Research for control: the onchocerciasis experience*

Tropical Medicine and International Health volume 9 no 2 pp 243 254 february 2004 Research for control: the onchocerciasis experience* Jan H. F. Remme Intervention Development and Implementation Research, UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, WHO, Geneva, Switzerland Summary Onchocerciasis control has been very successful in Africa and research has played a critical role. An overview of the main epidemiological and implementation research activities undertaken over the last 20 years in collaboration with the African onchocerciasis control programmes and of the impact this research had on control is given. The research included the development of epidemiological modelling and its application in programme evaluation and operational planning, research on disease patterns and disease burden in different bioclimatic zones to justify and guide control operations, community trials of ivermectin to determine its safety for large-scale use and its impact on transmission, rapid assessment methods to identify target communities for treatment and community-directed treatment for sustained drug delivery. Lessons learned during this unique collaboration between research and control are discussed. keywords onchocerciasis, research, modelling, ivermectin, vector control Introduction Onchocerciasis control in Africa has been very successful over the last two decades. The Onchocerciasis Control Programme in West Africa (OCP, see Figure 1) has eliminated onchocerciasis as a public health problem from the savanna areas of 11 West African countries through a control strategy based on vector control and ivermectin treatment. In the rest of the continent the disease is being progressively brought under control through communitydirected treatment with ivermectin, introduced through the African Programme for Onchocerciasis Control (APOC). Over 25 million people in high-risk areas were treated in 2002 and in communities that have received four or more treatment rounds, the infection levels are so low that they no longer constitute a public health risk. The achievement of this success has not been easy and many obstacles had to be overcome. Essential information on key aspects of the epidemiology of onchocerciasis was not available when the two control programmes were launched and answers needed to be found to critical strategic questions on where, when and how to apply the interventions. Both programmes responded to these challenges by embracing research to help find evidence-based solutions. Since then, research has played a major role in onchocerciasis control in Africa and has significantly contributed to its success. The close interaction between research and control for onchocerciasis has been rather special, and there are many lessons to be learned from this experience. This article gives an overview of some of the main research undertaken over the last 20 years in support of onchocerciasis control in * Dr Remme has been awarded the Eijkman Medal on October 12, 2001 for his contribution to tropical medicine, more specific for his work in the field of epidemiological research and control of onchocerciasis. Dr Remme has worked in oncho research for twenty years, initially at OCP (since 1983) and since 1991 at TDR. At the time of the award, Dr. Remme was co-ordinator of lymphatic filariasis and onchocerciasis research activities; presently he is co-ordinator of intervention development and implementation research at WHO/TDR. The Eijkman Medal Foundation was established in 1923 in honour of Christian Eijkman, former professor of hygiene at the University of Utrecht, The Netherlands. Renowned for his research in the former Dutch East Indies (now Indonesia), which led to the elucidation of the cause of beri beri, Christian Eijkman received the Nobel Prize for Physiology and Medicine in 1929. The aim of the Foundation is to encourage research in tropical medicine. The Eijkman Medal is awarded every two years to those scientists who have made a major contribution in this field, during a meeting of the Netherlands Society of Tropical Medicine and International Health. Prof. Hugo J. van der Kaay President, Eijkman Foundation The Netherlands ª 2004 Blackwell Publishing Ltd 243

OCP APOC Figure 1 African countries that are endemic for onchocerciasis and that are participating in OCP (light shading) and APOC (dark shading). Africa, and of lessons learned. The focus is on epidemiological and implementation research of immediate relevance to control in which I have had the privilege to be involved. Other important onchocerciasis research, e.g. on vectors, larvicides and drug development, is described elsewhere (Hougard et al. 1993; Boakye et al. 1998; Hoerauf et al. 2001). The OCP in West Africa: vector control Onchocerciasis is an important public health problem in Africa. Some 18 million people are estimated to be infected in the world (over 99% living in Africa) and the disease is responsible for the annual loss of close to 1 million Disability-Adjusted Life Years (DALYS; Murray & Lopez 1996; Remme, in press). The principal clinical manifestations are ocular lesions, resulting in visual impairment and blindness, and onchocercal skin disease (OSD). The relative importance of ocular and skin complications varies with parasite strain involved, with blindness tending to predominate in the African savanna and skin disease in forest areas. In the West African savanna, the risk of onchocercal blindness used to be very high along the rivers, where the vector breeds, and blindness could affect up to 50% of adults in the most endemic communities (Remme & Zongo 1989). The fear of blindness was responsible for depopulation of the fertile river valleys, and this made onchocerciasis a major obstacle to socio-economic development in West African savanna. This socio-economic importance of the disease was the main reason for the creation of the OCP in West Africa in 1975. Impact of vector control and epidemiological modeling The only available intervention in 1975 was vector control, which had shown promise on a small scale in several foci in East and West Africa. In Kenya, where onchocerciasis was found in isolated foci, the application of larvicides resulted 1in the local elimination of the vector Simulium neavei and epidemiological surveys done 18 years later showed that the parasite population had died out naturally (Roberts et al. 1967). In West Africa, e.g. in the Farako valley in Mali (Le Berre 1968), vector control was also effective in reducing transmission but a problem was the continuous influx of blackflies from surrounding areas. It was concluded that vector control was feasible in the West African savanna if carried out on a large scale (Walsh et al. 1981). Hence, OCP started large-scale vector control operations that involved the use of helicopters for weekly spraying of larvicides over the vector breeding sites in river rapids. It was a massive operation ultimately covering some 50 000 km of river over a geographical area of 1 235 000 km 2. In spite of some initial problems with long distance migration of infective blackflies, the extensive entomological evaluation data for more than 200 catching points suggested that vector control was effective and that onchocerciasis transmission had been interrupted in the central programme area. However, after 8 years of vector control, there was still no substantial decline in the prevalence of infection in the human population and this was beginning to raise serious concerns among the donor community about the impact of the expensive control operations. At that time, it was not clear what epidemiological trends could be expected under effective control, nor how many years of vector control were required, and to address these questions we introduced modelling in the epidemiological evaluation of the OCP (Remme et al. 1995). First a simple force-of-infection model was developed, which took account of four critical epidemiological parameters: the (unknown) longevity of the adult onchocercal worm, super infection, age-specific exposure and pre-control intensity of transmission (Remme et al. 1986). This model showed that the epidemiological trends during 244 ª 2004 Blackwell Publishing Ltd

the control period would vary according to age and endemicity level, that the prevalence was not an appropriate indicator for the evaluation and that a new index of intensity of infection in adults (the Community Microfilarial Load or CMFL) would be a much more sensitive indicator of the level of endemicity and the epidemiological changes after control. The subsequent application of the model in the re-analysis of the epidemiological evaluation data helped to extract the relevant epidemiological information on the impact of vector control. It was shown that the epidemiological evaluation data also contained evidence that vector control had been very effective and it was estimated that the parasite reservoir had already declined by some 70%. This information that the parasite population was dying out came very timely for donors and other partners, and strengthened their confidence in the OCP vector control strategy. The experience also demonstrated the operational value of epidemiological modelling to the OCP staff who became increasingly interested in applying modelling in evaluation and strategic planning. Now that the decline in the parasite population had been documented, the next major question was how long vector control needed to be continued and when it could be safely stopped. This question required the development of a more detailed model that covered the full transmission cycle. OCP decided to engage in the development of such a model but considered it important that the model could produce output comparable with that of the routine epidemiological and entomological evaluation data of the OCP so that the model would facilitate the interpretation of evaluation data and predictions could be continuously validated and updated. These considerations led to the creation, in collaboration with the Erasmus University of Rotterdam, of a sophisticated micro simulation model, ONCHOSIM, for the control of onchocerciasis (Plaisier et al. 1990). The first main application of ONCHOSIM was to predict the required duration of vector control. This depends to a large extent on the reproductive lifespan of Onchocerca volvulus, which was not known at the time. Based on a model-based analysis of available epidemiological evaluation data it was predicted that 95% of the parasites would reach the end of reproduction before the age of 13 14 years, and that 14 years of satisfactory vector control would be required to ensure that there was no longer any significant risk of renewed transmission and subsequent recrudescence of onchocerciasis infection (Plaisier et al. 1991a,b). Based on this prediction, vector control was stopped after 14 years in the original OCP area (WHO 1995) and the prediction proved later to be correct. To date, more than 10 years later, this area is still free from onchocerciasis transmission (Hougard et al. 2001). An example of the model predictions and the observed epidemiological trends is given in Prevalence of mf (%) and CMFL (mf/s) 100 80 60 40 20 14 years of vector control CMFL Prevalence Evaluation: vector infectivity below threshold 0 0 5 10 15 20 25 Years since the start of vector control Figure 2 for an onchocerciasis focus along the upper Comoe river in Burkina Faso, which was initially hyper-endemic. Disease patterns, parasite strains and programme boundary Observed Predicted Prevalence zero Figure 2 In the sentinel village of Folonzo along the Upper Comoe river in Burkina Faso virtually all adults were infected before the start of control and the Community Microfilarial Load (CMFL) was as high as 70 microfilariae per skin snip (mf/s). The observed epidemiological trends closely followed the model predictions with the prevalence showing little decline during the first 10 years of control while the CMFL started to drop soon after the start of control. When the vector control operations were stopped after 14 years of control, the prevalence of infection was still 10% but these represented low intensity, dying infections for which the model predicted that they would not result in renewed transmission. After the cessation of vector control the blackfly population rapidly returned to pre-control levels, but intensified entomological evaluation showed that vector infection levels remained extremely low and under the transmission thresholds defined with the model. The definite proof that cessation of control had not resulted in transmission came 10 years later when epidemiological surveys showed that the prevalence of onchocerciasis infection was zero. The mandate of the OCP was the control of the severe blinding form of onchocerciasis, which was responsible for the devastating blindness rates and underpopulation of many river valleys in the West African savanna. However, the southern boundary of this blinding form of onchocerciasis was not clearly demarcated. For large parts of the pre-forest and forest zones it was not clear if the lesser severity of ocular disease was due to a more benign forest form of onchocerciasis or if it concerned the blinding savanna form of the disease at a low level of endemicity. The OCP undertook, therefore, a series of ophthalmological surveys in the pre-forest and forest zones in order to clarify the epidemiological patterns of ocular onchocerciasis in this area. The analysis required the quantification of ª 2004 Blackwell Publishing Ltd 245

the level of onchocerciasis endemicity using information on onchocerciasis infection obtained with the standard diagnostic test, the skin snip, taken from the iliac crest and examined microscopically for the presence and density of Onchocerca volvulus microfilariae (mf). Skin snip surveys were carried out routinely by the OCP and the level of endemicity of surveyed communities used to be classified using the prevalence of mf. However, among highly endemic communities the prevalence of mf was a poor indicator of the level of blindness, and a better index of endemicity was needed. It was known that at the individual level, the severity of ocular disease is related to the intensity of infection. Hence, the CMFL, as the index best reflecting the intensity of infection at the community level, was introduced for the comparative analysis of ocular disease patterns in different bioclimatic zones. The study showed that community levels of ocular microfilarial loads, ocular lesions and blindness were linearly related to the CMFL (Remme et al. 1989b), and since then the CMFL has become the preferred epidemiological index of onchocerciasis endemicity. After correction for endemicity, the patterns in the forest zones were fundamentally different from those in the savanna: for the same level of CMFL the prevalence of ocular lesions and blindness in the forest zones were only a fraction of those in the savanna (Dadzie et al. 1989, 1990, 1992). Largely based on these epidemiological findings, the Southern Programme boundary was defined. It had always been assumed that the variation in disease patterns between bioclimatic zones was due to differences in parasite strains (Duke 1981), but this had never been proved. The development of an objective epidemiological methodology for classifying ocular disease patterns and the simultaneous development of DNA probes, which were believed to be strain specific (Erttmann et al. 1990), created the conditions to test the hypothesis in the field. Parasite samples were therefore collected from villages with the savanna and the forest ocular disease patterns, coded and classified using the DNA probes. The results were conclusive: about 95% of the samples were classified correctly (Zimmerman et al. 1992) and the findings supported the existence of O. volvulus strains with different pathogenicity. This had immediate operational implications and the probes were introduced in the entomological evaluation of the OCP to classify O. volvulus larvae in collected blackflies and better understand transmission of the blinding savanna strain, which was the prime concern of the OCP in those days. The establishment of a quantitative relationship between ocular disease and CMFL was also important to improve estimates of the disease burden of onchocerciasis. The new methodology was first applied to estimate the pre-control burden of blindness in the extension areas of the OCP where skin snip surveys were being undertaken to map the distribution of onchocerciasis before the start of control operations (De Sole et al. 1991, 1993). Ivermectin: a new tool for onchocerciasis control In 1987 there was a major new development with the emergence of ivermectin as an effective microfilaricide, its registration for the treatment of onchocerciasis and the decision by Merck & Co. to donate the drug free of charge for onchocerciasis control for as long as needed. The question was how to use this additional tool most effectively. Phase III trials had shown that the drug was effective in preventing ocular lesions, but information was urgently required on how safe the drug was in large-scale treatment and of the effect that mass treatment would have on onchocerciasis transmission. The OCP and the UNDP/ World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) therefore launched a number of community trials to answer those questions (De Sole et al. 1989; Taylor et al. 1990; Cupp et al. 1992; Abiose et al. 1993; Boussinesq et al. 1995). The largest trial, undertaken in the hyper-endemic focus of Asubende on the river Pru in Ghana, provided the most detailed information on the effect on transmission, showing a major reduction in vector infectivity but still significant residual transmission after treatment (Remme et al. 1989a) and a subsequent increase in infectivity levels to near pretreatment levels 12 months later. This pattern continued even after the third treatment round (see Figure 3) and extrapolation of these results to the long-term use of the simulation model ONCHOSIM resulted in the conclusion in 1989 that interruption of transmission may not be feasible and that treatment may need to continue indefinitely in hyper-endemic areas (Remme et al. 1990). However, because ivermectin treatment resulted in a major reduction in microfilarial loads in the human population, it was predicted that sustained annual treatment would be able to control onchocercal morbidity and eliminate the disease as a public health problem. The implications for the OCP were that vector control was still needed in the original OCP area to maintain interruption of transmission and eliminate the parasite reservoir, in order to bring the programme to a definite conclusion and reduce the risk of recrudescence to the minimum. Ivermectin provided an important additional tool that brought immediate relief to the infected population while modelling predicted that the control period for a combined strategy of vector control and ivermectin treatment could be shortened from 14 years for vector control 246 ª 2004 Blackwell Publishing Ltd

Vector infectivity No. of L3 in the head per 1000 parous flies 120 100 80 60 40 20 0 Ivermectin Ivermectin Ivermectin Sept Oct Nov Dec Jan Feb Sept Oct Nov Dec Jan Feb Sept Oct Nov Dec Jan Feb 1987/1988 1988/1989 1989/1990 Figure 3 Trend in vector infectivity levels in the focus of Asubende along the River Pru in Ghana. Vector infectivity was measured by the number of third stage Onchocerca volvulus larvae (L3) in the head per thousand biting Simulium damnosum s.l. The entomological evaluation of transmission was carried out from September to February during which period vector control was suspended for the purpose of the ivermectin trial. Each year, ivermectin treatment resulted in a major reduction in onchocerciasis transmission but after 12 months, transmission levels had returned to pre-control levels. alone to 12 years for the combined strategy (Plaisier et al. 1997). This became the strategy throughout the OCP with the exception of the north-western extension of the programme. Entomological studies had shown that this area was not a source of reinvasion of infective flies into the central OCP area and vector control was therefore not needed to protect the achievements in the original OCP area. Hence, in the north-west, onchocerciasis control was based on ivermectin treatment only for the purpose of morbidity control. In most of the area treatment was given annually but in three isolated meso-endemic foci, treatment was given at 6-monthly and 3-monthly intervals in order to further explore the feasibility of local interruption of transmission under favourable epidemiological conditions (Borsboom et al. 2003). In October 2001, a detailed review was undertaken of the evaluation data on 12 years of experience with largescale ivermectin treatment in the OCP and the results were consistent with the original predictions: CMFLs were close to zero, onchocerciasis was everywhere controlled as a public health problem but transmission was still ongoing in several foci (Borsboom et al. 2003). These results were presented at an international conference on the eradicability of onchocerciasis, which concluded on the basis of these findings that onchocerciasis is not eradicable with the current tools (Dadzie et al. 2003). The conference concluded that a top priority for onchocerciasis research remains the development of a drug that will kill or sterilize the adult onchocercal worm and thus enable interruption of onchocerciasis transmission in all endemic areas. TDR is trying to develop such a drug with the support of OCP and APOC. In the mean time, priority research needs are to optimize strategies for ivermectin-based control by further exploring under which conditions and with what strategies local interruption of transmission may be achieved, and to develop and improve drug delivery strategies to enhance sustainability. APOC: expansion of control to all endemic countries in Africa Outside the OCP, where more than 80% of all infected people lived, OCP s strategy of vector control was not feasible or affordable and these countries had been left looking over the fence. The emergence of ivermectin changed all and created a growing momentum to bring onchocerciasis control to the other endemic areas. But before ivermectin-based control could be implemented elsewhere, there remained a number of critical questions to be answered on: (i) where to target control, (ii) the justification for extension of control to areas where the parasite strain was less pathogenic to the eye, and (iii) how to distribute the drug to ensure and sustain high treatment coverage. TDR was asked to help answer these questions and strengthen the technical basis for a new APOC that would cover the remaining 16 endemic countries in Africa (Remme 1995). In response to this request, TDR launched a special initiative on Onchocerciasis Operational Research to address the questions of why, where and how to treat with ivermectin. Why treat? The burden of (skin) disease As mentioned above, the disease pattern of onchocerciasis varies with the parasite strains involved. There are large endemic areas in Africa where blindness is not common although the endemicity levels may be very high. In these areas, where about 50% of all infected persons live, skin manifestations are the main complications of the disease (World Bank 1996). A major question facing APOC was therefore how important OSD is as a public health problem. Limited previous studies on OSD were difficult to interpret and compare because of the different methods used to classify onchocercal skin lesions. Even less information was available on the psychosocial effects of onchocercal skin lesions. However, a study in Nigeria that was published around that time showed that in a community in the forest belt, adolescent girls considered onchodermatitis to be their ª 2004 Blackwell Publishing Ltd 247

Prevalence (%) 50 40 30 20 10 0 Troublesome itching Depigmentation Reactive skin lesion 5 9 20 29 40 49 60 69 10 19 30 39 50 59 70+ Age (years) Figure 4 The prevalence of onchocercal skin disease by age: combined results for 36 communities from East and West Africa. The prevalence of depigmentation follows an age-specific pattern that is similar to that for onchocercal blindness with the prevalence increasing with age and becoming significant from the age of 40 years onwards. The pattern for reactive skin lesions and troublesome itching was completely different: the prevalence was already high in children and plateaued from the age of 20 years onwards. Onchocercal skin lesions and severe itching were shown to have important personal and psychosocial effects not only on the affected individuals, but also on their families and communities. For the affected people, the most serious complication is itching, which is often very severe, and the cause of sleeplessness, fatigue and weakness. Troublesome itching leads to scratching, often with stones, twigs or knives, and results in bleeding wounds, sores and pain in the affected parts of the body. Reactive skin lesions were an important cause of stigma, and affected people s self-esteem and self-respect. Concern about onchocercal depigmentation varied across sites and among individuals, troubling in some areas, but not in others. The study showed that in endemic communities in forest areas, onchocercal skin disease is an important public health problem, which affects all age groups. most important health problem because of its severe social consequences (Amazigo 1993). Given the opportunity to intervene with ivermectin, it became critically important to clarify the disease burden caused by OSD. A multi-country study was therefore undertaken that applied a newly developed standardized dermatological methodology (Murdoch et al. 1993) and standardized methods for assessing the psycho-social impact of skin manifestations. The study showed that skin lesions and troublesome itching were much more prevalent and severe than anticipated (see Figure 4), and that they had profound psycho-social implications that made OSD a major public health problem for the affected populations (Ovuga et al. 1995; Brieger et al. 1998b; Vlassoff et al. 2000; Murdoch et al. 2002). The study resulted in a fundamental re-assessment of the burden of onchocerciasis: while skin disease was given little importance in the past, more than 50% of DALYs lost due to onchocerciasis are now attributed to severe itching (Remme 2003). Other skin manifestations are not yet included in the DALY estimates, although they are highly prevalent and have a major psycho-social and economic impact. Reactive skin lesions have severe social repercussions, OSD diminishes income generating capacity, and the school drop-out rate is twice as high among children from households whose head has OSD (Oladepo et al. 1997; Benton 1998). These findings provided a convincing justification to extend onchocerciasis control to the forest areas where the parasite strain is less pathogenic to the eye. Now that the importance of skin disease had been demonstrated, there was a need to further clarify the effectiveness of ivermectin treatment in OSD and to determine the most appropriate treatment interval as it had been suggested that annual treatment might not be adequate for OSD and that treatment may need to be given as often as every 3 months (Burnham 1995). A multicentre double-blind placebo-controlled trial was undertaken, which showed that ivermectin treatment resulted in a significant reduction in itching and reactive skin lesions during the first year after treatment and that there was no difference between 3-monthly, 6-monthly and annual treatment regimens (Brieger et al. 1998a). Hence, the annual treatment regimen was accepted for all endemic areas, including those with the forest strain of the parasite. The long-term effect of treatment on skin disease has not yet been documented, but the relevant evidence should become available shortly from the epidemiological evaluation of the impact of control by APOC. Where to treat distribution of onchocerciasis Outside the OCP, there was very little information on the geographical distribution of onchocerciasis. It was approximately known which African countries were endemic (and even that information proved later incorrect for three countries) but there was hardly any information on the actual geographical distribution of onchocerciasis within each country and therefore it was not known where ivermectin treatment was to be given. A WHO consultation had defined at what level of endemicity onchocerciasis should be considered a sufficiently important public health problem to warrant community-wide ivermectin treatment: ivermectin treatment was urgent or highly desirable where the prevalence of mf > 40% or the CMFL > 5 mf per skin (WHO 1991). The multicentre study on OSD 248 ª 2004 Blackwell Publishing Ltd

showed later that these thresholds were also appropriate for control of OSD. However, given the size of the area where onchocerciasis might be endemic (virtually all of tropical Africa) and the invasiveness of the skin snip method, it was out of the question to do skin snip surveys in all potentially endemic communities. There was therefore an urgent need for simple and rapid methods to identify communities where onchocerciasis is a public health problem and that require ivermectin treatment. For some years, the idea had been around to use specific and easy to diagnose complications of onchocerciasis, such as leopard skin or palpable subcutaneous onchocercal nodules, to identify endemic communities (Edungbola et al. 1987). However, there was no consensus on the validity of different approaches, and the concept had not yet been accepted by control programmes. Therefore TDR organized a consultation to analyse available data on alternative approaches, including extensive data from the OCP and several studies in Nigeria and Cameroon (TDR 1992). It was shown that prevalence of onchocercal nodules in adult males, identified through simple palpation, provided a good proxy indicator of the level of endemicity, which was reliable enough for community diagnosis of onchocerciasis. The prevalence of palpable nodules in adult males was about half the prevalence of mf in the total population, and the threshold for treatment was therefore set at a nodule prevalence of 20% (TDR 1992; Taylor et al. 1992). Following further validation in Nigeria, nodule palpation became the method for choice for rapid community diagnosis of onchocerciasis and its validity has since been confirmed in several independent studies (Whitworth & Gemade 1999; Vivas-Martinez et al. 2000; Kipp & Bamhuhiiga 2002). Still, a method for rapid community diagnosis was not good enough as there were too many potentially endemic communities to make it practical to visit them all. There was a need for something more simple and rapid, for which it would not be necessary to visit and survey all communities. In response to this need, a method for rapid epidemiological mapping of onchocerciasis (REMO) was developed that takes into account specific spatio-epidemiological characteristics of onchocerciasis, especially its relation to the spatial dispersion of the vector around breeding sites in rivers (Ngoumou et al. 1994). Villages are sampled from each river basin, starting with villages located close to river rapids where vector breeding sites are most likely to be found, and selecting villages at increasing distance from these sites and the river. Nodule surveys are carried out in the sampled villages, first in those close to the breeding sites to determine the presence or absence of onchocerciasis, and, if present, in the other villages to determine the geographical extent of the focus. With REMO, surveys in a sample of only 2 5% of all communities are used to draw an epidemiological map of the whole area, also covering communities that have not been surveyed, and identify areas where mass treatment with ivermectin is indicated. REMO came very timely and has been used extensively to map the distribution of onchocerciasis in the APOC countries and target treatment to areas where the disease burden is high (Ngoumou et al. 1994; Mace et al. 1997; Gemade et al. 1998; Noma et al. 2002). Distribution of Loa loa The community trials, in which over 50 000 treated people had been carefully monitored for adverse reactions, had indicated that ivermectin treatment was very safe. This was confirmed during many years of large-scale treatment until severe and in a few cases fatal neurological adverse reactions were reported in patients co-infected with Loa loa from a focus in central Cameroon (Gardon et al. 1997). All severe reactions had a very high intensity of Loa loa infection and a relationship between the risk of severe adverse reactions and the intensity of loiasis infection was established. Parasitological survey data showed a close relationship between prevalence and intensity of loiasis infection (Boussinesq et al. 2001; Takougang et al. 2002), and is was concluded that the risk of high intensity of loiasis infection, and thus of severe reactions, becomes unacceptable for routine ivermectin treatment when the prevalence of Loa loa infection exceeds 20%. Hence, it became urgent to determine the geographical distribution of the prevalence of loiasis and identify high-risk communities where special treatment and monitoring strategies would be required. Undertaking parasitological surveys at the required scale was out of the question, and there was again a need for a simple rapid assessment method. A study of several possible rapid assessment methods was therefore carried out in Nigeria and Cameroon (Takougang et al. 2002). The best performance was obtained with a method based on the history of eyeworm (whether worms moving along the white of the lower part of the eye have ever been experienced). A prevalence of 40% or more of eyeworm in a community, confirmed by showing a photograph of a worm in the lower part of an eye, was identified as the threshold corresponding to the 20% microfilariae threshold above which there is an unacceptable risk of severe adverse reactions to ivermectin treatment. The procedure, called RAPLOA, was shown to be highly sensitive and specific at the community level, largely because eyeworm is a well-known sign for which there are local names in all highly endemic communities. RAPLOA is now being used by APOC in Nigeria and Cameroon and further validation is ongoing in other parts of the continent. Work has also ª 2004 Blackwell Publishing Ltd 249

started to develop a rapid mapping method, similar to REMO, by combining RAPLOA with an environmental risk model for Loa loa that has been developed by the Liverpool School of Tropical Medicine and the University of Lancaster (Thomson et al. 2000). How to treat To eliminate onchocerciasis as a public health problem, annual treatment needs to be sustained over a very long time (Remme et al. 1990). A problem in ensuring sustained, high treatment coverage was the weakness of the health system in many of the endemic areas and their difficulty in delivering ivermectin treatment in a sustained manner to all target communities. Several attempts were made, therefore, by NGOs collaborating with the OCP during the early nineties to apply community-based approaches for drug delivery. As it was not at all clear how effective these different approaches were, OCP requested TDR to evaluate them with a view to develop guidelines for delivery methods that would be effective and sustainable. In 1994, TDR launched a multicountry study involving multi-disciplinary research teams from five African countries to evaluate and further develop methods for community-based ivermectin delivery (TDR 1996). Early in the study, the researchers discovered that there was little active community involvement in the community-based approaches, and that communities had virtually no influence on how treatment was planned and executed. But social scientists on the teams noted that these communities routinely organize much more complex traditional community activities very effectively. This led to the idea of community-directed treatment (ComDT) in which the community itself would be in charge of the design and implementation of ivermectin treatment. Community-directed Treatment (ComDT): In ComDT it is the community itself rather than the health services that directs the treatment process. The community decides collectively: whether they want ivermectin treatment; how ivermectin tablets will be collected from the medical store; when it will be distributed; how it will be distributed; who in the community will be responsible for the distribution and record keeping; and how the community will monitor the process. The health workers only provide the necessary training and supervision. This concept was tested in the second phase of the study through a large comparative intervention study of true community-directed vs. community-based treatment as designed for communities by control programmes. The study clearly demonstrate that ComDT is feasible and effective. Communities could effectively plan and implement ivermectin treatment, and they achieved higher treatment coverage if they were empowered to design and implement treatment their own way. It was concluded that ComDT is likely to be sustainable because of the commitment demonstrated by community leaders and community distributors, the high degree of involvement of communities, and their ability to recognize problems with their distribution methods and effectively modify them. On the basis of the study, ComDT was adopted by OCP as its ivermectin delivery strategy and it became the principal control strategy for the APOC programme in 1996. The main objective of APOC is now to establish effective and self-sustainable community-directed ivermectin treatment throughout the remaining endemic areas in Africa (World Bank 1996). The large-scale implementation of ComDT produced important new challenges and APOC requested TDR to help strengthen the evidence base for ComDT and undertake research on critical implementation problems. These included issues relating to the integration of ComDT in the health services and the sustainability of ComDT after cessation of APOC support. Follow-up studies showed that, although health workers initially had a very negative attitude to active community involvement in drug delivery, their attitude became much more positive after experience with ComDT. Poor communication and interaction between community members and health workers was also common but research showed that local stakeholders meetings of community representatives and health workers could significantly improve this and further enhance a positive attitude of health workers (Brieger 2000). So far, ComDT has been very effective (Katabarwa et al. 1999; Amazigo et al. 2002). Ivermectin treatment is popular and communities have responded enthusiastically to the concept of community-directorship in which they are responsible for planning and implementation. A recent external evaluation of APOC concluded: ComDT has been a timely and innovative strategy and communities have been deeply involved in their own health care on a massive scale. ComDT is a strategy which could be used as a model in developing other community-based programmes and is also a potential entry point in the fight against other diseases. 250 ª 2004 Blackwell Publishing Ltd

There is a growing interest at the international and national level to explore the use of the community-directed intervention strategy for interventions against other diseases, and the effectiveness of ComDT for treatment of lymphatic filariasis has already been demonstrated (Gyapong et al. 2001). This interest in ComDT provides an important opportunity to strengthen the sustainability of ivermectin treatment of onchocerciasis, and to contribute at the same time to health care development in some of the poorest populations in Africa (Homeida et al. 2002). But to ensure that proper advantage is taken of this opportunity, there is an urgent need for scientific evidence on the advantages, disadvantages and costs of multi-disease applications of ComDT as compared with other community-based approaches. On the request of the board of governors of APOC, on which the Ministers of Health of the participating countries are represented, TDR has launched a multicountry study to determine and compare the feasibility, acceptability and cost-effectiveness of community-directed and other community-based strategies for integrated delivery of multiple health interventions in Africa. The study will provide evidence on the advantages, disadvantages, and costs of the different approaches, show which interventions can be effectively combined with ivermectin treatment, what the additional health benefits would be and what modifications are needed to the current strategies to facilitate effective integration. The study will evaluate the incremental use of ComDT for other interventions with increasing complexity, ranging from simple interventions such as vitamin A supplementation to distribution and retreatment of ITNs, community-based DOTS for tuberculosis and home management of malaria. This innovative study could carry the results of onchocerciasis research considerably beyond onchocerciasis control and contribute to health care development in Africa in general. Discussion Research has played a critical role in onchocerciasis control. It has provided answers to key questions on the why, where and how of control, and these answers have had a significant impact on the effective implementation of the interventions. Evidence on the burden of disease in different geographical zones helped to justify intervention. Epidemiological research and rapid assessment methods helped to identify target areas for control. Community trials of ivermectin and model predictions helped to define cost-effective control strategies, and ComDT helped to ensure effective and sustainable ivermectin treatment. Other research that is not described here helped to develop the larvicides and entomological knowledge needed to optimize vector control operations in the OCP. There is little doubt that without research, onchocerciasis control would not have achieved its current success and that research has been very cost-effective. Research introduced new ways of thinking into control, although not all new ideas were initially well received. Modelling research introduced comprehensive epidemiological thinking, which led to the prospective use of evaluation data to predict future trends of importance for operational planning. But when modelling was first introduced in the OCP, many staff were skeptical about the usefulness of something as theoretical as modelling for an operational control programme. New ideas on the use of rapid assessment methods for community diagnosis raised eyebrows about the reliability of such crude methods and the suggestion that communities could take charge of treatment met concerns that there would be large-scale misuse of the drug if given by community members. However, once research had produced the evidence that the new approaches were effective and had demonstrated their practical relevance, control programme staff were quick to adopt and apply them. Research for control requires a good collaboration between research and control. In the case of onchocerciasis this collaboration was excellent, and an important reason was the genuine interest of OCP and APOC in research and their recognition of the need for innovation. The science culture within these two programmes, their interest in evidence-based planning and their flexibility in modifying the control strategies as required, has greatly facilitated the collaboration with researchers and the uptake of research findings. Unfortunately, not all disease control programmes have such a positive attitude towards research and there is often concern that highlighting unresolved control problems might negatively affect support for a programme from its partners. For onchocerciasis the experience was quite the opposite: health decision makers and donors knew by experience that disease control does not come without problems and they appreciated to be kept honestly informed, not only about successes but also about the remaining challenges. The fact that the onchocerciasis control programmes showed that they were clearly aware of the remaining key problems strengthened the confidence of donors in the programmes, and partners were generally pleased to see that realistic plans were being developed and implemented to address those problems through research. Another reason for success was the close link between research and the priority research needs of control. This ensured that research findings were of direct relevance to control and that they could be rapidly implemented. ª 2004 Blackwell Publishing Ltd 251

Most priority needs concerned urgent control problems, and there was often great pressure to produce the research findings as quickly as possible. A major challenge for research, therefore, was to produce research results within a sufficiently short time span to ensure that they were optimally relevant for control, while ensuring quality research, which takes time. Furthermore, the priority needs were continuously evolving, and this was another reason why research had to be very responsive and flexible. An important element of the onchocerciasis research activities has been research capacity building and research capacity utilization. More than 95% of the researchers who helped to resolve the research questions that were facing APOC were African scientists. These researchers now form an important network of epidemiologists, clinicians, social scientists and other African experts who are supporting APOC with monitoring and evaluation of ivermectin treatment programmes, and local operational research. The onchocerciasis experience shows that research can have a major impact on the control of tropical and neglected diseases of the poor, and that research for control can be very cost-effective. Unfortunately, research on diseases of the poor remains chronically underfunded and important opportunities to reduce the disease burden of the poor are being missed (Remme et al. 2002; Morel 2003). In order to make this change, there is a need for more and better communication of experiences, such as for onchocerciasis, that show the effectiveness of research for control. Acknowledgements The research described in this article is the result of the dedicated work of many individuals: scientists, technicians and support staff from the OCP, APOC and TDR, biomedical and social scientists from research institutions and Ministries of Health in the onchocerciasis endemic countries in Africa, and scientific collaborators from other parts of the world. I am grateful to the Eijkman Foundation for awarding the Eijkman medal for this research which I consider a recognition of the quality of the work of all scientists involved and their collective commitment to developing a strong, innovative evidence base for onchocerciasis control. References Abiose A, Jones BR, Cousens SN et al. (1993) Reduction in incidence of optic nerve disease with annual ivermectin to control onchocerciasis (see comments). Lancet 341, 130 134. Amazigo U (1993) Onchocerciasis and women s reproductive health: indigenous and biomedical concepts. Tropical Doctor 23, 149 151. 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