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

Soil-transmitted Helminthiasis

Etiology of Soil-transmitted Helminths

Large roundworms (Ascaris lumbricoides), hookworms (Necator americanus and Ancylostoma duodenale) and whipworm (Trichuris trichiura) are collectively considered to parasitize a significant proportion of the human population in developing countries, and the approach to control them is the same for all three.[33] Although infection with each of these nematodes has its own specific clinical characteristics, the main consequence is malnutrition and impaired development in infected children, often resulting in reduced physical fitness and cognitive capacity at older age. Humans are the only definite hosts and, because infection is promoted by a fecal-contaminated environment, improved hygiene and sanitation are important factors in the control of STH. Infection may occur already at very young age and, therefore, the effects on development can be severe.[34] Although, often, many individuals and sometimes almost an entire community are infected, most worms are usually found in a small number of people with familial or household aggregation, which seems to be determined, in part, by immunological and genetic factors.[35,36,37] This so-called overdispersion may strongly influence attempts to control the infection as the presence of heavily infected individuals in a community may result in a rapid reintroduction after successful treatment.

MDA for Soil-transmitted Helminths

The drugs most commonly used in MDA for STH are the benzimidazole derivative ALB and mebendazole.[38,39] Administration of the drugs is simple as they can be administered at a fixed dose of 400 mg for ALB or 500 mg for mebendazole in a single tablet. Since ALB is relatively more effective against hookworm and whipworm, the drug is generally preferred over other antihelminthics, such as mebendazole or levamisole and pyrantel. ALB, however, is not effective in the complete removal of the parasites from a population; aggregation of the results of a large number of studies has demonstrated that a single dose results in cure rates of 88% for roundworms and of 78% for hookworms.[40] The effect on whipworms (28% cure rate) is much less strong, possibly because these parasites are located in the lower intestines. Furthermore, early studies already demonstrated that infection levels may return to pretreatment levels within 1–3 years due to reinfection.[41,42,43] In addition, one recent study showed that ALB treatment during three or more consecutive days did not effectively remove the T. trichiura parasites in 67% of the patients and that even longer regimens are needed to treat heavily infected individuals.[44] A combination of ALB and IVM may be more effective in the treatment of whipworm infection,[45] and inclusion of IVM in MDA approaches as in integrated programs for the control of STH and LF or STH and onchocerciasis could be very beneficial. However, IVM has no effect on hookworms.

Preventive chemotherapy for STH of schoolchildren and adults in Uganda delivered through the National Control Program resulted in a reduction in the prevalence of hookworm infection by 79%, from 50.9% at baseline to 10.7% after two rounds of annual treatment and a reduction in the intensity of infection (number of eggs per gram in the feces) by 92.9%. However, a significant improvement of hemoglobin concentration and in early signs of disease was observed already 1 year after a single round of MDA.[46] The overall prevalence of roundworm and whipworm in the study population at baseline was low, and no significant reduction in prevalence was observed but the intensity of infection with roundworms decreased by 83%. Importantly, the reduction in hookworm infections was also observed in newly recruited children who had never received treatment suggesting a general decline in environmental transmission. Another indication that MDA reduces transmission was provided in a study in which targeted treatment of a school-aged population had an effect across all age groups.[47] A 6-year cross-sectional follow-up study performed in two villages in Northern Tanzania showed a reduction in both the prevalence and intensity of infection with roundworm and whipworm, but not of hookworm, and it was suggested that the reduction was likely to be the result of health-related interventions rather than a long-term consequence of chemoprevention.[48] For instance, open-pit toilets, consumption of contaminated water and the use of human feces for fertilization favor the spread of STH, and ending these (and other) unwanted practices could have a major impact. Again, disease education and community participation would have very important roles in achieving such improvements in sanitation and environmental hygiene.

As pointed out by Dickson[49,50] and by Hall,[51] drug delivery for deworming alone may be insufficient for children already suffering from the effects of infection to catch up on physical growth and mental capacity. Also, by improving appetite, deworming seems to improve physical growth but may not have an effect on cognitive performance. However, child development and, in particular, mental improvement is difficult to measure, especially if the prevalence of infection is relatively low or other factors that could influence growth and development, such as malaria, are involved as well. It is realized that for a maximum effect adequate replacement of the lost nutrients is needed, which is particularly hard for iron. Although iron is present in meat as well as in vegetables, it is more readily absorbed from meat than from vegetable foods, in which it is irreversibly bound to lectins, but this source of more easily accessible iron will be lacking in the diet of most children. Therefore, to compensate for the iron loss, deworming, therefore, should be supplemented with the provision of iron tablets during an extended period. As not all anemia is due to iron deficiency, other micronutrients may also need to be administered.[52] Not surprisingly, not all studies have demonstrated a positive effect of deworming, and iron and folic acid supplementation on child development since possible indicators, such as prevalence of worm infestation, child nutritional status and cognitive capacity, are difficult to measure and quantify.[53] A study performed in Zanzibar showed that, in older children (> 30 months), anemia was related to hookworm infection, while in younger children this was related to malaria.[54] This is a typical example that calls for an integrated approach tackling STH together with malaria and micronutritional improvements.

Drug Resistance

Some concern has been raised regarding the safety of anthelmintic drugs in very young children.[55] Side effects can vary at different ages. However, the combined data from several studies that included more than 2000 children below 24 months of age treated with ALB or mebendazole have not demonstrated severe adverse effects that could be related to the drug.[56] Hence, it was concluded that the potential health benefits favor the treatment of children over 12 months, provided the case for their use is established. Recent studies performed in Peru have demonstrated the beneficial effects of mebendazole treatment of pregnant women on anemia and birth weight, while no serious adverse effects were observed.[57,58,59] Treatment at an early stage could turn out to be important, as it will probably be easier to prevent the harmful effects of parasitic worm infections on child development than to reverse them at a later age. Currently, none of the anthelmintic drugs are licensed for use during pregnancy and, as is also true for the use of other drugs in MDA for other NTDs, the WHO guidelines should be followed in these and other special situations.[60] The original fear that the ALB may interact at the blood–brain barrier with other drugs that may be coadministered is less opportune since it has been demonstrated that the drug is not a substrate for P-glycoprotein, the protein that facilitates transport across the blood–brain barrier.[61] Mebendazole, by contrast, may interact with the P-glycoprotein.

The potential effect of MDA on drug sensitivity remains an important issue.[62] Drug resistance against anthelmintics, such as ALB used in livestock, is relatively easily induced and is already widespread among farm animals as a result of frequent drug use and restricted genetic diversity of helminthes within farms.[63] ALB acts through binding to helminth β-tubulin and disrupting microtubule-based processes in the parasites.[64] Resistance to the drug is thought to be induced by mutations at codon 200 of the β-tubulin gene causing an amino acid change from phenylalanine to tyrosine.[65] Resistance to the drug has been detected in many different parasites, including Wucheria bancrofti , and this illustrates the risk of developing drug resistance when a single drug is used and the drug pressure is high.[66] The mutation at codon 200 in the β-tubulin gene that confers resistance, however, has not been detected in the helminths Necator americanus and Ancylostoma duodenales isolated from schoolchildren living at Pemba Island, Zanzibar, showing a much reduced response to mebendazole after 13 rounds of treatment.[67] Perhaps other mutations on the β-tubulin gene confer resistance in these human helminths or, perhaps other, yet unknown, mechanisms are involved.

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