Impact of ivermectin on illness and disability associated with onchocerciasis

Authors


Authors
James M. Tielsch (corresponding author) and Arlyne Beeche, Department of International Health, Bloomberg School of Public Health, John 615 North Wolfe Street, E8132, Baltimore, MD 21205, USA. Tel.: +1-410-955 7934; Fax: +1-410-614 1419; E-mail: jtielsch@jhsph.edu, abeeche@jhsph.edu

Summary

The Onchocerciasis Control Program (OCP), one of the most successful vertical disease control programs in the history of public health, came to an end in 2003 with devolvement of responsibilities for control program activities passed to the countries affected. Fortunately, 15 years ago the Mectizan® Distribution Program (MDP) was founded to provide a complementary approach to controlling the disabling consequences of this parasitic infection. With over 250 million doses of ivermectin distributed over the past 15 years, the MDP is well on its way to both solidifying the progress made by the OCP and extending program reach well beyond the boundaries of the OCP. Through the extensive clinical testing protocols implemented in a variety of countries in Aftica, ivermectin has been proven to be a safe and highly effective treatment for onchocerciasis. Regular distribution to populations living in endemic areas has demonstrated significant reductions in blinding ocular complications, transmission, and disability caused by onchocercal skin disease. As yet undocumented, are the likely significant impact regular population dosing with ivermectin has on intestinal helminth infections, lymphatic filariasis, and human scabies infection. While there are significant barriers to continued program success, focussed attention on expanding and improving community-directed ivermectin distribution is likely to lead to further progress against this resilient infection.

Introduction

The 15th anniversary of the Mectizan® Distribution Program (MDP) in 2002 marked an important milestone in the continuing efforts to control the adverse consequences of onchocerciasis. The early post-licensure field trials provided strong evidence that the widespread distribution of ivermectin could complement the vector control strategies underway in West Africa and offer the potential to reduce the burden of onchocercal blindness and skin disease in areas outside those covered by the Onchocerciasis Control Program (OCP). The past 15 years have provided early evidence that the widespread use of ivermectin (over 250 million doses over the past 15 years) in communities endemic for onchocerciasis may live up to these high expectations. However, since 2003 the challenge has been even greater as one of the most successful vertical disease control programmes in history comes to an end. The WHO-managed, multi-country OCP will end and full responsibility for onchocerciasis control will devolve to the countries. This will place a significant additional burden for continued control on the MDP while we wait for the development of a safe, effective, and simple to deliver macrofilaricide.

This paper reviews the clinical development and testing of ivermectin for onchocerciasis, the available data on its impact on blindness and disability, and its ancillary benefits for other parasitic disorders highly prevalent in those countries affected by onchocerciasis.

Human trials of ivermectin for treatment of onchocerciasis impact on microfiladermia

Twenty years ago, ivermectin was known as a safe and effective anthelminthic drug for use in combating a variety of parasitic nematodes in animals. Its widespread use and therapeutic profile suggested that it might also be useful for the treatment of Onchocerca volvulus in humans. However, the tolerance of the drug in humans was unknown and there was concern that a highly effective microfilaricide like ivermectin might produce the same severe inflammatory reactions seen with diethylcarbamazine (DEC). Despite concern that adverse results in human trials might undermine ivermectin's use in veterinary medicine, Merck supported initial clinical testing of ivermectin for use in treating onchocerciasis. Phase one trials were promising. Relative to DEC and placebo, ivermectin resulted in significant and longer lasting decreases in microfilarial skin loads, and most adverse effects were mild and non-ocular (Brown & Neu 1990).

Phase two studies were conducted in Liberia, Senegal, Ghana and Mali. Doses ranged from 50 to 100 μg/kg and again, substantial decreases in microfilarial skin loads were observed. Furthermore, corneal and anterior chamber loads of microfilaria were greatly reduced and there was little indication that Mazzoti-type reactions occurred. The reduction in skin and eye microfilaria loads were prolonged and maintained for approximately 9 months (Greene et al. 1985; Lariviere et al. 1985; Awadzi et al. 1986; Diallo et al. 1986).

Phase three studies were conducted in Cote D‘Ivoire, Ghana, Guatemala, Liberia, Mali, and Togo. Patients received either 100, 150, or 200 μg/kg of ivermectin, although no differences between regimens were apparent after 3 months. Skin and eye microfilaria loads remained low after 1 year, and adverse reactions were mild, with no adverse reactions occurring in the eye (White et al. 1987). As a result of the minimal ocular and systemic side effects of treatment, it was decided that ivermectin would be safe for mass distribution (Taylor & Greene 1989a). This series of studies suggested that a dose of 150 μg/kg was adequate to produce a sustained reduction in microfilarial skin loads with an acceptable safety profile. As a result, ivermectin was registered in France in 1987.

Given that adult O. volvulus can live 12–15 years, and that ivermectin is primarily a microfilaricide, it was anticipated that once distribution programmes began, regular treatment would be required for at least 15 years before it would be safe to stop in any particular community. It was also assumed that, as the ocular complications associated with significant visual loss in onchocerciasis were not reversible, an extended period of ivermectin distribution would be required before significant reductions in the cross-sectional prevalence of blindness and visual impairment would be observed.

Post-licensure studies followed the phase three trials and were conducted primarily in West Africa. These large community studies were designed to evaluate the effectiveness, safety, and acceptability of ivermectin at the community level and to provide preliminary evidence related to the impact of regular ivermectin dosing on transmission. From 1987 to 1988, eight community-based studies were conducted within the OCP area and five were conducted in areas outside the OCP. The study communities represented various epidemiological conditions including hyper- and meso-endemic areas with and without vector control (Dadzie et al. 1987, 1989a, 1991; Taylor et al. 1989b). These studies suggested that annual ivermectin treatment might be sufficient to control ocular disease caused by onchocerciasis, even in areas of high endemicity.

The effects of ivermectin on microfilaridermia were evaluated with longitudinal skin snip surveys. The overall effect of ivermectin treatment in the various study areas was a reduction of 96–99% in skin microfilariae within the first few months of treatment (Remme et al. 1990). However, the time to recrudescence varied between areas. Ivermectin treatment was also associated with decreases in the number of microfilariae found in onchocercal nodules in the post-licensure studies (Albiez et al. 1988).

The multi-year follow-up studies have shown a significant impact on decreasing microfilarial skin loads. After 5 years of treatment in Asubende, there was a 90% reduction in skin microfilaria (Alley et al. 1994). In Gami, Central African Republic, a drastic reduction in both the prevalence and intensity of O. volvulus microfilaridermia was observed after 5 years of annual treatment in the community (Kennedy et al. 2002). Repeated doses of ivermectin appear to have a cumulative effect, and multiple annual doses of ivermectin have resulted in a slower repopulation of the skin by microfilariae (Whitworth et al. 1992).

Impact on adult Onchocerca volvulus

A variety of studies have been conducted to estimate the potential effects ivermectin might have on adult O. volvulus. The majority of these studies used the standard dose of ivermectin (150 μg/kg), and varying re-treatment regimens. Higher doses of ivermectin did not enhance any effects of the drug on adult O. volvulus. No additional impact on adult O. volvulus was observed when 800 μg/kg every 3 months was used compared with standard doses (Gardon et al. 2002).

The effect of ivermectin on the reproductive cycle of adult O. volvulus has been well described in the literature. Although there is controversy on some aspects of this relationship, it is reasonably clear that multiple doses of ivermectin have little direct impact on oogenesis (Duke et al. 1990; Chavasse et al. 1992; Kläger et al. 1996). There is some effect on fertilization of adult females with increasing doses associated with significant reductions in the proportion of female worms containing sperm (Duke et al. 1991, 1992; Chavasse et al. 1993), although the spermatozoa themselves are normal (Albiez et al. 1988).

Multicellular stages develop within the female O. volvulus uterus and are released from the vulva as stretched microfilaria. This development is impeded by multiple doses of ivermectin, likely because of paralysis of the lower uterus (Duke et al. 1992). This results in an accumulation of normal and degenerating microfilaria, which intensifies after multiple treatments (Awadzi et al. 1986; Albiez et al. 1988; Chavasse et al. 1992). It is likely that ivermectin's impact on fertilization is indirect and a result of obstruction of the uterus with degenerating microfilariae (Albiez et al. 1988; Chavasse et al. 1992).

Both single and multiple doses of ivermectin are associated with fewer adult males in nodules (Awadzi et al. 1985; Greene et al. 1985; Duke et al. 1990, 1992; Gardon et al. 2002). In contrast to adult females, adult males are mobile and capable of inseminating females residing in different nodules. It has been postulated that ivermectin may alter the mechanisms that allow adult O. volvulus to locate each other. This could account for males’ migration from nodules after multiple treatments. The males’ migration may also account for the decrease in inseminated females observed after numerous ivermectin dosages (Duke et al. 1992).

Results from a variety of studies suggest that repeated ivermectin doses results in an increase in the proportion of dead and moribund adult worms, primarily females (Duke et al. 1990, 1991, 1992; Chavasse et al. 1992; Gardon et al. 2002). Nonetheless, the majority of adult worms appear to remain unaffected, healthy, and capable of reproducing (Duke et al. 1990; Kläger et al. 1996). While ivermectin does have a significant effect on adult O. volvulus, its role in onchocerciasis control is clearly dominated by its microfilaricidal activity.

Wolbachiae

Wolbachia endobacteria are symbionts of arthropods and are also found in filarial nematodes, including Onchocerca volvulus. Recent evidence suggests Wolbachia bacteria contribute to the inflammatory pathology associated with disease (Taylor & Hoerauf 1999; Saint Andréet al. 2002). There is a symbiotic relationship between Wolbachia endobacteria and O. volvulus, and its depletion has a long-term adverse impact on worm fertility. In Ghana, 6 weeks of daily doxycycline resulted in almost complete depletion of Wolbachiae by 11 months and an inhibition of embryogenesis in female O. volvulus (Hoerauf et al. 2000, 2001). Among patients receiving both ivermectin and doxycycline, there was an absence of microfilaridermia in more than 90% and very low microfilariae intensities in the remaining cases. In participants receiving ivermectin alone, microfilariae began to recrudesce within 4 months of treatment (Hoerauf et al. 2001). These data suggest that treatment for Wolbachiae infection may be complementary to ivermectin in controlling onchocerciasis and its associated morbidity (Saint Andréet al. 2002). However, the extended doxycycline regimen required for a significant impact on fertility is currently impractical for a mass chemotherapy approach. Nonetheless, the concept of an effective, safe and easily administered drug that can cause permanent sterility in adult O. volvulus through its impact on Wolbachiae, may be just as important as a macrofilaricide for future progress in onchocerciasis control.

Safety of ivermectin

Ivermectin is a safe and well-tolerated drug. The incidence, but not severity, of adverse effects attributed to ivermectin is related to the pre-treatment intensity of microfilariae in the skin (De Sole et al. 1989; Rothova et al. 1989; Chijioke & Okonkwo 1992; Zea-Flores et al. 1992; Njoo et al. 1993). In endemic areas, the intensity of microfiladermia increases with age corresponding to the higher incidence of adverse reactions observed in persons 20 years of age or older in communities using mass distribution of ivermectin (Zea-Flores et al. 1992). No deaths attributed to ivermectin treatment have occurred in mass chemotherapy safety trials (De Sole et al. 1989; Pacquéet al. 1991a; Zea-Flores et al. 1992). Furthermore, the incidence of adverse reactions caused by ivermectin in these community studies has been lower than the incidence reported in the clinical trials (De Sole et al. 1989).

The most common adverse effects attributed to ivermectin treatment were oedema, fever, puritis, and pain, although their relative frequency varied among sites (Pacquéet al. 1991a; Chijioke & Okonkwo 1992; Zea-Flores et al. 1992). Most adverse reactions occurred within 24–48 h after treatment, and were mild to moderate in severity, transient, and manageable by primary healthcare workers. These reactions are generally self-limiting and become less severe with subsequent treatments (Pacquéet al. 1991a; Chijioke & Okonkwo 1992; Zea-Flores et al. 1992). Few adverse reactions are severe and have included severe sustained postural hypotension and dyspnoea, the latter was not observed in the clinical trials (De Sole et al. 1989; Chijioke & Okonkwo 1992).

The original guidelines for use of ivermectin in community-based distribution programmes call for excluding pregnant women, children younger than 3 years, and women nursing infants under 3 months. There have been no trials that have specifically assessed ivermectin's impact on pregnant women and their newborns; however, this issue has been addressed as a part of the large, post-licensure studies. In a 3-year community-based study in Liberia, only 31% of pregnant women were aware of their pregnancy during the ivermectin dosing rounds, and 50% of these would be treated unintentionally during the first trimester if routine pregnancy testing was not a part of the distribution protocol. Among the dosed and non-dosed pregnant women, no significant difference in birth defects was detected (Pacquéet al. 1990a). These results have led to increased flexibility in the population eligible for ivermectin treatment. Where the risk of blindness is high, treatment has been extended to include pregnant women or women that have been nursing for at least 1 week (Brown 1998). Neither the incidence nor the severity of side effects of ivermectin treatment is associated with concurrent intestinal parasitic infection. On the contrary, ivermectin treatment gives the additional benefit of significantly reducing Ascaris lumbricoides worm loads (Njoo et al. 1993). Additional trials have shown that dosages 10 times above the highest FDA approved dose (200 μg/kg), as well as regimens consisting of higher than standard and more frequent doses, were shown to be well tolerated with no central nervous system toxicity (Guzzo et al. 2002).

Ivermectin's safety, ease of administration, and high efficacy for both onchocerciasis and ascariasis has led to its wide acceptance among communities endemic for onchocerciasis (Pacque et al. 1989; Pacquéet al. 1990b).

Impact on transmission

When microfilarial skin loads decline, blackflies take up fewer microfilariae with each blood meal (Cupp et al. 1986; Prod'hon et al. 1987). The uptake of fewer microfilariae results in the production of fewer infective L3-stage larvae, which in turn, affects the annual transmission potential (ATP) resulting in a lower intensity of transmission (Cupp et al. 1986). In Liberia, after two annual doses of ivermectin, the number of infective flies with L3 larvae was reduced by 82–89%, and a 63–97% reduction in the intensity of transmission was observed (Trpis et al. 1990). In Ghana, a reduction in transmission intensity of 65–85% was observed 3 months post-treatment (Remme et al. 1989).

In addition to this standard approach for assessing transmission, young children have been used as sentinel populations for assessing initial infections with O. volvulus. As the majority of children under 5 years of age have not been treated, this approach allows the identification of incident O. volvulus infections. Results have demonstrated a significant impact of mass ivermectin chemotherapy on decreasing transmission. In Senegal and Guinea Bissau, no new infections in children aged 0–5 years were detected after eligible persons within the community had been treated with ivermectin (Boatin et al. 1998). In Liberia, after only 2 years of ivermectin distribution among persons older than 12 years of age, the prevalence of infection in 5-year-old children decreased by 21%, and a reduction of 45% in the incidence of infection in 7–12-year-old children was observed (Taylor et al. 1990). Finally, in Cameroon, the prevalence of skin microfilariae and mean microfilarial skin densities were reduced by 55% and 77% respectively in 5–7-year-old children that had never been treated with ivermectin (Boussinesq et al. 1995).

In areas with seasonal O. volvulus transmission, it has been suggested that the most effective use of ivermectin would be to treat high-risk populations just prior to the period of highest vector density. In Mali it was shown that treated individuals remained non-infective to competent blackflies for up to 6 months post-treatment. This time interval was considerably longer than the 3-month vector-breeding period during which intense transmission occurs (Cupp et al. 1986). In addition, ivermectin is an effective prophylactic agent against juvenile worms in the bovine model (Tchakoute et al. 1999). If a similar effect occurs in human infection, this supports the argument for timing ivermectin distribution just prior to the high transmission season.

In the Americas, mathematical modeling suggests that twice-yearly treatment and high coverage (85% or higher) can eliminate the infection in the Guatemalan foci. In Africa, elimination of infection is a longer-term goal and there remain serious questions about its feasibility. Mathematical models suggest that periods of over 35 years will be required for areas with medium or greater levels of endemicity, significant heterogeneity in prevalence, and annual treatment with modest coverage of 65% (Winnen et al. 2002). There is some concern that the models used to make these projections do not adequately account for a variety of factors that can affect their estimates (Borsboom et al. 2003). A recent review of programme performance data from the OCP areas suggests that elimination of transmission is unlikely in most situations and that programs may be required for the foreseeable future (Borsboom et al. 2003).

Impact of chemotherapy with ivermectin on blindness caused by onchocerciasis

Impact of combined ivermectin and vector control

The OCP proved that vector control was an effective approach to controlling onchocerciasis. Over the period of OCP operations, it was responsible for 25 million hectares of land for resettlement and agriculture, more than 35 million people freed of O. volvulus infection, and the prevention of >2 00 000 cases of blindness (Molyneux 1995). While vector control can be highly effective when performed well, control of ocular onchocerciasis occurs more rapidly when both ivermectin chemotherapy and vector control are practiced concurrently (Abiose 1998). Mathematical modelling suggests that the duration of vector control required to reduce recrudescence to less than 1% could be reduced from 14 to 12 years when combined with annual ivermectin treatment at a coverage of only 65–70% (Molyneux 1995; Plaisier et al. 1997). However, this combined approach is unlikely to be implemented in the future except in selected locations.

Impact of ivermectin chemotherapy without vector control

The African Program for Onchocerciasis Control (APOC) was established to maintain and extend the success of the OCP in areas endemic for onchocerciasis outside the OCP. A similar programme has been established in the Americas, the Onchocerciasis Elimination Program of the Americas (OEPA), but the disease is highly focal and of only modest intensity in these populations. Both programmes use a strategy based on the distribution of ivermectin at the community level. Significant impact on ocular onchocerciasis has been observed in APOC areas. In a holoendemic area of Ghana, ocular microfilarial loads in the anterior chamber and cornea decreased to 20% and 10% of pretreatment levels (Dadzie et al. 1990). Reduction in the prevalence of ocular lesions including sclerosing keratitis, iridocyclitis, and optic atrophy have been observed however, the reductions have not been significant in all studies, likely because of the relatively limited follow-up period (Dadzie et al. 1991; Whitworth et al. 1991; Cousens et al. 1997; Abiose 1998; Kennedy et al. 2002). The lack of significant impact of chemotherapy on already present severe ocular disease suggests that the prevalence of these advanced signs will decline slowly over time as these individuals die and the population becomes characterized by persons with low or absent microfilarial loads. Estimated numbers of cases of blindness avoided based on the initial 15 years of ivermectin distribution are difficult to obtain as the distribution of various O. volvulus strains, their intensity of infection, and their pathogenicity is not as well understood as it was for the OCP area. However, given the significant reductions in microfilarial infection achieved with regular ivermectin distribution, these numbers are likely to already approach that observed over a similar period of time with intensive vector control.

The most important question for APOC and for the OCP areas is whether mass treatment with ivermectin alone can achieve and/or maintain the burden of infection adequate to achieve control programme objectives. As elimination of infection is unlikely, most observers have settled for programme objectives that call for control of ocular and other systemic morbidity caused by onchocerciasis. Data from the OCP areas suggest that dramatic reductions in risk of blindness have been achieved with ivermectin alone (Borsboom et al. 2003). However, continued transmission requires that control programme efforts be extended indefinitely.

Impact of ivermectin on other morbidities

Onchocercal skin disease

Until recently, the importance of onchocercal skin disease (OSD) as a disabling condition was underestimated. In addition, the geographic distribution of OSD did not match that seen for the ocular complications of onchocerciasis. The reason for this discrepancy is unclear but is likely because of differences in strains of O. volvulus. OSD tends to occur with higher prevalence in forest areas, while ocular disease and blindness are more prominent in Savannah regions (Dadzie et al. 1989b). Even after the introduction of ivermectin distribution as a control strategy, communities plagued primarily by OSD were not targetted for mass chemotherapy.

Skin reactions to O. volvulus infection vary, and the montage includes depigmentation, skin lesions, itching, and dermal atrophy. Troublesome itching was found to be one of the most important symptoms of onchocerciasis in a Pan-African study conducted to evaluate the importance of OSD (World Health Organization 1995). Strong associations have been found between the prevalence of skin lesions and troublesome itching and onchocercal endemicity (World Health Organization 1995). Despite that, O. volvulus loads are not linearly associated with disease severity, and low and high parasite intensities can result in skin reactions (Ghalib et al. 1987; Mukhtar et al. 1998; Makunde et al. 2000).

Studies on the severity and impact of troublesome itching and OSD began in the 1990s. Qualitative research studies confirmed that OSD and troublesome itching had a negative impact on the mental health and social acceptability of both genders (Brieger et al. 1997, 1998a; Vlassoff et al. 2000). The burden of illness associated with OSD and itching was higher that expected with Disability Adjusted Life Years (DALYs) lost roughly equivalent to that estimated for ocular disease and blindness (Remme 1998). This finding resulted in an expansion of the ivermectin distribution programme to include communities affected primarily by OSD.

During the period when vector control was the only strategy for control of onchocerciasis, persons already afflicted with onchocercal skin manifestations did not benefit directly from the intervention. Early studies suggested that ivermectin was associated with improvement in severe itching and a decrease in the prevalence and severity of skin lesions (Somo et al. 1993; Whitworth et al. 1996). In a multicentre trial conducted in Ghana, Nigeria and Uganda, significant reductions in the prevalence and severity of lesions were observed and the prevalence of severe itching was reduced by 40–50% (Brieger et al. 1998b; Ogbuagu & Eneanya 1998). Depigmentation however, is not affected by ivermectin treatment (Pacquéet al. 1991b; Burnham 1995; Kennedy et al. 2002).

Ectoparasitic infections

Scabies is a highly prevalent infection of the skin caused by infestation with the mite Sarcoptes scabiei. The female mite lays her eggs in burrows in the skin, larvae emerge after 2–3 days, they mature, mate, and the process begins again. Infection can cause significant itching and discomfort and scratching can result in secondary bacterial infection by a variety of pathogens including group A Streptococcus and Staphylococcus. The crusted form of the disease, Norwegian scabies, is characterized by intense infestation and severe symptoms and is typically associated with immune system dysfunction. The prevalence of scabies infection has not been well described, especially in areas of Africa where onchocerciasis is present. However, several reports suggest that the prevalence can exceed 30% in pre-school age children and 6% in older children (Masawe & Nsanzumhgire 1975; Dunne et al. 1991; Henderson 1991). Topical agents such as lindane, permethrin, and benzyl benzoate have been the preferred approaches to treatment but these often require multiple applications and have significant side-effects (Green 1989; Wendel & Rompalo 2002). Recently, ivermectin has been shown to be highly effective against both the typical and the crusted forms of scabies (Glaziou et al. 1993; Meinking et al. 1995; Wendel & Rompalo 2002). An important ancillary benefit to the ivermectin distribution programme is a reduction in the prevalence and severity of scabies in the population. This may also contribute significantly to the acceptability of chemotherapy with ivermectin in these communities.

Infection with head lice caused by Pediculus humanushumanus is also a common infection in developing countries. As a part of an ivermectin trial for onchocerciasis in Sierra Leone, Dunne et al. compared the prevalence of head lice in children 5–18 years of age in those receiving ivermectin vs. placebo. Receipt of ivermectin was associated with a 46% reduction in the prevalence of head lice (Dunne et al. 1991) providing further support to the ancillary ectoparasitic effects of ivermectin.

Intestinal helminth infection

Intestinal helminth infections are widely prevalent in areas endemic for onchocerciasis and throughout the developing world. While ivermectin is ineffective against hookworm and only modestly effective against Trichuris, it is highly effective against Ascaris infection. Ascaris infection, especially high intensity infections, can impair absorption of both macro- and micronutrients and can reduce appetite (Stephenson 2001). The evidence for an impact of deworming on growth and well being of children in the developing world is mixed and depends on the intensity of transmission and reinfection (Dickson et al. 2002). In general, there is modest evidence that regular (once or twice yearly) deworming of pre-school age children can lead to modest improvements in weight gain. Little information is available on the effects of reducing the burden of Ascaris infection in older children or adults. While only modest effects on growth can be supported by the current literature, recent work for the Global Burden of Disease Project suggests that underweight is the leading risk factor for disability life years (R. Black, personal communication, 2003). Therefore, even modest improvements in weight gain in vulnerable populations may translate into significant improvements in health status of young children. Unfortunately, the current ivermectin distribution programme does not include children under 5 years, the most vulnerable group for growth retardation caused by intestinal helminth infection. Expansion of the age range for dosing with ivermectin to children under 5 years would likely provide significant additional benefits to the population over and above that associated with control of onchocerciasis.

Lymphatic filariasis

More than 1 billion persons are at risk for lymphatic filariasis and over 100 million are infected (Michael et al. 1996). This disease is caused by infection with either Wuchereria bancrofti or Brugia malayi. The complications of these infections are a result of lymphatic obstruction and secondary bacterial infection and include lymphoedema, hydrocele, elephantiasis, and chyluria. Similar to onchocerciasis, much of the tissue damage in lymphatic filariasis is a result of the immune response to the microfilaria and there is no safe and effective macrofilaricide for use in disease control programmes. Both DEC and ivermectin are effective at clearing microfilaria from the blood but do not result in elimination of the infection from individuals (Kazura et al. 1993; Das et al. 2001). The effectiveness of ivermectin, its safety for use in areas also endemic for onchocerciasis, and its single dose regimen has resulted in significant momentum for using ivermectin as a first-line microfilaricide in filariasis control programmes (Cao et al. 1997). In 1997, the WHO called for the elimination of lymphatic filariasis as a global public health problem and established the Global Alliance to Eliminate Lymphatic Filariasis. Following on the success of the MDP for onchocerciasis, Glaxo Smith-Kline announced that it would donate albendazole to the programme for as long as was necessary. Merck followed this by pledging ivermectin for distribution in combination with albendazole in those countries with coexistent onchocerciasis and lymphatic filariasis. As of 2001, over 17 million doses of ivermectin have been distributed through this programme (World Health Organization 2002). The current target for elimination of lymphatic filariasis is 2020.

Barriers to control programme effectiveness

The achievement and maintenance of onchocerciasis control has been, and continues to be, based on the vigilance, commitment, and participation of all involved and affected by the disease. As with any effort, there are foreseen and unforeseen barriers to the successful achievement of the programme's objectives. Five main barriers of concern are discussed in this section, and their relative importance as an obstacle to the control of onchocerciasis. These are vector and human migration, Loa loa coinfection, political instability, drug resistance, and control programme sustainability.

Vector and human migration

The migration of competent, infective blackfly vectors is a substantial threat to the control of onchocerciasis. National borders are insignificant to vectors when suitable habitats for vector propagation are located beyond man-made boundaries. The OCP used aerial larviciding to drastically reduce the blackfly population in a designated area referred to as the ‘core’, which was eventually freed of O. volvulus circulation. When infective blackflies from surrounding regions began to infiltrate, aerial treatment was then extended to the surrounding areas in order to protect the core's ‘parasitic insularity’ (Hougard et al. 2001). Eventually the blackfly populations returned to pre-treatment levels; however, the success of the protection was evident in the continued absence of onchocerciasis from the core area. The prevention of exogenous contamination of O. volvulus by infective vectors into parasite-free areas will require novel approaches, and the extension and continuation of mass ivermectin distribution into surrounding endemic areas.

Another impediment to the maintenance of areas containing highly efficient vectors, but free of O. volvulus, is human migration from areas still infected with onchocerciasis (De Sole & Remme 1991; Ochoa et al. 1997). In order to prevent the intensification of disease and parasite dispersion in such areas, vigilant mass ivermectin treatment is necessary, especially in the absence of vector control. Without appropriate interventions, there is a danger that new foci of active transmission could be formed (Guderian & Shelley 1992).

Loa loa coinfection

Treatment with ivermectin has been shown to significantly decrease Loa loa microfilaraemia levels in patients by 90% (Chippaux et al. 1998). However, adverse effects, including severe and sometimes fatal encephalopathy, can occur with treatment of persons heavily infected with Loa loa (Gardon et al. 1997). The use of geographical information systems with effective mapping, modelling and monitoring, can help to delineate areas with high Loa loa transmission (Thomson et al. 2000). As a result, appropriate precautionary measures prior to ivermectin distribution must be implemented in order to minimize any associated adverse effects. Such measures could include avoidance of communities with high levels of L. loa infection or pre-treatment testing of individuals to exclude those with high intensity infections. The optimization of these epidemiological tools may permit the continuation of the safe and effective control of onchocerciasis, and the added benefit of an effective treatment for low intensity L. loa infections.

Political instability

Political instability is a considerable obstacle to the implementation and effectiveness of any infectious disease control strategy. Many countries endemic for onchocerciasis are also plagued with political unrest, war, and/or mass displacement of their own or neighbouring citizens. Continuation of control programmes under such conditions requires extreme dedication. Furthermore, sporadic control efforts have limited beneficial impact on the target population. Despite these obstacles, the presence of political instability is not synonymous with the failure of control programmes. In Sudan, a temporary cease-fire was brokered in 1995 during which ivermectin administration occurred, and a water filter programme for the prevention of guinea-worm infection (Homeida et al. 1999). Although the efforts were admirable, the resulting coverage of 37% in 1998 was still far below the 65% coverage required to eliminate onchocerciasis as a public health problem (Amazigo et al. 2002a). Attempts to continue infectious disease control programs during times of political instability are beneficial to those fortunate enough to be directly affected; however, the achievement of programme goals are significantly hampered and often beyond realization.

Drug resistance

Resistance to ivermectin has been described as unlikely (Taylor & Greene 1989a). Sensitivity tests to ivermectin have been conducted for four different geographical isolates of O. volvulus, and their sensitivity was found to be comparable (Tgaboto et al. 1994). Furthermore, only minimal drug resistance has been detected so far in parasites found in veterinary practice. This lack of detectable resistance is important, as these non-human animal parasites have been exposed to ivermectin far longer and with greater intensity than susceptible human parasites. Unfortunately, the current lack of evidence of resistance is not proof of future absence. It has been suggested that there is a strong selective pressure for adults to resume reproduction after ivermectin treatment. Microfilariae produced by such resilient adults could have an increased selective advantage and potentially dominate transmission, leading to hardier macrofilariae (Grant 2000). Thus, routine performance of sensitivity tests in populations with circulating O. volvulus strains is crucial, as such tests would allow the rapid identification of developing resistance to ivermectin (Taylor & Greene 1989a).

Programme sustainability

With the conclusion of the Onchocerciasis Control Program, the responsibility for control activities will be absorbed by the countries and the African Program for Onchocerciasis Control. Although countries endemic for onchocerciasis will become more involved in its control, the capacity of countries to assume monitoring and control activities is unequal. The disparity in health policies and infrastructures among these countries will influence the successful integration of control activities into national health systems (Hougard et al. 2002). An early obstacle will be the maintenance of enthusiasm of the population during programme development. The programme approach that has met with greatest support is that of community-directed treatment; however, its execution must still be tailored to each country's financial and social capabilities (Amazigo et al. 2002b). Furthermore, once a control programme is implemented, its success has been linked to a variety of factors including health education, direct involvement by community members, and community satisfaction with the programme (Shu et al. 1999; Katabarwa et al. 2002). Thus, the sustainability of onchocerciasis control has formidable obstacles. However, the collaboration of participating countries can yield novel ideas that will assist in the achievement of satisfactory ivermectin coverage, community self-monitoring, and programme cost-recovery.

Conclusions

The discovery of ivermectin as a safe and effective drug for onchocerciasis and the development and operation of the MDP is one of the success stories of public health in the late 20th century. While the impact of the current programme is difficult to measure in absolute terms, it is clear that the direct and indirect benefits of the mass distribution of ivermectin have had a profound impact on the survival and quality of life for many millions of persons living in onchocerciasis endemic areas. Barriers to continued programme success are formidable, but the current approach of involving the communities themselves in the direction and operation of the distribution programme provides strong optimism for future success. Elimination of infection is possible in parts of Central and South America, but continued and aggressive control programme activities will be required in Africa to improve and maintain the benefits already achieved through this pioneering public–private partnership.

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