The role, impact and organization of drug treatment as a means of onchocerciasis control with particular reference to ivermectin and to the OCP area

WORLD EEALTE ORGANIZATION NATIONAL ONCHOCERCIASIS COMMITTEES Tenth meeEtng cotonou. 3-5 June 1986 ORGANISATION I{O}TDIALB DE LA SA}ITE ONCHOCERCIASIS CONTROL PROGRAMME IN WEST AFRICA pRocRAMl.{E DE LUTiE CONTRE L,ONCHOCERCOSE EN AFRTQUE DE L'ouEsr Noc10.4 (ocP/86 .3) ORIGINAL : ENGLISH THE ROLE IMPACT AND ORGANIZATION OF OF ONCHOCERCIASIS CONTROL WITH TO IVERMECTIN AND TO DRUG TREAT}'{EMT AS A MEANS PARTICULAR REFERENCE TIIE OCP AREA il @ WORLD HEALTH ORGANIZATIONORGANISATION MONDIALE DE LA SANTE )cP /86.3 ORIGINAL: ENGLISH ONCHOCERCIASIS CONTROL PROGRAMME ]N THE ROLE, IMPACT AND ORGANIZAT]ON OFAS A MEANS OF ONCHOCERCIASIS !,ITH PARTICULAR REFERENCETO IVERMECTIN AND TO THE OCP WEST AFRICA DRUG TREATMENT CONTROL AREA A. 1. 2. The The of TABLE OF CONTENTS BACKGROUND AND GENERAL CONSIDERATIONS. search for a drug..purposes and effects of drug treatment in the contextonchocerciasis control. .. . operations. Page 3 3 3 B oU 9 10 77 11 11 B. 3. 4. 5. 6. IVERMECT]N Regi.stration. Caveats and exclusion criteriae. Dosage and formulation. Marketing and distrlbution control. ORGANIZATIONAL ASPECTS OF IVERMECTIN DISTRIBUT]ON. General considerations. Organization of ivermectin conducted vector controlOrganization of ivermectin maintenance/ survei J-1ance distribution during period of OCp 4 4 4 5 5 5 5 6 7 C. POTENTIAL USE OF IVERMECTIN IN THE OCP AREA. 7 . General considerati.ons.B. Use of ivermectin in the pre-Extension area (1985 boundaries)9. Use of ivermectin in the Extension areas. D. 10. LL. L2. distribution duringperiod: Devolution the post-OCpand ivermectin. E. POTENTIAL USE OF SERODIAGNOSIS. 13. General considerations.14. Use of an immunodiagnostic test. F. 75. 76. DISTRIBUTION OF IVERMECTIN AND TECHNICALSupport to the strengthening of health care COOPERATION. 72 T2 L2 Support to procurement of ivermectin. delivery systems.. ocP /86.3 Page 2 G. FURTHER THE OTHER Page ]NVESTIGATIONS AND OPERATIONAL RESEARCH USE AND DISTRIBUTION OF IVERMECTIN IN CONCERN]NG OCP AND ONCHOCERCIASIS-INFESTED AREAS. 77. rssues and studies of direct relevance to the use of i.vermecti-n....18. rssues and studies of direct relevance to the distribution of ivermectin 1-2 t2 74 H. POTENTIAL USE OF IVERMECTIN IN AREAS hIITHOUT OCP-LIKE CONTROL POTENTIAL USE AND EFFECT OF A ONCHOCERCIAS IS - INFESTED PROGRAMMES. 14 t5 76 L9 the its J. MACROFILARICIDE. Annex 1: Estimation of the number of beneficiaries of ivermectin treatment in the OCP area (1987) Annex 2: Recapitulation of organization of potential use of ivermectin and of the distri.bution within the OCP area...... Annex 3: Estimation of manpower requi.rements for large-scale case- treatment in Western Extension area.. ocP /86.3 Page 3 A. BACKGROUND AND GENERAL CONSIDERATIONS 1. The search for a drug 1.1 In the absence of an effective and convenient anti-onchocerciasis drug amenable to large-scale distribution, the basic technical approach of theOnchocerciasis Control Programme in West Africa (OCP) has so far consisted of controlling the vector in order to interrupt the transmission of the parasite. However, OCP is making considerable efforts through the Onchocerciasis Chemotherapy Project (OCT) to identify and develop medicanents of potentialinterest to the control of the di.sease. 2. The purposes and effects of drug treatment in the contelt of onchocerciasis control 2.L The use of a drug in the control of onchocerciasis could serve two purposes:to treat patients suffering from the disease and to control transmission.Transmission-control by neans of a drug would mean reducing/eliminating theproduction of microfilariae in the already infected part of the population(chemotherapy) and/or preventing larval stages of the parasite in previously non-infected persons from developing into reproductive adult h,orms(chemoprophytaxis) I however, with the present limited knowledge of the two modesof action their respective contributions to the control of transmission will notbe considered separately in this paper. 2-2 The use of a drug for the first purpose, i.e. the management of individual cases of onchocerciasis (case-treatment), aims at alleviating human suffering by easing symptoms of the disease, preventing its serious skin and ocular manifestations and, eventually, achieving conplete cure. Although the emphasishere is on the treatment of individuals, the suppression/eliminaiion of the microfilaria load will also contribute to transmission-control. 2.3 Given an ideal drug and perfect logistics, complete transmission-control and elimination of the 0. volvulus reservoi.r should theoretically be possible without vector control. In practice, however, for some time to come (it'ever) no drug is1ikely to conform with the requirements (1001 effective, no side-effects, no exclusion criteriae, etc.), and the demands for delivery systems and on resources could well exceed the national capacity. Anti-onchocerciasis drugs are therefore not likely to replace larviciding in the OCP area as a means of transmi.ssion- control. 2.4 It is expected that the effect of drugs used in the OCP area would be equally potent as regards the treatment and control of both the "blindingil("savannatt) and "non-b1i.nding" (,forest") forms of onchocerciasis. 2.5 Whether the drug is a macrofilaricide or a microfilaricide, the ultimateeffect should, in principle, be the same both in respect to transmission-control- and to case-treatment. The difference will be one of application. One singletreatment should suffice for the macrofilaricide (under ideal conditions) wtrite amicrofilaricide will need to be given at regular intervals (depending on theduratj,on of its effect) until the reproductive female worms dil out 7tZ-tSyears) (unless it also had a cumulative macrofilaricidal effect). ocP/86.3 Page 4 B. IVERMECTIN 3. Registration 3.r Phase rrr trials of j-vermectin h,ere started j-n 1985 and Merck, sharpe & Dohme (MSD) intends to apply for registration based on a twelve-mcnth fo11ow-up of these t,riars. rt is hoped that approval wi.I1 be granted by July 1987. The application will probabry be submitted to the French Drug Registration authorities which, in case of acceptance, should facilitate the approval of thedrug for use by all those countries in Africa, America and Asia where onchocerciasis is endemic. 3.2 There may be a time-lapse of some months between registration and marketing. 4. Caveats and exclusion criteria 4.f MSD is like1y to put forward a number of caveats for the use of ivermectin, most of rohich might be issued as exclusion criteriae by WHO. At the present titrethe following population groups would probably be excluded from treatment: - children below a certain age, say eight yea"s1. - women of child-bearing age unless a pregnancy test, or history and absence of signs, show them not to be pregnant. - r^romen who are breastfeedingl . - persons with severe disease of the Iiver, kidney or central nervous system. - persons living in an area exposed to epidemics of cerebro- spinal fever or human trypanosomiasis at the time of theproposed ivermectin treatmentl. 4.2 Furthermore, MSD will in all likelihood issue the following additional caveats: - initially, ivermectin should be used only i-n the treatment of human onchocerciasis. - the minimum interval between single doses should be six months although three-month intervals might eventually be permitted(see paragraph 5.2 below). 4.3 Also, the company wi1I, no doubt, make available to the medical professioninformation regarding such pharmacodynamic aspects of ivermectin as the degree to which it is retained in the body with possible later release, its possible toxic manifestations, and the antidotes to be used if toxicity occurs. lMay subsequently be relaxed. )cP /86.3 Page ! 5. Dosage and formulation 5.L The minimum effective single dose of ivermectin recommended by MSD is 1ike1yto be 110 mcg/kg, but scored tablets of 6 mg will be manufactured permitting easy dosage in the range of 50-200 mcg/kg. 5.2 The maximum interval between individual doses may vary according to thepurpose of dispensing the drug. It would thus appear that one dose every six months might maintain adequate microfilarial suppression for most purposes(including transmission-control) although three to six month intervals could be necessary for case-treatment when there is a high risk of ocular onchocerciasis developing into blindness, However, an interval of three months must, for the ti.me being, be regarded as the minimum compatible with safety. Ivermectin is known to persist in the body (especially in fat and certain other issues) for atleast a month after a single dose, and it must be considered that there is an asyet unassessed risk of toxicity associated with the dosage given more frequently than once every three months. 5. Marketing and distribution control 6.1 It is 1ikely that ivermectin will be supplied by MSD through WHO only for use in onchocercj-asis-afflicted countries at a very reasonable or zero cost. 6.2 In order to avoid individuals receivi.ng the drug, either i.nadvertently ordeliberately, at shorter intervals than the minimum recommended (see paragraph 1.2 above) a fairly strict control must be kept on the delivery system and thisin particular if nultiple outlets are available (e.g. hospitals, health centres, OCP sectors/sub-sectors) to each of which an individual might apply for treatmentin relatively quick succession. c. POTENTIAL USE OF IVERMECTIN IN THE OCP AREA2 7. General considerations 7.7 The main-characteristics of j.vermectin which make it particularly amenableto use within the OCP area can be summarized as follows: it can be given orallyin a single dose, repeatable probably every three to twelve months; it is highly effective as a microfilaricide, without serj.ous side-effects; and thus suitablefor large-scale distribution as and when required. 7.2 It is important to stress that ivermectin is effective against the forms of 9.vol-vulus found in both savanna and forest areas in west Africa (and inGuatemala). It is reasonable to assume that it will act satisfactorily againstall geographical forms of the parasite. 7.3 One limi.tation on the use of ivermectin would be that perhaps half of thefemale population will escape treatment if the above mentioned exclusion criteria(pregnant and lactating women as hre1l as children below the age of eight) continue to apply. A rough assumption is that onty 6J"l of the total infectedpopulation will be treatable. 2see A.rrre* 2 for recapitulation. ocP /86.3 Page 6 7.4 However, the reduction in the effect on transmlssion control resulti.ng from exclusions would not attain 35%, as suggested in the precedi-ng paragraph, if thefindings of a study carried out in Cameroon rain-forest villages (main vector: S.squamosum)3 ,."" valid also in the OCP area. According to this study 85"/" of transmission originated from persons between 11 and 40 years; up to age 20, males and females contributed equally to transmission but above 20, males contributed 1.5 times as much as females; and children aged 6-10 years were responsible for only about 6% of the total transmission. The application ofthese estimates to the si.tuati.on in the OCP area would seem to indicate that the reducti-on in transmission control due to the exclusion of children, pregrrant andlactating women from treatment, would be in the order of 20-25/" rather t]nao 35%. 7.5 An attempt is made in Annex 1 to estimate the numbers of persons who, iflarge-scaIe treatment with ivermectin were contemplated, would actually qualifyfor receiving the drug (estimates for 1987). At the same time, an analysis of these figures throws some interesting light on the cost-effectiveness of usingivermectin in various parts of the OCp area. 7.6 The calculations have been made separately for the original QCP area and forthe three extension areas, viz rvory coast (1979), the western Extension(1986/87) and the Southern Extension (LgB6/87) areas. Separate estimates are made j-n Annex 1 for the numbers of persons to be treated if a diagnostic surveypreceded treatment of detected positives and if a blanket treatment of communities in the endemic areas were made without prior diagnostic surveys. 7.7 These estimates are referred to in the following when arriving at conclusj"ons regarding the use of ivermectin. It should be stressed that many ofthe assumptions on which the calculations are based are open to discussion. B. Use of irre"mectin i., the pre-Extension area (1985-boundaries) 8.f Onchoeerciasis has now been controlled in the major part of the original Programme area (002 01) to the extent that it is no longer a public healthproblem and that transmission of the parasite is virtually interrupted. However,there remains a reservoir of 0.volvulus which, although greatly diminished, might sti11 have the potential fo" beco*:.ng a source of renewed transmission. Further research is therefore required to determine the leve1 of the parasite(microfilariae) load at which vector control may eventually cease. In the few residual- areas where low-Ieve1 transmission continues, the risk of developing ocular manifestations is probably insignificant (ATp below 300). B.Z The situation in areas exposed to reinvasi.on of infective savanna blackflies remains unsatisfactory insofar as the downward trend of the community load ofinfection has been halted and the continuing exposure to new infections gives rise to onchocercal eye manifestations. 8.3 In those parts of the original oCP area where transmission is virtuallyinterrupted and vector control is at the maintenance Ievel (e.g. 0OZ 01) thlrewill be Iittle, if any, use of ivermectin for the purpose of transmission- control. Also the need for treatment of individual patients will beinsignificant insofar as very few clinical cases remain after more than ten yearsof continuing vector control. 3Duke, B.o.L. and Moore, p.J. (1968): ,,The contribution of different age groupsto the transmission of onchocerciasis in a Cameroon forest vilIage". Annals of , 22-28. ocP /86.3page 7 8'4 The principal use by the Programme of ivermectin within the original OCparea will therefore be the treatment (or prevention) of ner4r cases thit may occurdue to reinvasj-on of infective blackflies or as a result of persistent l-ocalizedfailure in larvicidal control such as has occurred i.n a few sma11 foci. Giventhat larviciding will extend to the OCP Extension areas over the next tr,ro orthree years, the problem of reinvasion should become one of minor concern.However, should isolated instances of reinvasion of infective savanna blackflies(ATP above 300) ever occur, large-scale distribution wourd be instituted inexposed villages both for the purpose of transmission-control and case-treatment.rvermectin could be used in a similar manner and with the same i.ntentions 1ncases of resumptj-on of transmission due to 1oca1 failure of larviciding in alimited geographical area. In such places it would be used as a supplement tolarviciding with the goal of reducing the microfilarial reservoi" mtie rapidlythan would otherwise occur. B'l For the sake of completeness, nention should be made of the possibility ofi-vermectin being utilised for transmission-control in ci.rcumscribed instances ofunmanageable resistance to larvj,cides although such instances are unlikely tooccur in the original OCp area. B'6 The following consideration concerning cost-effectiveness of ivermectintreatment in the original OCP ar:ea supports the conclusions arrived at i.nparagraph 8.3 above. According to the estimates in paragraph 2 of Annex 1, ifbranket treatment for the prr"pos" of transmi""io"]"o"tro1 were instituted, atotal of more than four million people in the o"iginar ocp area woufd have to begiven the drug in one year (1!8/) to reach the 335 0oo persons sti11 harbouringparasites' rvermectin would thus be dispensed to rS people to catch one lightlyinfected casei a cost-effectiveness ratio Iikely to decrease even further withtime. B'l The conclusion to be drawn from these estimates would seem to be thativermectin treatment in the original OcP area for the purpose of vector controlwould invorve considerabl-e extra expense without the expectation of any greatadditional benefit to that obtained by simply ,.iii."g for the elimination of thereservoir through natural death of parasites. B'B rhe treatnent by ivermectin of patients suffering from the non-blinding formof onchocerci'asis within forest and mixed rorest/sav€lnna areas, now excluded fromcontrol by OcP, would become the responsibility of the national healthauthorities, possibly with some technical advice from the programme. 9. 9'7 rn paragraph 2.2 above it is suggested that the ideal drug dispensed underperfect conditions of logistics could-by itself "."rrIt in complete transmission-control achieved in the Ocp area by larviciding as a sote means of contror.However, as there is no complementarity in the action of the two methods (atleast during the attack/consolidation phase) a choice imposes itself. Given,therefore, that vector control has proved itself to be capabre of completeinterruption of transmission, and insofar as the distribution of ivermectin w111be encumbered by a number of technical and operational restrictions, larvicidingwill remain the preferred, and exclusive, method of transmission-control in theExtension areas during the attack,/consolidation and beginning of the maintenancephase. ocP /86.3 Page B 9.2 0n the other hand, with a high morbidity 1evel, reaching hyperendemic proporti.ons in many parts of the Southern and Western Extension areas, there is a considerable potential for the use of ivermectin to allevlate the symptoms of onchocerciasis and prevent the further development of ocular manifestations in the large populations afflicted by the disease. 9.3 As and when the Extension areas move into the maintenance phase with agradually dininishing community load of infection and greatly reduced risk of transmission, ivermectin will come to play the same role as that described in the preceding section in regard to the original OCP area, i.e. to control sporadi.c occurrences of localized 0. volvulus transmission and to treat patients infected by the disease during such outbreaks (should they ever occur). 9.4 According to the calculations made in paragraph 6 of Annex 1, blanket treatment with ivermectin would (in 1987) cover a total population j-n the Extension areas of slightly more than three million in order to reach the one nillion requiring treatment. Three persons would therefore be given the drug to catch each infected case (often heavily infected). Blanket treatment might therefore be the most cost-effective approach to ensuring that all cases of onchocerciasis in high-risk areas are treated. However, further thought might be given to the economy of scale. It could thus be argued that once the initial "extra" efforts had been expended on case-finding, large-scale treatment limited to persons showing symptoms of the disease might be less expensive than conducting "indiscriminate" blanket treatment once or twice a year for aprolonged period. 9.5 As in the original Progranme area, ivermectin could also be used on a large scale to control the non-blinding "forest" type of onchocerciasis within the Extension areas with the understanding that the role of OCP in this respect would be limited to the provision of technical advice. D. ORGANIZATIONAL ASPECTS OF IVERMECTIN DISTRIBUTION4 10. General considerations 10.1 When considering the relative cost-effectiveness of indiscriminate blanket treatment and of large-sca1e distribution confined to infected persons, as has been attempted in the two preceding sections, other factors than the number of persons to receive the drug should be taken into account, as for example, the likelihood that current diagnostic methods will miss a considerable popufation of lightly infected cases and the eventual pricing of ivermectin. 10.2 The need to avoid repetition of dosage leading to excess of the limits of safety (see paragraph 5.2 above) implies that records will have to be kept of all persons treated, a requirement which constitutes an important operational constraint on whichever delivery system is instituted. 10.] The success of an ivermectin distribution programme (and indeed of any form of large-scale chemotherapy) will depend on the extent to which nati.onal health care systems are able to ensure the required population coverage and to continue doing so at the prescribed intervals during a prolonged period (12 years or nore). Prerequisites for a community-based delivery system in any country would 4see Annex 2 for recapitulation. ocP /86.3 Page p appear to be political commitment and managelial competence; a reliable and effecti,ve logistic and communicatj.on system; well-motivated, well-trained and well-supported staff; the ability of the health system5 to penetrate into even the most remote areas; and adequate funding. Proven ability to cope with otherpublic health programmes, such as EPI, in the recent past might serve as a good yardstick by which to measure a countryrs potential ability for ivermectin distribution. 10.4 Fo11ow-up exami.nations should be carried out in a sma11 number of indicator villages with a vlew to determining the degree of thoroughness with which ivernectin distribution is being carried out checking inter alia on the validity of census figures, the Lssuing of tablets, and the immediate post-treatment 1eve1s of ivermectin in plasma or urine in order to assess the assiduity of the drug distributors. Such villages could also be used for assessing the success of case-treatment in terms of decline of microfilarial denslties in the skin and in the'eye. A particular aspect of fol1ow-up would be the monitoring of the possible development of resistance to ivermectin. LL. Organization of ivermectin distribution during period of OCP conducted vector control operati,ons 11.1 As a general principle ivermectin distribution schemes should be based on and conducted by the existing national health care systems as part of the ongoing disease control activities. 11.2 However, in the case of large-sca1e application of the drug for the purpose of case-treatment in the Extension areas (see paragraph 9.2 above) the present staffing and communication facilities of most of the national health care systems will probably not enable them to cope on their own with this additional workload.Insofar, therefore, as OCP will be conducting attack/consolidation operations in the two Extension areas while J-arge-sca1e treatment with ivermectin is underway, the OCP entomological surveillance network could very well be "mobilized" to aid nationally directed drug distribution. Lax periods of the dry season when the entonological situation is comparatively quiet would be particularly convenient. The involvment of the Programme in nass case-treatment would seem perfectlyjustified even if OCP's main concern lies in the field of transmission -contro1. An added reason for making use of OCP staff in such large-scaIe distribution progranmes would be, at least in the Western Extensi-on area, that all 1ocalpersonnel, although asslgned temporarily to the Programme, remain on the payroll of the governments concerned. 11.1 An attempt is made in Annex 3 to obtain an idea about manpower requi.rementsfor the liestern Extension area (as an example) if blanket treatment were applied twice a year for the purpose of treating all infected cases in the area. According to this estimation, 45 teams (11! technicians, 45 drlvers) would be needed as compared with 400 na.tional staff assigned to OCP in that area for entonological surveillance a1one. 1I.4 An advantage of instituting ivermectin distribution at an early stage of operations (attack/consolidation phase) would be that the national health care systems became experienced in the management of mass application of the drug. They would thus be prepared for handling 1oca1 instances of renewed transmissionby means of drug control during the maintenance phase after the Programme has moved out of the area (see section 12 below). 5Possibly aided by other socioeconomic sectors. ocP /86.3 Page 10 11.! During the first part of the maintenance phase in the Extension areas when OCP carries on with vector control as required, large-sca1e application ofivermectin for case-treatment purposes will continue although on a gradually reducing scale j-nsofar as the original risk of repeated 0.voIvu1us infectionsgiving rise to serious ocular manifestations has been removed by vector control and the adult female worms begin to die out. Several modifications could thenbe made to the distribution scheme, including giving the drug once yearly insteadof twice; concentrating on originally hyperendemic communities, and, possibly,limiting the treatment to persons who have been identified during previoustreatment rounds as patients actually suffering from onchocerciasis, according toa set of easily applied signs and symptoms. The number of dlstribution teams would therefore be gradually reduced and by the time OCP vector control ceases in a given O0Z there should be little, if any, need for case-treatment to be handledby special teans. 11.6 Special operational arrangements might be required for the coordination oflarge-sca1e OCP supported case-treatment programmes in savanna areas and those conducted by the national health authorities in neighbouring/overlapping forest zones for the control 0f the non-blinding form of the disease. L2. 0rganization of ivermectin distribution during the post-ocp *aiate. irr""re"tin 12.1 Devolution has until recently been seen as a process of transfer of OCpoperations (including vector control) to the Participating Countri.es, although ata reduced scale. Recently, however, it has become clear that devolution in that sense is an outdated concept; at the time the Programme "hands over" there willno longer be a need for vector control (onchocerciasis prevalence being at a1eve1 at which transmission is excluded). What will then be required is rather "nationally directed, integrated surveillance and control" of the disease. 12.2 The challenge facing the national health authorities at that stage willtherefore be twofold : to ensure that nerd cases of onchocerciasis which may occurare actually detected (as any other endemic disease under epidemiological surveillance) and that appropriate acti-on is taken for their control. Thiscontrol will rely on the application of community-wide drug treatment of thepopulations among whom the new cases have appeared and in which recrudescence oftransmission (local breeding) is suspected. 12'J The gradual assumption by Participating Countries of this the final stage ofonchocerciasj,s surveillance and control will fo1low the same pattern in theoriginal and in the Extension areas, the former commencing the process within acomparatively near future and the latter in about eight to ten y"."s. t2'4 \t is expected that both the surveillance and the control of onchocerciasiswill be integrated within the existing (and possibly reinforced) health caresystems. Insofar as the use of the drug is concerned, i.vermectin will serve bothpurposes: transmission-contro1, should new cases occur due to 1oca1 breeding ofsavanna blackflies, and case-treatment of the patients thus contaminated.Another group of beneficiaries would be the originally infected populations inthe Extension areas who have been treated since the start of attack operations;at the time of cessation of OCP operations in a given 002, this group will havebeen reduced considerably in si.ze and should ,o Iorrg." require a speciar set-upfor its treatment (see paragraph 11.! above) ocP/86.3 Page 11 12.! Although it is anticipated that community-wide appli.cation of ivermectin for the control of circumscribed retransmission would normally be handled by the existing 1ocal health care system, instances might occur when reinforcement could be required either from other parts of the health services or by recruiting additional personnel on a temporary basis. Such personnel would work under the instructions and control of the health services. 12.6 Again, indi-vidual national health authorities would decide on the extent to which ivermectin will be utilized for the control of "forest onchocerciasis" and could call upon OCP, and possibly WHO, for technical recommendations. E. POTENTIAL USE OF SERODIAGNOSIS 13. General consi.derations 11.1 The Programme is strengthening its research in the field of serodiagnosis of onchocercal infections. The availability of a sensitive, specific and easily handled immuno-diagnostic test, capable of detecting recent infections (andpossibly distinguishing between savanna and forest type), would help to ensurethat newly infected patients could be detected and treated at an early stage of the disease, i.e. before microfilariae in the skin become a source of transmission. A1so, a test fulfilling the above criteria would make thedetection of instances of circumscribed transmission in otherwise transmission-freed zones easier. This would facilitate corrective action (transmission- control through drug distribution) and thereby eliminate the risk of further spread. 13.2 In this connection it is worth stressing that newly infected persons are not very likely to constitute a "hidden" source of infection during the prepaterrtperiod of the disease (from Ll dermal penetration until the onset of cutaneous manifestations) as blackfly cannot ingest microfi.lariae before they appear i.n the skin and subcutis and where they may give rise to itching. The fj-rst microfilariae are usually detectable in skin-snips only after, say, nine monthsto three years following penet,ration by the larvae. (N.8. : microfilari.ae may, however, be present in the skin and transmissable without positive skin-snips or symptoms). 13.3 Failing the development of a sensitive immunodiagnostic test suitabLe forfield use, it may be necessary to consider using ttre llazzotti test, eithergeneralized or as a patch test, to detect microfilariae at a very early stage after their arrival in the skin. 14. Use of an immunodj-agnostic test 14.1 Should an operational immunodiagnostic test be found, case-treatment mightbe "individuarized" rather than based on large-scale application and, as mentioned above, transmission-control instituted at an early date. 14.2 However, the cost of applying and reading the test on a large-sca1e selectj.ve population basis would be quite high, in particular if "detection rounds" were to be made every six to twelve months. itiL," ocP /86.3 Page 12 F. DISTRIBUTION OF IVERMECTIN AND TECHNICAL COOPERATION 15. Suppo"t to the st.e.gthe.inF of health care delirre"y systems 1!.1 The organization and management of drug-distribution programmes in theParticipating Countries will put considerable strain on the national health care systems, which are already operating under serious constraints as regards manpower and material resources. It is therefo're encouraging that several representatives of the donor community at recent sessions of the Joint programmeConmmittee have expressed readiness to support countries j-n the programme area in respect to their assuming operational responsibility for post-OCp surveillance and control of onchocerciasis. 1!.2 The strengthening of the health care systems to be able inter-a1ia to deal with large-scale distribution of ivermectin must continue to be given priority attention. wHO, through its regional office for Africa, is reinforcing itstechnical cooperation with its Members through a process of decentralization ofauthority and operational responsibility. Particular emphasis is placed upon thedevelopment of primary health care systens which in West African countries wi1lplay an essential role in the conduct of future schemes for the distribution ofivermectin. 15.3 Furthermore, WHO has a constitutj,onal role to play in ensuring that externalsupport to health development is provided in a coordinated manner and accordingto policies and priorities comnonly agreed upon. The bilateral donor agencies which have already indicated willingness at JPC sessions to assist participating countries in strengthening their health care delivery systems should be encouraged to consult with WHO/AFRO in order to ensure that a1l efforts to enhance these systems are well coordinated. 16. Support to procurement of ivermectin 16.1 Another field in which international solidarity will be of importance isthat of supply of ivermectin. Although it is expected that the drug will bedistributed at almost no cost, large quantities could be required, in particularfor case-treatment in the Extension areas, and the total cost of distribution might very well be beyond the reach of some of the countries concerned. Severalorganizations and agencies, governnentaL and non-governmental, part1cu1ar1yinterested in the prevention of blindness, might bu pr"pur"d to help in thisrespect. WHO/AFRO and OCP could make an important contribution by -rganizingbulk-supply of the drug and possibly by setting up a revolving or spe-ia1 fund. G. FURTHER INVESTIGATIONS AND OPERATIONAL RESEARCH CONCERNING THE USE ANDDISTRIBUTION OF IVERMECTIN IN OCP AND OTHER ONCHOCERCIASIS-]NFESTED AREAS L7. rssues and studies of direct relevance to the use of i.vermecti,n 1/.1 The following issues wil_I need to be addressed: a' mode of action of ivermectin on 0nchoqerca at the biochemical andmolecular Ieve1s I -ll b. c. d. ocP /86.3 Page 1l degree and duration of effect of j.vermectin in reducing the number of0.volvulus Ll developing in simulium fed on mlcrofilarial camiers indifferent environments and "ecto"s histology of skin i.n onchocereal patients after ivermecti.n treatment,together with other immunological and biochemical investigations todetermi.ne why the Mazotti reaction is so much less intense than with DEC effect of multiple doses of ivermectin, at different reproduction of Onchocerca worms (0. volvulus in mancattle) and on pGsiU:-e o,ac"ofilaricidal acti.riay-;"of concentration and persistence of the drug in iarft nodules intervals, on and 0. gibsoni in well as estimates worms and epidemiological studies on effect of community-wide ivermectintreatment on microfilarial reservoir and on the amount of transmissionof 0. volvulus (measured by ATp) occu*ing in and around isolated communi.ties in endemic onchocerciasis areas without satisfactory vectorcontrol- f' therapeutic potential of ivermectin followed by a course of 1ow-dose suramin (or any other macrofilariacide developld in future) especiallyas regards prevention of development of eye lesions; curing acutepruritic skin lesions; and alteration of toxic manifestations associated with suranin g' optimal interval of dosing to prevent development of eye lesions and tocure/prevent acute pruritic dermal resions and "sowda,' h. the safety of ivermectin in pregnant r^romen, children below the age of eight years i. tolerance to ivermectin in patients receiving antimalarials (e.g.chloroquine, quinine and pyrimethamine/sulphonamide) or other drugsIike benzodiazepines j' possible caution re. use of ivermectin in areas where Loa Ioa ando. volvulus co-exist as i-vermectin treatment coura, -tffi""iiv, cause severe reactions in brain or retina due to sudden death of largenumbers of L. Ioa microfilariae k' collectj'on and analysis of data on possibre adverse reactions followingthe marketing of ivermectin within lh" OCp u.""a 1' close watch for devel-opment of resistance to ivermectin even if thisunlikely; however, should resistance occur it would probably spreadvery s1ow1y due to long generation turnover time in O.volvulus andabsenceofmicrofi1ariamu1tip1icationintr,evecio*ffi""Je,oura be Iikely to spread more rapidly in areas without vector control, whilespread would be almost nil as 10ng as adequate vector control ismaintained. 1/'2 Although the more basic research j-ssues would seem to be the concern of MSD,OcP will have to be involved in studies relating to some of theepideniological,/operational research subjects listed above. e. lactating women and ocP/86.3 Page 14 18. Issues and studies of direct relevance to the distribution of ivermectin 18.1 In connection with large-scale application of ivermectin, OCP could usefully undertake the following studles: an estimation of the cost of diagnostic surveys of O.volvu1us immediately followed by ivermectin treatment of all persons found positive and not subject to exclusion criteria (on a country-by-country basis ) an estimation of the cost of instituting blanket treatment without a pre-treatment diagnostic survey, but observing the exclusion criteriae(on a country-by-country basis) prediction as to the 1eve1 of community load of infection below which no transmission would occur if savanna blackfly were allowed to re- enter the area predictions as to the possible effects of ivermectin treatment on the human microfilarial reservoir in different parts of the OCP area and On the amount of transmission that would result if the S.damnosum s.1. population were allowed to build up again (on the basis of pre- treatment diagnostic survey and on the basis of blanket treatment; consideration given to the effect of applying exclusion criteriae) R & D field studies to identify various organizational and managerial approaches to large-scale application of ivermectin for the purposes of transmission-control and case-treatment (on a country-by-country basis) and cost/benefit studies area-wise R & D studies to identify the gradual decline in workload associated with large-scale case-treatment in Extension areas following effectivo vector control and the dying out of female worm. POTENTIAL USE OF IVERMECTIN IN ONCHOCERCIASIS-INFESTED AREAS WITHOUT OCP-LIKE CONTROL PROGRAMMES 19.1 As in the OCP area, ivermectin could serve the dual purpose of case-treatment and transmission-control in countries where onchocerciasis is endemic and where no systematj,c, complete-coverage vector control programme has been instituted. 19.2 To secure an epidemiologically significant effect on transmission within a given onchocerciasis-infested area, ivermectin would need to be given at regular intervals to all infected persons. If the area in question extends to the limits of transmission of the disease so that there is no risk of infective blackflies entering the area from outside sources, ivermectin dlstribution over a period of L2-75 years should, theoretically, result in the human 0.volvulus reservoir dying out and the disease being eliminated. However, under practical field conditiorrs with probable incomplete cover'age at irregular intervals and the need to apply the exclusion criteria, the effect of large-sca1e ivermecti.n distribution on transmission may only be palliative with the prospect of an indefinite continuation. a. b. d. e. f. H. ocP/85.3 Page 1! 19.3 Obviously, the situation in a more confined endemic area exposed to reinvasion of infective blackfly would be even more unsatisfactory, insofar as any temporary ivermectin-induced reduction in transmission of the parasite would cancel out once drug distribution ceased and infective blackfly from the outsidejoined with those sti1l active in the area to bring the human 0.voIvulus reservoir back to its pre-distribution level. However, there would be a beneficial effect in terms of preventing infected persons from developing serious eye-1esions. 19.4 0n the other hand, if large-sca1e distribution of ivermectin is like1y to have only a temporary effect on transmission, the use of the drug for the purpose of case-treatment (preventing seri,ous skin and eye manifestations) could be of considerable benefit to those infected by the disease for as long as the treatment continued, even if the risk of re-infection would persist. J. POTENTIAL USE AND EFFECT OF A MACROFILARICIDE 20.1 The availability of the long-acting microfilaricide, ivermectin, by no meansprecludes the pressing need for a non-toxic macrofiLaricidal drug, suitable for large-sca1e use. It may be that one of the new Ciba-Geigy compounds, CGP 6140 or CGP 20376, would fill this role within the foreseeable future, but meanwhile research for others must be intensified. 20.2 Large-sca1e distribution of a macrofilaricide aiming at the populations already infected by, or exposed to, onchocercj.asis would greatly enhance the effect of vector control and reduce its duration. Furthermore, in areas without systenatic vector control, blanket treatment by a macrofilaricide in combination with ivermectin, might conceivably reduce the human reservoir of O.volvulus in all its forms to a non-transmi,ssable level within a comparatively-Etort time. 20.J Fina11y, as with ivermectin, a macrofilaricide would be used also for the control, and possibly elimination, of the non-blinding (t'forest") form of onchocerciasis. -rI ocP/85. 3 Page 16 Annex 1 Estimation of the number of beneficiaries of ivermectitr treatment in the OCP area (1987) 1. Table I below refers to the original OCP area. For each of the seven countries it gives (a) the estimated number of persons infected with 0.vo1vulus in 1974; (b) the numbers probably stil1 infected in 1987 (taking these to be 291 of the 1974 fieures); (c) the number of those in (b) able to take treatment with ivermectin (taken as BO'/. of those in (b), assuming that exclusion criteria will apply only to pregnant/lactating women and those with severe disease of liver, kidney, etc. - not to children under 8, who will no longer be part of the infected population); (d) the estimated total population over 10 years o1d living in erstwhile endemic areas ln 1987 (taken as tLO'/" of the OCP Planops figures for 1984 Less 20% for those under 10); and (e) the number of those in(d) who would be able to take ivermectin treatment (8O% of those in (d) ). 2. For the original OCP area 423 000 (probably lightly) infected persons would require treatment in 1987, and 338 000 would be able to take ivermectin. If blanket treatment was given to all those over 10 years of age who could take ivermectin and will then be living in the erstwhile endemic areas it would be necessary to treat nearly 1l persons j,n order to catch each lightly infected case1, and the cost-effectiveness of treatment j,s likely to continue decreasing even more rapidly with each succeeding year. Table I ORIGINAL OCP AREA Country Total (a) Nunber of persons infected with 0.vin 19fl- (b) Number of persons infected with 0.vin 1967 423 000 (c) Number able to take treatment with ivermectin (d) Population over age of 10 in erst- while endemic areas Number of those in(d) able take treat- ment with ivermectin 310 000 (e) Benin Burkina Faso Ghana Ivory Coast MaIi Niger Togo 120 000 540 000 310 000 200 000 320 000 20 000 Bo ooo 30 000 150 000 78 0oo 50 000 Bo ooo 5 000 20 000 128 000 62 000 40 ooo 64 000 4 ooo 16 000 190 000 2 640 000 998 0oo 620 ooo 704 000 44 ooo 192 000 152 000 2 Lr2 000 798 000 496 ooo 563 000 35 000 154 000 lThis ratio could of course only to those communities withintensity 1eve1s. be i.mproved if blanket the highest original (a) Source-PAG report 1!J4(b) At 25% ot L974 figures(c) At 801 of figure in column (b) (i.e. assuming pregnant/lactating women, etc. )(d) OCP planops estinate for 1984 with 3 .5'/" arnuai- 20% for those under 10 years o1d(e) Bo% of (d) A11 figures rounded to nearest 1000 20% exclusions from growth = t7O% cf 1984, lets treatment were to be applied(L974) prevalence and ocP/86.3 Page 1J Annex 1 3. Table II relates to the extension into southern Ivory Coast which took placein 1979. The same assumptions have been made as for Table I except that the 1987figures for the number of persons infected have been calculated ut 5O% of the1!/! figures. In 1987 there will be 255 oOO infected persons requiring treatment and 204 OO0 able to take it. Blanket treatment in the endemic areas wouldinvolve treating 1 389 000 persons, i.e. 6.8 persons would have to be treated inorder to catch each infected case. 4' However it should be noted that the degree of larvicidal control achieved inthe southern Ivory Coast has been less than completely satisfactory so that thetotal number of infected persons in 1987 ,ry ,"11 be considerably greater than isshown in Table II. Furthermore, most of the onchocerciasis i.n this area is ofthe forest form, whose control is essentially a national responsibility. Table II EXTENSTON JvOnVloasr GgTg) Country Ivory Coast (a) Number of persons infected with 0.v 510 000 (b) Number of persons infected with 0.v (c) Number able to take treatment (d) Population over 6 years of age living in erstwhile endemic areas (e) Number of those in (d) able to take treatment with ivermectin 255 000 204 000 1 738 000 1 390 000 (a) Source pAG(b) At 50% ot t)l) figures(c) Ar Bo/" of 2(d) tlo"/" of ocP pranops 1pB4 ress !2% for those under 5 years old 5' Tables rrr and rV on the following page refer to the western and SouthernExtension areas respectively, where rarviciaing is due to start in 19g6/87. Foreach-country are-given (a) the estimated numbei of persons infected witho.volvulus in 1987 (based on the Senegambia report fig,r"." + 3/,); (b) the numberof these able to take treatment with ivermectin (take; as 65%-'of'those in (a),i''e'excluding chilglen under B, pregnant and lactating women, etc.); (c) thepopulation that will be living in the endemic areas iI rg8z iu"""a'o., in"Senegambia report figures prui 3%); and (d) the numbers of those in (c) who willbe able to take ivermectin (again' 6>.1 of i"i l. - 6' For the liestern and Southern Extension areas respecti.vely 1 082 OOo and525 ooo persons require treatment with ivermectin in ig8z ."a"zos-0oo"Jra342 0oo would be able to take the drug. rf blanket treatment h,ere to be given to ocP /86.3 Page 18 Annex 1 all those living in the endemic areas it would be necessary to treat 2 277 OOO ana BZ5 000 persons respectively. In other words blanket treatment would involve treating ].2 persons in the r^restern extension and 2.4 persons in the southern extension i.n order to catch each infected case (many of which would be heavilyinfected). Table III EXTENSION AREA (WEST) 7986/87 Number of persons infect- with 0.v in tew- (b) Number able to take treatment with ivermectin (c) Population living in endemic areas Number of those in (c) able to take treatment vrith ivermecti.n Country (a) Seneganbia report + 3%(b) 65% ot 1 (i.e. excluding children under B years old; pregnant/lactating women, etc. )(c) Senegambia report + 3%(d) 65% or 3 Table IV EXTENSTON 4qEA (SOUTH) 7986/87 Guinea Guinea Bissau Mali Senegal Sierra Leone 577 OOO 31 000 288 000 52 000 134 000 375 000 20 000 187 ooo 34 000 87 ooo 103 000 72L OOO 206 000 412 ooo 339 000 57 ooo 469 ooo 134 000 268 ooo Subtotal 1 082 000 703 000 3 5o2 oioo z zll ooo Country Subtotal (a) Number of persons infect- with 0.v in$q- (b) Number able to take treatment with ivermectin (c) Population living in endemic areas 1 270 000 (d) Number of those in (c) able to take treatment with ivermectin 525 OOO Benin Ghana Togo 103 000 144 000 67 ooo 94 000 500 000 377 000 393 000 325 OOO 245 000 255 0OO (a) Senegambia report(b) 65% or t(c) Senegambia report(d) 65% or 3 * 3'/" * 3"/" ocP /86.3 Page 1! Annex 2 Recapi-tulation of the potential use of ivermectj.n and of the organization offi within the OCp area Operational phase:. I Pur.pos€ _> It Transrnission-control Case-treatment blindins I non-blindine form form Attack/consolid- ation(Extension areas) . organization -no scope for ivermectin; transmission control by OCP larviciding -1arge-scale ivermectin distribution .national with OCP teams -1arge-scaIe ivermectin distribution .national with 0cP technical advise Maintenance,OCp . organization -no scope (as above) -continuation of i-vermectin distribution in Extension areas .national with OCP teans ( fewer) -as above .as above Maintenance, national . organization -use of i.vermectin for control of locaI out- breaks of transmission . national -as above and treatment ofttoutbreaktt cases . national (PHC ) .as above .as above I i I cP /86.3 age 20 lAnnex 3 Estlmation of manpower requirements for large-scale case-treatment in Western Extension area 1. One team of three technicians and one driver should be able to register and treat 540, say, 500 persons per dav (B hours) counting on tr^ro minutes perperson and two hours transport. 2. If the target population is to be treated once a year during two rounds of two nonths each, 50 000 persons in all would be "covered" by one team in one year. 3. 2 277 000 persons would be included in the progranme of blanket treatment in the Western Extensio., a"""1 thus requiring the services of, say, 45 tearns(135 technicians and 45 drivers) during four months of the year. lSee Annex 1, Table III. rtl