started as early as 1974 by vector control alone under the initiative of the Onchocerciasis Control Programme.[129] Later, through the African Programme for Onchocerciasis Control and Onchocerciasis Elimination Program for the Americas, IVM was administered annually or biannually with the aim to eliminate onchocerciasis.[130,131] Presently, the disease has been eliminated as a public-health problem in 11 West African countries. In 17 other countries, most in sub-Saharan Africa, approximately 20% of the population at risk is being treated.

As in LF, IVM acts primarily on mf by killing circulating mf and reducing their production by temporarily inhibiting the release of intrauterine mf from reproductive female worms but does not kill adult female worms.[132,133] Given the very long lifespan of adult female worms of up to 15 years, it has been estimated that MDA should be continued for a minimum of 20 years but, depending on the coverage and other factors, control may take 25–35 years or more.[134] In different countries and areas in West Africa where MDA has been in effect for over a decade, surveys have demonstrated that transmission is still ongoing in some regions and, furthermore, in one area where the prevalence of infection had become very low, a significant recrudescence occurred within a few years after interruption of the program.[135] The authors concluded that MDA will be unlikely to result in completely controlling the disease in West Africa. It is not clear yet whether the low levels of ongoing transmission after MDA is a result of reinfection by exposure to infected black flies or due to low MDA treatment coverage, surviving fertile female worms, or reduced drug susceptibility, and it has been suggested that reduced immunocompetence is affecting the efficacy of IVM treatment in some areas.[136] The efficacy of IVM treatment may be increased by increasing the frequency of drug administration to every 3 months.[137] The use of higher dosages of 400–800 µg/kg bodyweight is not recommended owing to observed edematous swelling and subjective ocular complaints observed in some patients.

Drug Resistance

Suboptimal responses to IVM were first noted in studies in Sudan and Ghana, and it was suggested that drug resistance either by selection of pre-existing strains or through de novo development played a role.[135,137,138,139] A recent investigation in Ghana showed that in four out of ten communities that had received between ten and 17 rounds of IVM mass treatment, mf repopulation levels reached approximately 54% of pretreatment levels within 90 days after treatment – an alarmingly high repopulation level compared with that of a community from the same area that had never been treated with IVM before.[140] This result shows that although circulating mf still respond to IVM, adult female worms rapidly reassume mf reproduction after IVM exposure, and indicates that female worms have become resistant to the sterilizing effect of IVM.

Genetic analysis of adult worms from Ghana and Cameroon has demonstrated that IVM treatment causes a genetic selection resulting in less genetic diversity, which may well reflect the selection of parasites that show increased tolerance to IVM.[141,142,143,144] Selection was already demonstrated for the β-tubulin genes, the P-glycoprotein gene and the glutamate-gated chloride channel gene and γ-aminobutytic acid receptor gene belonging to the ABC transporter genes. At present, it is unclear why IVM treatment would select for specific β-tubulin genotypes as this protein does not seem to be the target of IVM.[145] The β-tubulin genes and P-glycoprotein genes, however, are also thought to be involved in IVM resistance in Haemonchus contortus, a trichostrongylid nematode of livestock, but no formal evidence is available that mutations in these genes contribute to resistance in O. volvulus as a drug-resistance test for this pathogen does not exists. In the absence of an in vitro assay system for measuring drug resistance, molecular polymorphic markers for these genes may be used to follow selection for IVM resistance in the field.[146]

Grant proposed the existence of different IVM targets, one that is expressed in mf and leads to the rapid death and disappearance of mf fromthe skin and to the death or delayed release of mf present in the uteri of resident adult female worms, and one that leads to infertility of the adult female worm.[147] Resistance of mf and of adult female worms may act through different mechanisms that may involve different sets of genes. It has been demonstrated in B. malayi that the level of resistance is sex dependent and that, in this parasite, the putative IVM receptor, the glutamate-gated chloride channel gene protein, was expressed at much higher levels in female worms compared with male worms, probably rendering them more sensitive to IVM.[148] Two putative P-glycoprotein genes were found to be expressed stage specifically in O. volvulus with high levels observed in IVM-sensitive larvae isolated from black flies and low levels in drug-tolerant adult female worms.[149] Clearly, further studies are needed to determine the role and contribution of each of the different putative IVM resistance genes to IVM resistance in O. volvulus and whether the action and expression of these genes is different in mf and adult worms.

As MDA based on IVM may not stop transmission owing to surviving adult female worms and emerging drug resistance, alternative options for treatment have been investigated. A possible target is the O. volvulus endosymbiont Wolbachia, treatment of which with tetracycline antibiotics sterilizes the adult female worm.[150,151] It was demonstrated that a combination of a singlet dose IVM with multiple doses of doxycycline (DXC; 100 mg/day orally for 6 weeks) resulted in a prolonged elimination of mf from the skin of infected individuals.[152,153] A recent randomized, placebo-controlled trial in Ghana showed that administration of DXC for 6 weeks in combination with two rounds of IVM was macrofilaricidal, with over 60% of the female worms found dead.[154] However, evidence was obtained that new Wolbachia -containing worms were acquired after the administration of DXC, suggesting that, in order to be effective, repeated treatment may be needed. While the use of tetracyclines is not amenable for MDA because these long courses are not feasible, potentially it could be applied in the treatment of drug-resistance cases. The use of anti-Wolbachia antibiotics may also be applicable to LF.[155,156,157]

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