Prospects for the control of neglected tropical diseases by mass drug administration

Abstract

The prospects for the control of neglected tropical diseases, including soil-transmitted helminthiasis, shistosomiasis, lymphatic filariasis, onchocerciasis and trachoma, through mass drug administration, are exemplified by the elimination of the trachoma as a public-health problem in Morocco. In spite of this and other striking successes, mass drug administration programs are faced with major challenges resulting from suboptimal coverage and lack of efficacy. At current suboptimal coverage rates, programs may need prolongation for an extended period, increasing costs and undermining sustainability. Community participation through health education and information appears to be crucial to improve coverage and to achieve sustainability. Implementation of complementary measures, such as vector control, improved hygiene and environmental sanitation, are important to further control transmission and to prevent re-emergence of the infection and, again, may only be achieved effectively through community-based initiatives. To reduce costs and to relieve pressure on the health system, combining neglected tropical disease programs in areas where diseases coexist and integration with existing control programs for malaria, tuberculosis and HIV/AIDS is advocated. The risk of developing drug resistance is of particular concern in view of the lack of alternative drugs, and reduced treatment efficacy due to emerging resistance is evident for the soil-transmitted helminths and onchocerciasis. Given the risk for the development of drug resistance and the need for a high degree of participation, close attention should be paid to the monitoring of the coverage and efficacy of the different program components.

Keywords::

• albendazole
• azithromycin
• community
• compliance
• coverage
• diethylcarbamazide
• efficacy
• health education
• helminthiasis
• hygiene
• infectious
• integration
• ivermectin
• lymphatic filariasis
• neglected
• onchocerciasis
• participation
• poverty
• praziquantel
• resistance
• sanitation
• schistosomiasis
• trachoma
• tropical
• vector control

Disease burden & poverty control

The WHO estimated that, in 2002, the world-wide burden of disease according to the disability-adjusted life years (DALYs) due to infectious diseases was as high as 457.7 million. Respiratory tract infections have the highest toll on health, accounting for almost 21% of the disease burden due to infectious diseases. Other significant contributors to the disease burden are HIV/AIDS (19%), malaria (9%) and tuberculosis (TB, 8%), diseases that receive much attention also in terms of financial resources for research and prevention. Vaccine-preventable childhood infections (11%) and diarrheal diseases (14%), largely preventable by the provision of clean water, obeying food hygiene and sanitation, are of equal importance. According to the WHO 2002 estimates, the group of so-called neglected tropical diseases (NTDs), which include, among others, the soil-transmitted helminths (STH), schistosomiasis, lymphatic filariasis (LF), onchocerciasis and trachoma, contribute to approximately 5% of the global disease burden due to infectious diseases (Table 1)[1]. While NTDs are believed to collectively cause the death of over half a million people annually, their impact on public health stems largely from disability and morbidity, sometimes affecting a major proportion of the population in endemic areas [2]. The burden of disease due to NTDs may well have been underestimated, as subtle but often chronic disease manifestations that may not be easily recognized owing to lack of appropriate diagnostic tools or epidemiological information are perceived to have a profound impact on well being and proper functioning in society. A reassessment of the morbidity due to STH led to an increase in the DALYs from 4.7 million, as estimated by the WHO, to 39 million, or almost 8% of the disease burden due to infectious diseases, as estimated in a study by Hotez and coworkers [3]. The impact of other NTDs may have been underestimated as well; the clinical manifestations are easily overlooked and, hence, these diseases are often under-reported. For example, the impact of schistosomiasis in Asia appears to be much higher than previously estimated [4].

Some of the NTDs, such as STH, have a severe economic impact in almost all developing countries, while others, such as schistosomiasis, onchocerciasis and LF, are more confined to specific regions and countries where they have a deep impact on society. As these NTDs are largely preventable, it is increasingly recognized that their control is a major strategy to reduce poverty by improving educational outcomes and worker productivity [5]. For five of the NTDs with a total burden of disease with 52.1 million DALYs, or 11% of the total disease burden due to infectious diseases, control programs have been initiated based on community-wide drug administration to at-risk populations [6,7]. These five NTDs are STH, schistosomiasis, LF, onchocerciasis and trachoma, and their control is considered to be highly cost-effective, particularly, when control efforts are combined in areas where diseases coexist [8].

Control through mass drug administration

Control programs for STH, schistosomiasis, LF, onchocerciasis and trachoma became possible by the availability of inexpensive (often donated by the main pharmaceutical companies), effective and safe drugs that can be administered to affected communities during annual or biannual mass drug administration (MDA) programs. These essential drugs are albendazole (ALB) or mebendazole for the treatment of STH, praziquantel (PZQ) for schistosomiasis, ALB and diethylcarbamazide (DEC) or ALB and ivermectin (IVM) for LF, IVM for onchocerciasis and azithromycin (AZM) for trachoma [9–13]. Many countries have successfully implemented MDA programs with one of the success nations being Morocco, formerly one of the 55 countries endemic for blinding trachoma that successfully controlled the disease in 2006. The mass administration of these drugs is attractive as it can be performed through school teachers, local drug dispensaries or public-health teams after some training.

Fundamental to the expected success of the MDA programs is the assumption that once the prevalence of infection is reduced to below a critical threshold level, transmission will remain low and re-emergence of the disease as a public-health problem is unlikely and may be controlled by other factors, such as natural immunity. Although MDA is the cornerstone of the control programs, they all require additional measures, such as vector control, improved hygiene and environmental sanitation and health education and information [14,15]. These complementary measures may be more difficult and expensive to implement than drug administration and results usually are difficult to gauge. The importance of these measures and, in particular, health education and information should not be underestimated. Most MDA programs appear to be less effective than originally planned and, depending on the initial disease prevalence, need to be continued during a much longer period, a situation that in view of the risk of the development of drug resistance is also highly undesirable. Mathematical modeling has demonstrated that coverage is the most critical factor determining the effectiveness of MDA. Different studies have demonstrated that the coverage of MDA programs is too low and that health education and information, together with community participation and mobilization, are important tools for improvement of coverage and that improved hygiene. Sanitation and vector control are essential to prevent re-emergence of the infection after successful drug administration [16]. Therefore, health-education and community-participation programs should be initiated at a very early stage, and other accompanying measures should be started as soon as the disease prevalence is reduced by MDA. In this respect, it may be recalled that some of the NTDs were once very common in Europe and some other developed countries where they have disappeared as a result of economic development and improved hygiene, sanitation and changes in lifestyle [17]. It is fundamental to understand that poor hygiene and poor sanitation are not synonymous with poverty and that, by simple changes in lifestyle through education, major changes can also be achieved also in resource-poor communities.

The importance and effectiveness of vector control, improved hygiene and environmental changes and the role of public-health education therein can be illustrated by the success of the control program for dracunculiasis (guinea worm), a nematode parasitic infection caused by Dracunculus medinensis. This poverty-related disease that affects mostly communities without safe potable water supplies has been successfully eliminated from almost half of the endemic countries. This was achieved by improving water supplies and filtration of water, control of the copepod (water fleas) intermediate host and larvae using temephos insecticides and case containment allied with health education [18,19]. Currently, the total number of cases has been reduced by over 99% with probably less than 10,000 cases remaining, most of them in remote rural areas in Sudan and Ghana. These remaining cases appear to be limited to nomadic communities who still rely on unsafe stagnant pools or wells for their drinking water supplies [20]. Although complete control of this disease may not be achieved within the next few years, it can be a reality in the near future, provided that sufficient resources remain available to eliminate the remaining foci.

Improved efficacy through integration

Mass drug administration programs may take a considerable toll on the capacity of the health system. Therefore, careful attention needs to be paid to the training and strengthening of the field staff involved in the program, and integration with existing healthcare delivery systems should be attempted as much as possible [8]. Furthermore, as MDA for different NTDs can be achieved through similar strategies and means, an integrated approach will yield significant cost savings in areas where several diseases coexist [21–23]. The efficacy of MDA combinations for STH and LF and for STH and schistosomiasis have been reported (Table 2). The efficacy of the concurrent administration of two drugs was equal or better than that of each of drug alone [24–26]. Crucial for coadministration of drugs in MDA programs is that the drug combinations do not show pharmacokinetic interactions and show no increased adverse effects. Studies have demonstrated the safety of combinations of ALB and IVM, and ALB and DEC for treatment of coinfections of LF and STH, of ALB and PZQ for schistosomiasis and STH, and of ALB, IVM and PZQ triple therapy but not for combinations with AZM [27–30]. Important in this respect is that a recent study in Thailand revealed no clinically relevant drug interactions between PZQ, IVM and ALB when administered concurrently as single oral doses in healthy volunteers [27]. In general, adverse effects are mild, limited to infected individuals and generally considered acceptable provided that individuals receiving the drug are informed well. Furthermore, the frequency of events falls after the first or second round of treatment. Since many of the countries where these NTDs are important public-health problems also cope with malaria, TB and/or HIV/AIDS, integration with control programs for these major health problems may provide additional benefits. An initiative to look into the possibility of combined malaria and trachoma control was started in the Amhara region in Ethiopia [31]. MDA programs also have the potential for combining with immunization for the main vaccine preventable diseases.

The implementation of an integrated approach for NTD control and prevention in resource-poor communities is not an easy task and the problems that may be faced should not be underestimated. The communities that are plagued most by these NTDs are marginalized and neglected, dwell in unsanitary and crowded settings, live in remote areas or places that are difficult to access and are often devoid of most, if not all, basic prerequisites and conditions for improvement, including work, education, healthcare and nutrition. To be successful, an integrated effort for NTD control should be supported by a community-based initiative that places broad-based emphasis on health protection and promotion with a clear planning and targets that are supported and agreed upon by the entire community, including local authorities, such as community and religious leaders and to all of whom it is clear that these targets once met will upgrade the living conditions [32]. Community participation and mobilization provides a means to give people greater control over their own health and make problems more easily identified and solved. However, as integration means a certain degree of complexity additional guidance, training and program control are essential.

This article, has reviewed the literature for evidence for reduced MDA efficacy for NTDs and drug resistance and put these findings in a context of essential disease knowledge and facts of disease control programs. Investigation of drug resistance is hampered by lack of test systems and knowledge of the mechanisms of action of the major drugs used in MDA. Development of reduced drug sensitivity and, possibly, the emergence of resistant strains is of concern for STH, LF and onchocerciasis, which rely on the use of ALB and or IVM; signs of drug resistance or reduced efficacy are much less evident for PZQ used in control programs of onchocerciasis and has not been reported for AZM used in the control of trachoma. Low coverage of MDA and suboptimal efficacy of drugs used appear to be a major thread to the success of the programs and are a major risk for drug-resistance development. Appropriate health education delivered during the early stages of the MDA programs and stimulation of community participation appear to be essential prerequisites for optimal coverage and, hence, success of MDA programs. Unless coverage is improved and further commitments are made to fully enroll these programs; elimination of these NTDs as a public-health problem in much of the endemic areas in resource-poor countries may not be realized and diseases may persist or re-emerge. Implementation of complementary measures, such as vector control, improved hygiene and environmental sanitation, is crucial to the success of MDA programs and should be fully implemented once MDA programs have been rolled out and morbidity is reduced. Combining programs and integration with ongoing efforts to control the major tropical infectious disease may help to reduce costs and reduce pressure on the health system. Integration will increase complexity of measures and should be pursued gradually once effectiveness of the MDA program is established. A strong public-health system is a prerequisite for the success of MDA programs and efforts should be undertaken to strengthen the health system in endemic countries with a weak government to allow introduction of the MDA programs and make them available to communities that are still plagued with these diseases.

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 [35–37]. 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 [41–43]. 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 [57–59]. 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.

Schistosomiasis

Etiology, pathology & treatment of schistosomiasis

Urinary schistosomiasis is caused by infection with the flukeworm Schistosoma haematobium and intestinal disease is caused by infection with Schistosoma intercalatum, Schistosoma mansoni, Schistosoma japonicum or Schistosoma mekongi. With the exception of S. japonicum, these pathogens have freshwater snails as an intermediate host and cercariea produced by the snails penetrate the human skin when in contact with infested water. The snail that functions as intermediate host for S. japonicum is amphibious. Disease is primarily caused by the deposition of eggs by adult female worms in blood vessels surrounding the bladder and intestines. Hematuria is the main sign of urinary schistosomiasis and major findings are bladder and urethral fibrosis and hydronephrosis in advanced cases. Intestinal schistosomiasis presents with a number of nonspecific findings, including diarrhea and blood in the stool, with liver enlargement and other pathological findings in more-severe cases [68–70]. Iron deficiency due to blood loss is the major cause of morbidity in schistosomiasis. The amount of iron lost owing to S. haematobium can be very dramatic as large amounts are lost with the urine from hemoglobulin that passes the bladder and patients will require iron supplementation. The use of PZQ in MDA has proven to be a very effective but, unfortunately, the high cost of this drug prohibits its use in many countries [71]. Despite many years of widespread use, no signs of emerging resistance have yet been observed; even though isolates from Egypt with diminished drug sensitivity have been reported, no evidence has been found for a reduced effectiveness of the drug in MDA programs in Egypt [72]. The drug is safe and no serious side effects have been observed, even when administered to pregnant and lactating women [73,74]. The dose of PZQ is based on bodyweight and is 40 mg/kg for S. haematobium infection and 60 mg/kg for S. japonicum infection, or even more conveniently may be based on height [75,76].

MDA for schistosomiasis

Different studies have demonstrated that a single round of community-based PZQ treatment in a high-endemic area results in an extended period of low transmission of S. mansoni and S. haematobobium[77–80]. A very recent study performed in Uganda showed that two rounds of treatment administered to children and adults in high-risk areas resulted in an overall 83% reduction of the prevalence of S. mansoni and a mean reduction in egg burden of 92% [81]. However, experience in China with the control of S. japonicum has demonstrated that, after termination of the control program, which was based on treatment of humans and animals with PZQ, and depletion of the snail population using the molluscicide niclosamide, the prevalence of infection increased again [82]. Furthermore, although MDA is effective in reducing the prevalence of infection in high-prevalence areas, it is much less effective in low-prevalence areas [83]. The control of S. japonicum was more successful on Bohol Islands in The Philippines where, by high coverage of selective mass treatment based on stool examination accompanied by successful snail control, the prevalence of the infection has been kept low for more than two decades [84]. While such an approach may work in isolated communities it has proven to be less effective elsewhere. Furthermore, snail control is expensive, difficult to sustain and the use of molluscicides has negative effects on the environment. Given the complex lifecycle of these blood flukes, mathematical modeling has been employed to predict the outcome of control strategies. One model has emphasized the importance of environmental and seasonal factors to consider [85]. In addition, it can be foreseen that infrastructural water-management projects may have a huge impact on the habitat of snails (and intermediate hosts and vectors of other infectious diseases) and mathematical modeling may help to predict the effect of changes in water management on the frequency and transmission dynamics of infectious diseases [86]. If through increased contacts any such negative affects are foreseen, control and preventive measures should be taken. Water-management projects may also lead to less contacts and, hence, less risk of disease. Health-impact assessment implemented early in the project development plan may assist in mitigating negative health impacts and enhancing positive effects [87].

It has been noted that the problem of schistosomiasis is underestimated in sub-Saharan Africa and that national health authorities have been reluctant to develop a commitment toward its control because the required public-health effort is judged disproportional high [88,89]. Therefore, integration with other programs in areas of overlap should be considered. Individuals infected with food-borne trematodes, such as the liver flukes Clonorchis sinensis, Opisthorchis felineus and Opisthorchis viverrini, the lung flukes Paragonimus spp., and the intestinal flukes Fasciolopsis buski, Echinostoma spp., Heterophyes heterophyes and Metagonimus yokogawi, may also benefit from PZQ or ALB treatment [90], providing another argument for setting up MDA programs based on these drugs.

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 [98–101]. 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 [110–112]. 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].

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 [123–127]. 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 [135,137–139]. 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 [141–144]. 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 from the 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 [155–157].

Trachoma

Etiology of trachoma

Trachoma is a chronic follicular keratoconjunctivitis caused by repeated eye infection with the intracellular bacterium C. trachomatis of, in particular, the tarsal conjunctiva underlying the upper eyelid [158,159]. In endemic communities, the pathogen is spread from eye to eye by flies (Musca sorbens) contaminated fingers and human secretions. These repeated infections produce scarring and lead to the inwards turning of the eyelashes (trichiasis), which causes, in addition to constant discomfort, damage of the corneal surface, corneal opacification and may, eventually, result in blindness. The prevalence of active trachoma is often higher than 20% and may approach 100% in some areas of intense transmission [160]. In endemic areas, trachomatous trichiasis may be observed in 10% of people aged 40 years and over and bilateral trachomatous trichiasis may be responsible for 10–40% of all blindness [161].

MDA for trachoma

The infection may be treated by topical application of antibiotics. However, compliance in self-administration of eye ointments is low because they are difficult to apply, sting and temporarily blur vision. Therefore, the use of eye ointments is not recommended for the control of trachoma. Ocular chlamydial infection may also be treated with a single oral dose of AZM [162–164], and when the drug is administered to an entire community it is possible to reduce the prevalence of infection to a low level, provided that the administration of the drug is accompanied with a set of specific measures [14,162,165–167]. The recommended strategy for the prevention of blinding trachoma relies on the annual administration of one oral dose of AZM (20 mg/kg bodyweight to a maximum of 1 g) in combination with trichiasis surgery (to prevent eyelashes from damaging the cornea), improved hygiene and sanitation (to reduce the risk of infection and the number of flies, and to contain the spread of the infection) and health education [168,169]. This strategy is called SAFE, ‘S’ stands for corrective eyelid surgery, ‘A’ for antibiotics for treatment of individuals with signs of active disease and MDA to at-risk communities, ‘F’ for facial cleanliness hygiene promotion and ‘E’ for environmental improvements, such as provision of sanitation and water. These measures are primarily intended to minimize discomfort (by surgery) and to control the infection by disrupting transmission and prevention of new infections. A review of the literature has demonstrated that surgery for trichiasis does not prevent blindness, even if AZM is administered at the time of surgery, and while antibiotic treatment has only a modest effect on the development of active trachoma, neither does face washing or fly control by spraying or provision of latrines [170–173]. Health education might be effective [174], and seems to be essential to increase participation and to take away prejudices and fears for surgery. However, by controlling the pathogen and prevention of its transmission and spread the number of new cases is strongly reduced. The control of trachoma by SAFE is recommended for all eligible individuals in areas where the prevalence of the clinical sign ‘trachomatous inflammation follicular’ is at least 10%, and in areas where the prevalence is lower than 10% for those communities with a prevalence of at least 10% [175,176]. The SAFE policy was first started less than a decade ago and has been very successful. For instance, by implementing the SAFE strategy between 1997 and 1999, Morocco has virtually eliminated the disease. In 1992, approximately 5.4% of the population of this country showed signs of trachoma with almost all cases concentrated in five arid and rural provinces. SAFE was applied in a staged approach with annual treatment of everyone in areas with more than 20% of children under 10 years of age showing signs of active trachoma. In areas where infection rates were lower, treatment was focused on affected children and their families, and in areas where the level of infection was less than 10%, cases were treated individually. This strategy has resulted in a 99% reduction of active trachoma in children in a period of less than 6 years. In 2010, it is expected that trachoma will be controlled in several other countries, including the Gambia, Ghana, Mauritania and Vietnam, and other countries will probably follow in subsequent years. The trachoma situation probably is worst in Ethiopia in which almost the entire rural population, approximately 65 million people, is at risk [31].

Evaluation of the SAFE strategy has demonstrated that, in general, the coverage of drug administration is acceptable but that the quality and quantity of surgery is inadequate [177]. Furthermore, the scarcity of good-quality water supplies often hampers improvement of personal hygiene. Although the elimination of the infection from a village as demonstrated in Nepal and Tanzania [168,169] is possible, the infection, unfortunately, tends to return over time [165,166,176,178,179]. Mathematical modeling has indicated that, in a country-wide approach, depending on the prevalence of infection, elimination from a large proportion of communities is feasible in a period of 5 years provided that treatment coverage is at least 90% and the treatment is administered biannually [180]. However, the model also indicated that in hyperendemic areas and with the WHO recommended coverage of 80%, elimination would take at least 12 years. Beside coverage, several factors may influence the effectiveness of the SAFE strategy. It has been found that MDA strongly reduces the number of face flies that are infected [181], and this might be an essential factor in the interruption of transmission and elimination of the infection. Individuals who did not receive the drug during MDA have a reduced chance of becoming infected, indicating that a single dose already reduces transmission [182]. However, a single dose of AZM may not be sufficient to clear the infection from sites other than the eye, and it was demonstrated that children with a chlamydial-positive nasal discharge at the time of drug administration had an increased risk for ocular reinfection with the same pathogen [183]. Such extraocular sites could be important sources of chlamydial eye infections through direct transfer by fingers or via clothes, bed sheets or towels. Furthermore, waning immunity may make communities more susceptible to reinfection after successful MDA [184].

Clinically active trachoma has disappeared almost completely from some villages in Western Nepal, and it has been argued that the elimination of the infection is only in part the result of the antibiotic treatment programs that had been in place [185]. It was noted that, in these villages, no specific attempts were made to improve hygiene and sanitation, such as building of pit toilets or building water supplies as measures for fly control and to improve facial cleanliness. Other secular effects, such as increases in economic prosperity or, perhaps, education, may have helped to eliminate the disease. A reduction in the prevalence of active trachoma has also been noted in a village in The Gambia long after a modest antibiotic administration program was completed and in a district in Malawi in the absence of organized distribution of antibiotics [186,187]. Most probably, general improvements in the standard of living had contributed to the observed reduction of trachoma. Recent economic development and improved living conditions may also have contributed to some extent to the success of the SAFE program in Morocco. The prevalence of active trachoma was reduced significantly by MDA in communities in rural Ethiopia [188]. However, it is increasingly recognized that in areas with extreme poverty, trachoma remains a substantial health problem after MDA and that major educational and environmental improvements are crucial to control the infection in particular in such areas [189]. After MDA, children with ocular discharge and the presence of flies are risk factors for active trachoma and, hence, children remain an important target group in communities that already have received MDA. To increase the effect of the SAFE strategy, biannual MDA may be considered in high-risk areas; after 2 years of biannual MDA, ocular chlamydial infection was observed in only one out of eight rural communities in Ethiopia compared with six out of eight after annual treatment [190].

Drug resistance

In spite of the enormous number of people that have received treatment, no evidence of emerging drug resistance has been presented; a single study performed in Tanzania did not reveal any evidence of reduced AZM or tetracycline susceptibility [191]. Drug resistance in Chlamydiae is very rare, and resistance to macrolides particularly seems to be difficult to induce in vitro[192]. Macrolide drug resistance in organisms with single copies of the rRNA genes in their genome, such as Chlamydia, usually arises by mutations in 23S rRNA at the antibiotic contact site but other mechanisms, such as mutations in the ribosomal binding proteins, may be involved as well. Mutations in the 23S rRNA have been demonstrated to occur in some rare Chlamydia pneumoniae isolates and these were associated with high-level resistance [193,194].

Given the profound impact of blindness on physical and social well-being as well as on the economic prospects of individuals, their relatives and communities in which they live and the considerable improvement that relatively small but apparently crucial changes may have on the prevalence of trachoma, urgent efforts should be taken to realize such changes in the communtities that are the most affected.

Expert commentary

The goal of MDA programs is to eliminate disease as a public-health problem by reducing diseases prevalence rates to a level that will interrupt transmission and that will make re-emergence of the disease unlikely. The almost complete disappearance of LF after MDA from several countries, including some African countries, and the successful control of trachoma in Morocco have clearly demonstrated that the control of these NTDs is also possible in resource-poor communities in developing countries. However, it has become increasingly clear that delivery of MDA to all target groups may not be easily achieved due to lack of funding and/or infrastructure. In addition, programs suffer from suboptimal coverage and the consensus is that, at current coverage rates, prolongation of treatment with additional rounds of MDA during additional years is needed or that MDA should be intensified and administered more frequently. Coverage may be improved by strengthening health education and stimulating community participation. Research is needed to determine optimal strategies to improve coverage of MDA under different cultural conditions. The implementation of complementary program measures, such as vector control, improved hygiene and environmental sanitation, which aim to remove factors that contribute to the transmission of the pathogens, is essential for a prolonged effect of MDA and to prevent re-emergence of the disease. Studies are needed to address the efficacy of these measures and their optimal delivery in resource-poor communities. The implementation of a quality system could be another means to improve efficacy by improving and adjusting measures at an early stage [195]. Geographical information systems and remote sensing are important tools to understand the ecology and epidemiology of neglected diseases, to help to identify target populations and to assess the efficacy of the MDA control measures [196,197].

The development of reduced drug sensitivity or even resistance is of major concern because alternative drugs for MDA are not able to respond to drug resistance should it occur. However, evidence that altered drug sensitivity plays a role in the observed suboptimal effect of MDA is weak but, with the extension of programs and increased drug pressure, it could become an important issue, particularly in the cases of onchocerciasis owing to the use of a single drug in combination with the very long lifespan of the adult female worms and in the cases of STH and LF owing to the simple mechanism by which resistance to ALB is developed (Table 3). With the progression of the different programs, the implementation of effective monitoring systems for MDA efficacy will be crucial and a shift to targeted case detection and treatment may be needed in order to eliminate foci of transmission and to identify emerging drug-resistance at an early stage. Unfortunately, viable alternatives to current MDA programs are not readily available. However, drug-discovery programs for some of the NTDs have yielded promising compounds that may be developed into effective drugs [198]. Vaccine developments are, at best, still at the stage of basic research [199–206].

Mass drug administration takes a high toll on the limited capacity of the health services. In addition, interest in the control of NTDs will lessen when their prevalence becomes lower and, hence, programs may become unsustainable when the target is within reach. Therefore, at this stage, combination of MDA programs in areas where NTDs overlap appears to be the main strategy to reduce costs and to ensure sustainability. Integration with control programs for the major tropical infectious diseases, such as malaria, including combination of MDA for NTDs with bednet programs, is an option to consider [207,208]. MDA programs also could be merged with immunization activities.

The persistence of remaining foci of infection of Guinea worm in nomadic tribes in some remote areas in Africa illustrates the fact that these diseases are less easily controlled in these more-vulnerable and often marginalized communities. Disease may re-emerge from such communities and, therefore, specific efforts should be undertaken to reach these communities. Less-accessible groups, such as nomadic tribes or children that do not attend school, may be affected more severely. In particular, in countries or areas with low education participation, inclusion of such groups is important. However, delivering healthcare to people with a low level of literacy can be problematic, even if this comprises simple messages or measures [209]. Therefore, special programs to address such groups should be developed.

Finally, there is an urgent need for control programs for other NTDs, such as strongyloidiasis, Chagas disease, human African trypanosomiasis, leishmaniasis and Buruli ulcer. Patients with strongyloidiasis may profit from IVM administration [210,211] and miltefosine, a new drug for visceral leishmaniasis, potentially could be used in MDA [212,213]. Patients with some of these other NTDs could benefit from health education, vector control or the use of bednets as well. However, the development of affordable drugs and vaccines remains of utmost importance for the effective control of these diseases.

Five-year view

The prospects for the MDA programs in resource-poor countries are complex and there is a clear need for priority setting, improved efficacy and coverage and long-term sustainability. Community participation and mobilization, together with health education and information, will be essential to improve success and integration in coendemic areas in a ‘NTDs’ public-health program, and with control programs for the major tropical diseases is crucial for sustainability. This will require accurate disease mapping and identification of target populations using geographic information systems and remote sensing methods [197], establishment of broad partnerships with defined roles for all partners, development of clear educational and information programs and creation and implementation of simple and effective monitoring tools. While MDA is an important tool to reduce disease prevalence emphasis on control measures, including vector control, hygiene and sanitation, is of utmost importance for a long-lasting interruption of transmission. Effective disease control requires the close collaboration of experts from a wide variety of disciplines, including public-health experts, engineers to build the safe and clean environment and infrastructure and communication experts to develop health information packages, and efforts should be undertaken to have these and other disciplines work together effectively [214]. Research into drug discovery and vaccine development remains important but expectations for the emergance of any short-term solutions are low.

Search strategy

Medline was searched for publications published during the past decade using the terms ‘mass drug administration’ and ‘drug resistance’ in combination with any of the following specific key words: soil transmitted helminthes, schistosomiasis, onchocerciasis, lymphatic filariasis and trachoma. Relevant publications were selected and supplemented with publications on specific relevant topics.

Table 1. Neglected tropical infectious diseases and mass drug administration programs.

Disease	DALY estimates (millions)	Etiology (n, millions)	Symptoms	Vector/host/mode of transmission	Diagnosis	Treatment (in MDA)	Methods of prevention and control besides MDA	Example of operational program/initiative	Ref.
Soil-transmitted helminths	4.7–39.0	Lumbricoides, roundworm (807), Trichuris trichuria, whipworm (604), Necator americanus and Ancylostoma duodenale, hookworm (576)	Impairment of child growth and development intestinal obstruction (Ascaris lumbricoides), colitis, diarrhoea (T. trichuria),Iron deficiency and anemia (A. duodenale)	Fecal contaminated environment	Egg counts by microscopic stool examination	Benzimidazole antihelminthics: albendazole (400 mg) and mebendazole (500 mg) single dose	Sanitation (closed toilets), improved housing (cement floors), fly control and health education	2001 World Health Assembly resolution: regular deworming of at least 75% of all at-risk school-age children	[301,302]
Schistosomiasis (snail fever)	1.8–4.5	Schistosoma haematobium (130), Schistosoma mansoni (73), Schistosoma japonicum and Schistosoma mekongi (2)	Impairment of child growth and development, hematuria and renal failure plus bladder cancer in urinary schistosomiasis, diarrhea and disturbed liver function in intestinal schistosomiasis	Fresh water and amphibious (S. japonicum) snails and contact with infested water	Examination of urine for hemoglobulin and microscopic examination of stool for eggs	Prazinquantel (40 mg/kg for S. mansoni and S. heamatobium or 30 mg/kg for S. japonicum) or number of tablets based on body height	Snail control and use of molluscicides and proper water management	Schistosomiasis Control Initiative/Global Network for Neglected Tropical Diseases: once-yearly MDA treatment based on school surveys	[303]
Lymphatic filariasis (elephantiasis)	5.6–5.8	Wuchereria bancrofti, Brugia malayi and Brugia timori (120)	Acute adeno-lymphangitis and acute filarial lymphangitis, lymphatic obstruction, hydrocele, edema of the legs (elephantiasis), Psychiatric illness	Mosquitoes (C. quinquefasciatys and others)	Examination of venous blood sample (collected at night), Ultrasonography	DEC (6 mg/kg) or IVM (400 mg) plus ALB (400 mg)	Mosquito control, Bed nets	PacELF: MDA for the Western Pacific, GAELF: MDA for Africa and Asia	[304,305]
Onchocerciasis (river blindness)	0.5–1.0	Onchocerciasis volvulus (37)	Disfigurement of the skin (hanging groin), visual impairment and blindness	Simulium blackfly	Microscopic examination of skin snips	IVM (150 µg/kg)	Vector control, indoor residual spraying and bednets	Community directed MDA treatment with ivermectin through a network of community drug distributors, APOC	[306,307]
Trachoma	2.3–4.0	Chlamydia trachomatis (84)	Trichiasis Visual impairment and blindness	Flies	Examination of tarsal conjunctiva of upper eyelid	Azithromycin (20 mg/kg)	Environmental sanitation (dryness, dust, dirt, dung, discharge and density overcrowding), facial hygiene (flies, feces, faces, fingers, fomites), health education and eyelid surgery	International Trachoma Initiative	[308,309]

ALB: Albendazole; APOC: African Programme for Onchocerciasis Control; DALY: Disability-adjusted life year; DEC: Diethylcarbamazide; GAELF: Global Alliance to Elliminate Lymphatic Filariasis; IVM: Ivermectin; MDA: Mass drug administration; PacELF: Pacific Programme to Eliminate Lymphatic Filariasis.

Table 2. Efficacy of drug combinations for mass drug administration.

Country and treatment	Disease	Pretreatment prevalence (%)	Reduction (%)		Ref.
Haiti: single-dose ALB 400 mg + single-dose DEC 6 mg/kg	Roundworm Hookworm Whipworm Lymphatic filariasis	34.5 10.3 55.5 34.7	93.3^* 81.6 27.4 80.4		[24]
Haiti: single-dose ALB 400 mg + single-dose IVM 200–400 µg/kg	Roundworm Hookworm Whipworm Lymphatic filariasis	33.5 7.8 42.7 12.6	100.0^* 100.0 79.6 63.2	81.8^‡ 100.0 79.1	[25]
China/The Phillipines: single-dose ALB 400 mg + single dose PZQ 40 mg/kg for Schistosoma mansoni and Schistosoma heamatobium (or + PZQ 30 mg/kg for Schistosoma japonicum)	Roundworm Hookworm Whipworm Schistosomiasis: S. japonicum (China) S. Japonicum (The Phillipines) S. mansoni S. heamatobium	51.7 60.5 81.8 50.0 52.0 83.7 89.7	13.1^§ 20.9 72.3 6.7 6.7 38.5 43.6		[26]

^*Determined 5 weeks after treatment.

^‡Determined 4 months after treatment.

^§Determined 45 days after treatment.

ALB: Albendazole; DEC: Diethylcarbamazide; IVM: Ivermectin; LF: Lymphatic filariasis; MDA: Mass drug administration; PZQ: Praziquantel.

Table 3. Evidence for reduced effectiveness of drugs used in mass drug administration.

Disease	Drug used in MDA	Reduced sensitivity/resistance and effect on MDA	Comment	Ref.
Soil-transmitted helminths	Albendazole	Reduced response to MDA reported for Zanzibar	Mutation conferring drug resistance to albendazole in β-tubulin gene not observed	[64]
Schistosomiasis	Praziquantel	Not observed	Isolates with reduced in vitro response reported from Egypt	[69]
Lymphatic filariasis	Diethylcarbamazide/albendazole, ivermectin/albendazole	Not reported	Increased number of parasites with albendazole drug resistance conferring mutation in β-tubulin gene observed in worms isolated in Burkina Faso	[63]
Onchocerciasis	Ivermectin	Reduced responses reported from Cameroon, Ghana and Sudan with increased repopulation levels shortly after treatment plus spread of resistant strains to nearby communities	Mechanism of action of ivermectin not delineated in detail and a drug-sensitivity test is not available	[140–142]
Trachoma	Azithromycin	No evidence of emerging resistance	Drug resistance in Chlamydiae to macrolides is rare and are thought to be related to rare mutations in the 23S ribosomal RNA gene	[192–194]

MDA: Mass drug administration.

Key issues

• • Neglected tropical diseases (NTDs), including the soil-transmitted helminths (STH), schistosomiasis, lymphatic filariasis (LF), onchocerciasis and trachoma, almost exclusively affect poor and marginalized communities in developing countries, and these diseases combined account for a large proportion of morbidity, mortality and poverty.

• • NTDs may be controlled by mass drug administration (MDA) and the implementation of preventive measures, such as improved hygiene, sanitation, vector control and health education.

• • The control of the NTDs has become possible by the availability of safe and affordable drugs that are effective in a single dose and that may be administered during MDA.

• • The control of the NTDs will contribute to improved well being, economic development and increased prosperity.

• • Many countries have adopted MDA programs for the NTDs and, as these programs are highly cost effective, the implementation of these programs should be strongly advocated.

• • Current MDA programs are successful in spite of specific shortcomings including low coverage, need for program extension and pressure on the development of drug resistance.

• • MDA programs should be made available for more countries, particularly for countries in sub-Saharan Africa suffering from schistosomiasis owing to the costs of praziquantel.

• • A high coverage (>80%) is fundamental to the success of the MDA programs and should be promoted by health education, integration and quality assurance.

• • To consolidate the efficacy of MDA, the effective implementation of vector control and of measures to improve hygiene and environmental sanitation needs to be prioritized.

• • Failure to improve coverage and effective implementation of vector control, improvement of hygiene and sanitation may result in program failure and re-emergence of the NTDs.

• • Integration of MDA programs and embedment within existing health structures is essential to further increase the efficacy and to reduce the costs of the MDA programs for the NTDs and elevate their toll on the health system.

• • Coadministration of drugs used in MDA programs does not lead to significant side effects, allowing integration of programs.

• • Safety studies to investigate the coadministration of azithromycin are needed to facilitate program integration.

• • Community participation and mobilization are essential for implementation in resource-poor communities and will contribute to sustainability.

• • The control of STH, LF and onchocerciasis, which relies on the use of albendazole and or ivermectin, is faced with reduced drug sensitivity or the emergence of drug-resistant strains; signs of drug resistance are much less evident for praziquantel used in control programs of onchocerciasis and has not been reported for azithromycin used in the control of trachoma.

• • To assess the efficacy of the MDA programs and to prevent the development and spread of drug-resistant strains, adequate monitoring systems should be developed.

• • Targeted disease identification and treatment actions may be considered in areas where MDA has been applied and re-emergence is suspected owing to a suboptimal coverage or reduced drug efficacy.

• • The feasibility of eliminating NTDs as a public-health problem in resource-poor countries is illustrated by the example of blinding trachoma, which has been successfully controlled in Morocco, and by the example of dracunculiasis that has been eliminated from approximately half of the countries where it was once endemic.

• • The lack of viable alternatives for currently used drugs is cumbersome and calls for intensified efforts into drug and vaccine development for the NTDs.

• • Attention needs to be paid to the development of public-health structures in countries with weak medical systems and governments.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.