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Trente ans de lutte contre l’onchocercose en Afrique de l’Ouest. Traitements larvicides et protection de l’environnement

 | 
Laurent Yaméogo
, 
Christian Levêque
, 
Jean-Marc Hougard

Références des articles présentés sur le cédérom / Papers references presented on CD-ROM

Onchocerciasis Control in West Africa

Current Status and Future of the Onchocerciasis Control Programme

D.H. Molyneux

Texte intégral

1The Onchocerciasis Control Programme (OCP) in West Africa is the largest and most successful human disease control programme currently being executed1. The OCP celebrated its 20th anniversary in 1994 and has been subject to a series of reviews since 1974. Its initial objective was to eliminate onchocerciasis as a public health problem in seven countries [Benin, Burkina Faso (formerly Upper Volta), Côte d’Ivoire, Ghana, Mali, Niger and Togo].

2In 1986, the programme was extended to include Guinea, Guinea-Bissau, Senegal and Sierra Leone when it was recognized that the original programme area could not be protected on a permanent basis without extension westward to eliminate the human reservoir of Onchocerca volvulus in areas from which savanna blackflies were invading the core area. Extension of the programme further south into Benin, Ghana, Cote d’Ivoire and Togo was initiated in 1979 through 1986. Until the late 1980s, when ivermectin was registered for use, control was based solely on the weekly larviciding of breeding sites of Simulium damnosum cytospecies.

3Control operations started in late 1974 with the environmentally acceptable larvicide temephos (Abate), an organophosphate compound. However, in 1980, resistance to temephos was detected2, a finding which followed the earlier discovery in 1976 that S. damnosum savanna cytospecies were capable of long-distance migrations from areas outside the limits of the programme area, carrying with them infective larvae3. These two events provoked reconsideration of the programme’s long-term future by an Independent Commission which reported in 1981 (Ref. 4).

4Resistance was controlled by the introduction of new larvicides, particularly the biocide Bacillus thuringensis sérotype H. 14 (Bt H14), which became used at low river discharges13. Its timely introduction when temephos resistance was becoming a problem prevented resistance spreading. Bt H14 is a larvicide with a specific toxicity for Dipteran larvae with no side effects on other nontarget invertebrates and fish. The ecological and environmental issues involved in the programme are reviewed by an Ecological Group which oversees the activities of the National Hydrobiological Teams, whose monitoring activities ensure that the larvicides in use have no long-term environmental impact.

5The programme’s success has been documented on many occasions in terms of both humanitarian and socioeconomic results (see Box l)5,6. This success is recognized as being due to several factors1,5, including clear objectives, a realistic timeframe, choice of best available technology, contracting out specialized tasks, priority given to operational research, a high degree of autonomy, delegation of authority, long-term commitment of donors and participating countries, specified mid-term goals in six-year financial planning cycles, transparency and free flow of information among constituent bodies, strong vertical management and high-quality staff. To these qualities can be added high levels of motivation, a willingness to embrace new ideas to refine microstrategy and consistent adherence to overall control imperatives.

6The World Bank considered that the achevements of the OCP (Box I), when expressed in economic terms based on increased agricultural productivity, represent a rate of return on investment of around 20%, which far exceeds that normally associated with health projects. Hence, OCP is a success not only in health terms, but also in économic and development terms: indeed, the programme has been described as a unique ‘development partnership’ by the United Nations Development Programme (UNDP).

7Given the annual expenditure of around 27 million US dollars during the current phase and the investment made to date by a consortium of some 22 donors over a 20-year period, it is vital that all aspects of programme operations are reviewed on a regular basis. This is undertaken by an Expert Advisory Committee which meets annually to review progress and report to the governing board of the programme, the Joint Programme Committee, which is made up of donors and participating countries. The programme has also been reviewed independently in 1981 (Ref. 4), 1986 (Ref. 7) and 1990 (Refs 1, 8), emphasizing that a constant evaluation process has been undertaken. All reviews have concluded that the overall strategy, ie. larviciding on a weekly basis, to reduce transmission over the maximum duration of the life of the adult worm, is the only appropriate means of control in the absence of an effective macrofilaricide to kill adult worms.

8Larviciding alone has been proven to be successful in the original core area. However, to maintain the core area free of blinding O. volvulus it was necessary to extend the programme both west and south to eliminate the adult worm in the areas from which reinvasion occurs by migrating savanna blackflies, Simulium sirbanum and Simulium damnosum ss.

9The programme was recently reviewed again during 1994 at a point midway through the (penultimate) IVth phase9. The review was conducted by the Expert Advisory Committee of the programme to provide the Joint Programme Committee (the goveming body of the OCP) with a report on progress since the 1990 review1,8, and to provide a prospective of the future of the programme, predicting the end point of the programme and an estimate of the costs.

10The programme, while initially based solely on vector control, has benefitted remarkably from the provision of Mectizan® (ivermectin), free of charge, by Merck Sharpe and Dohme. This drug, which rapidly reduces skin microfilarial loads and causes régression of some of the ocular lesions, prevents blindness developing in some individuals who are vulnerable, in spite of vector control10-11.

11Mectizan®, given annually, at an oral dose of 150μgkg-1, now plays a major role in reducing ocular morbidity in the extension areas and in a few problematic sites in the original programme area. Distribution is in the hands of national teams with OCP support non-governmental organizations and the communities themselves where the highest levels of compliance and coverage are achieved (65–75%).

12In areas where Mectizan® distribution occurs concurrently with vector control, there has been a more rapid improvement in ocular morbidity compared with that achieved in the core area some years ago when vector control alone was available.

Box I. Achievements of the Onchocerciasis Control Programme
• 125000-200000 people have been prevented from going blind.
• Over 30 million people in 11 countries are protected from damaging ocular lesions due to Onchocerca volvulus infections5.
• 10 million children born since the programme began have been spared the risk of blindness from O. volvulus.
• 1.5 million people originally infected are now no longer so.
• 25 million hectares of riverine valley and adjacent land has been made available for resettlement; enough to support some 17 million people.
• Over 400 professionals have been trained in various areas of relevant health sciences, such as epidemiology, vector biology and control, hydrobiology, ophthalmology and public health management.
• Over two million people are under ivermectin treatment within the programme area.
• As a result of 20 years of operations in the core area, the disease (as a public health problem) has been eliminated from Burkina Faso, Niger, large areas of southeast Mali, and northern areas of Côte d’Ivoire, Ghana, Togo and Benin.

13At present, Mectizan® is given to over two million people annually in the programme, mainly in extension areas. The evidence available on the effect of Mectizan® distribution on transmission of infection is equivocal, but in some areas (Gambia river basin in Senegal) where (for epidemiological reasons) twice-yearly distribution is undertaken, there is evidence that transmission has been reduced considerably as no infections have been found in the under-five age group born since distribution began, or in adults known to have had no infection before treatment started in the area.

14Mectizan® is also important in the context of potential recrudescence control as well as in a very restricted number of areas where larviciding has not been totally satisfactory (eg. Dienkoa, Burkina Faso; Bui, Ghana) or in areas bordering Nigeria (eg. R. Sota in N.E. Benin) where infected blackfly infiltration cannot be prevented as there is no vector control in Nigeria. Similarly in extension areas where vector control is unnecessary to protect the core area (Guinea-Bissau. Senegal), or where it is considered that transmission is due to O. volvulus which causes the less-severe form of the disease and the vector is non-migratory (eg. S. leonense in Sierra Leone), then Mectizan® distribution alone is appropriate.

15Since 1990, the programme has made remarkable progress in enhancing its efficiency of larviciding operations12. There are now seven larvicides available for vector control. Resistance to temephos has regressed. The seven larvicides approved for use are the organophosphate compounds temephos, pyraclofos and phoxim; the pyrethroid permethrin; the biocide Bt H14; the carbamate carbosulfan and, most recently, a pseudopyrethroid etofenprox. Hougard et al. 12 have summarized the recent development and the rationale behind the rotational use of insecticides, their relative cost-effectiveness, the conditions under which each is used, and the environmental problems inherent in each.

16The availability of the seven compounds means that any blackfly resistance can be readily controlled and their rotational use reduces the likelihood of it occurring at all. Each insecticide is used at particular river discharge levels, and restrictions are placed by the Ecological Group on the number of consecutive cycles when permethrin and carbosulfan can be used (six). The choice of insecticide is dépendent on many parameters: river discharge levels, insecticide and transportation cost potential of development of resistance and the distance downstream from the point of application over which insecticide is effective (‘carry’ distance). Improvement of computer-based insecticide-delivery Systems in helicopters allied to almost instantaneously available information on river discharges is obtained via solar powered ‘balises’ (hydrological monitoring stations) transmitting river levels via a geostationary satellite to a ground station in Toulouse for processing before transmission back to the programme area for use by vector controllers and pilots. The OCP is the world’s largest user of real-time hydrological data. Over a prolonged period, the programme has undertaken much work on blackfly cytotaxonomy and encouraged research to develop methods in identification of adult blackflies13. An identification method for adult flies has been developed based on morphometrics providing a reliable method for identification14. It is expected that DNA methods will also soon be available for this purpose.

17Adult Simulium identification, together with the ability to recognize blinding and non-blinding Onchocerca volvulus strains using DNA methods based on PCR of different O. volvulus stages, has provided vital epidemiological information, enabling OCP to make major savings on vector control15. Differentiation between O. volvulus and O. ochengi using PCR has shown that the annual transmission potential (previously regarded as being unacceptably high in public health terms) in some savanna areas was due to O. ochengi L3 stages in savanna flies confusing the epidemiological picture. This differentiation has also enabled some river Systems (eg. in Mali) to be eliminated from vector control activities. Onchocerca ochengi, which is closely related to O. volvulus, has proved to be an excellent model for chemotherapy and immunological studies16.

18Insecticide treatment of extension areas which commenced in the late 1980s has confirmed that treatment of savanna blackfly breeding sites in Guinea and northern Sierra Leone prevents invasion of the core area by the savanna cytoforms.

Current Epidemiological Situations

19There has been a continuing reduction in ail epidemiological parameters in areas under control by larviciding alone, ivermectin alone or by a combination of both methods. This is borne out by reduced annual transmission potentials, throughout the area of savanna blackfly transmission of blinding O. volvulus.

20Classical skin snipping for parasitological diagnosis for measurement of community microfilarial loads (CMFL) is becoming less valuable. Invasive diagnostic procedures should be avoided if possible (as they pose a risk of HIV infection, and are becoming unacceptable to local populations). In addition, there is reduced sensitivity of skin snipping where microfilarial loads have been lowered where Mectizan® is distributed. The search for an immunological, or a DNAbased technique is in the process of development. A tricocktail antigen test based on an enzyme-linked immunosorbent assay (ELISA) detection System is now being evaluated before a decision is made to make it operational in the programme, while studies of PCR-based methods for detecting parasites are being pursued.

21In reviewing the overall epidemiological situation, we must consider the role and influence of human migrants carrying patent onchocercal infection from outside the programme area in the south where non-blinding strains are present. Such populations may influence the CMFLs, annual transmission potentials and prevalence if the migratory status and strains of O. volvulus present are not considered. In such situations, PCR will be invaluable in determining strain identity.

22Mectizan® distribution has continued to be expanded; over two million people have been treated annually over the past two years. OCP has been closely involved with non-govemmental organizations in Mectizan® distribution, particularly in developing community selftreatment and evaluating the epidemiological impact.

Development of a Macrofilaricide

23The OCP has supported extensive research (through the Onchocerciasis Chemotherapy project and Macrofil, a combined OCP/TDR funding committee) to seek an effective chemotherapeutic agent which will kill adult O. volvulus, a macrofilaricide. Despite extensive studies, the prospect of finding a compound with the characteristics of Mectizan®, a safe drug with limited side effects which can be used via mass treatment without medical supervision, is remote within the timeframe of the programme. However, the long-term value of a macrofilaricide effective against Onchocerca, Wuchereria and Brugia is widely recognized. In the context of OCP, the mass distribution of such a compound could have reduced the duration of vector control by rapidly removing the adult worms, and hence the reservoir of infection. As things are, this is unlikely to be accomplished because only three options for a macrofilaricide are now under consideration. One of the candidate compounds (amocarzine) has been undergoing trials in Ecuador; before further clinical trials commence in Africa, a review will be made of the results of a three-day regimen (6 mg kg-1 oral dose daily) (total drug given, 18 mg kg-1) taken with food.

24A further product under test is a product of the University of Michigan (UMF 078). The compound has good macrofilaricidal effects and is in preclinical and efficacy trials. The development costs of UMF 078 would have to be borne entirely by the OCP/TDR Macrofil Project. Given the time necessary to get a drug into use, it was not considered by the recent review9 that OCP should support the Macrofil programme beyond 1997. There is no likelihood that the achievement of the programme goals could be influenced by further research on a macrofilaricide, even though the availability of such a drug would be of great value outside the programme area as well as for lymphatic filariasis control.

25The potential macrofilaricidal properties and tolerance of higher dose levels of Mectizan® are currently under investigation. However, it is important that higher dosages do not produce effects which might jeopardize the use of Mectizan® as a microfilaricide at current dose levels both within and outside OCP.

26There is also recognition that, while the likelihood of the development of resistance to Mectizan® is limited in O. volvulus (due to the long duration of the life cycle), the danger of resistance developing in other nematodes (eg. Haemonchus contortus and the model Caenorhabditis elegans) is. greater. Therefore, the development of a method for detecting resistance in O. volvulus should be pursued. While the risk of resistance to Mectizan® developing cannot be excluded, the combination of vector control and Mectizan® distribution dramatically reduces (and may totally eliminate) its likelihood. This is an additional justification for maintaining vector control until adult worms are eliminated from the populations in areas which could act as a source of reinvasion of the core area.

Modelling

27The OCP has benefited considerably in recent years from the development of the ONCHOSIM model17. This model has been used extensively to inform decisions relating to the cessation of control under different scenarios of larviciding duration and Mectizan® distribution either alone or combined with vector control. Initially the model was tested using the standard epidemiological parameters: annual transmission potential, CMFL, prevalence of microfilaria and prevalence of blindness. It was realized at an early stage that there was close correlation between predicted and observed figures, and that ONCHOSIM would provide an increasingly valuable tool to inform the decision-making process towards the programme conclusion.

28Experience has shown ONCHOSIM is a robust predictive tool of considerable value and, on the basis of simulations on risks of recrudescence in various control scenarios, it has been concluded that the combined use of Mectizan® and larviciding was required for 12 years to reduce the risk of recrudescence to less than 1%. Hence, the period of larviciding could be reduced by two years when ivermectin was given annually and concurrently at a coverage of 65-70%. This compares with the 14-year period of larviciding alone which has been shown to be required in the core area to eliminate all adult worms9.

29If combined larviciding and Mectizan® distribution were maintained for only 10 years, Mectizan® distribution would have to be continued at a coverage of 65% annually for a further 10-year period to reduce the risk of recrudescence to less than 1%. If Mectizan® itself were used alone (65% coverage), continuous treatment for at least 20 years would be required to reach an epidemiological situation where the risks of recrudescence are reduced to a similar level. These predictions mean that combined larviciding and Mectizan® should be maintained for 12 years in extension areas where blinding O. volvulus transmitted by migrating blackflies capable of reinvading the core area occurs. To achieve this, control will need to continue until 2002.

30ONCHOSIM simulations will be required in future to determine the possible impact of any macrofilaricidal effects of high dose Mectizan® on parasite fecundity and the requirements for the control of possible recrudescence. ONCHOSIM has also assisted in defining the parameters for resumption of treatment or unsatisfactory post-control epidemiology based on the number of L3 stages per 1000 parous females.

31In addition to OCP research (see Box 2) hydrobiological teams have made the major contribution to our knowledge of the aquatic ecosystems of West African rivers22. The development of ONCHOSIM (see above) has demonstrated the value of modelling in informing control strategy. The extensive operational research in Mectizan® delivery both within and outside the programme has made the cost-effective delivery of this drug a reality. The TDR/OCP collaboration is supporting the ongoing development of an immunological test for O. volvulus in order to avoid skin snipping. The prospect of a non-invasive, DNAbased test is also being investigated.

Devolution

32For many years, OCP has been seeking to devolve the responsibility for maintaining the programme achievements and skills to the participating countries to enable them to maintain the achievements of the programme when external support has finished. Devolution is the process by which OCP provides support for country activities to enhance their capacity and ensure that

Box 2. Research Requirements for the Onchocerciasis Control Programme
Applied research has been an integral part of OCP and has made a major contribution to its success. This has been sustained through contracting out necessary research as well as via maintenance of strong links with the WHO/TDR programmes. Major findings on the biology of Simulium and Onchocerca have resulted over a 20-year period:
• The phenomenon of Simulium migration and hence reinvasion3;
• Resistance development and its subsequent control as a result of insecticide research and refinement of rotational larviciding strategies12,18;
• The development of methods of blackfly identification, improved cytotaxonomy, isoenzyme, DNA methods. cuticular hydrocarbons, and morphometrics 19,20;
• Development of DNA/PCR methods for Onchocerca differentiation and subsequent deployment to inform control strategy15;
• Identification of O. ochengi in cattle and its development as a chemotherapeutic and immunological model16;
• Development of new insecticides, particularly the improved formulation of Bt H14 (Ref. 21);
• Better understanding of epidemiology of O. volvulus in the context of geographical distribution, strains and severity of ophthalmological lesions10,11;
• The definition of new blackfly species and cytoforms14.

33capacity is sustainable to detect and manage recrudescence of onchocerciasis. The mandate for OCP is strictly that relating to onchocerciasis and, in that context, over 400 Fellowships have been provided, countries have developed their own devolution plans, technical manuals have been drawn up, sensitization and education activites have developed, epidemiological surveillance of sentinel villages established and Mectizan® distribution Systems have been put in place in partnership with the countries, NGOs and local organizations. These significant achievements reflect OCP’s commitment to providing the health services with the most appropriate support to achieve the long-term objectives which are to eliminate the public health problem of onchocerciasis and ensure the countries can sustain that achievement. Over recent years, however, the challenge of devolution has been how onchocerciasis surveillance and control can be incorporated into a multi-disease surveillance and control System appropriate to country devolution plans which identify particular diseases for incorporation into disease surveillance and control Systems. It is now recognized that such an approach is not within the mandate of OCP itself. OCP is specifically a vertical activity; however, the maintenance of its achievements post OCP must be within a disease-surveillance System that is affordable within the varied health Systems in the participating countries. The challenge over the forthcoming years will be how onchocerciasis surveillance is integrated, as the disease will necessarily be of limited public health importance, into health Systems which are in the process of signifiant structural change, which have excessive demands placed upon them already and which will be less able to depend on OCP technical and financial support. It is expected that WHO, via the Regional Office, will play an increasing role in supporting country disease-surveillance Systems while, in parallel, changes in the health sector driven by the World Bank will ensure that such Systems fit a policy environment which reflects the new radical approach to health care provision through decentralized structures.

34The conclusion of the recent midterm review was that the programme has been highly successful; it confirmed the reasons for that success and considered that, to achieve its long-term goals, the programme should continue its present strategy of combined larviciding and Mectizan® until 2002. Research on macrofilaricides, while necessary in the wider context, should not be supported by OCP beyond 1997.

Acknowledgements

35I am grateful to members of the Expert Advisory Committee of the OCP, and the former Director, Ebrahim M. Samba, for support and encouragement Ole W. Christensen and J. Frank Walsh, as well as OCP staff, were particularly helpful in making suggestions about the manuscript.

Meetings on Onchocerciasis Control
The World Bank is organizing a Donors Conference to discuss funding for the African Programme for Onchocerciasis Control (APOC) in Paris in October 1995. This will be followed by two meetings to be held at the World Bank in Washington DC: (1) the first meeting of the Joint Action Forum of APOC, 4-5 December, will be attended by the Ministers of Health of onchocerciasis-endemic countries and prospective donors; and (2) the Joint Programme Committee of the Onchocerciasis Control Programme (OCP), the governing body of the OCP consisting of representatives of the 11 participating countries and the 22 donors, 6-8 December, will be hosted by the Government of the United States.

Bibliographie

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Auteur

David Molyneux is at the Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK L3 5QA. Tel: +44 151 708 9393 x226l, Fax: +44 151 707 0155, e-mail: fahy@liv.ac.uk.

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