WORLD HEALTH ORGANIZATION ORGANISATTON MONDTALE DE LA SANTE ONCHOCERCIASIS CONTROL PROGRAMME IN WEST AFzuCA PROGRAMME DE LUTTE CONTRE L'ONCHOCERCOSE EN AFRIQUE DE L'OUEST EXPERT ADVISORY COMMITTEE Eighteenth session Ouasadousou. 2-6 June 1aq7 OCP/EAC18.2 ORIGTNAL : FRENCHI REPORT OF THE MEETTNG ON OPERATIONAL RESEARCH AND STRATEGIES (Ouagadougou, l1-13 March 1997) 27.05.97 EAC. I 8 Ouagadoueou. 2-6 juir/June I 997 I NOTE DOCUMENT : OCP/EAC I 8.2. Report of the meeting on Operational Research and Strategies Page 13, paragraph 3.3, line 10. Please read : document OCPA/CU-PET/DOC/001/97. Thai* you for your comprehension.. Rapport de la r6union sur les Recherches op6rationnelles et strat6gies Page 15, paragraphe 3.3, ligne I l. Veuillez lire : document OCPA/CU-PET/DOC|00L{97 . Merci de votre comprdhension 27.05.97 IWORLD T{EALTH ORGANZATION ORGANISATION MONDI,ALE DE LA SANTE Onchocerciasis Control Programme in West Africa Programme de Lutte contre l'Onchocercose en Afrique de l'Ouest CONTENTS Pages I. INTRODUCTION 2 2 l3 15 2l 30 34 36 2. BRIEFING REPORTS ON RESEARCH IN OCP 3. GENERAL INFORMATION 4, ATTITUDE WHEN FACED WITH RECRUDESCENCE OF INFECTION 5 6 7 8 TIMETABLE FOR TTIE CESSATION OF LARVICIDING. TRANSFER OF OCP RESIDUAL ACTIVITIES AND ASSETS RECOMMENDATIONS ANNE)G Report of the Meeting on Operational Research and Strategies ll-13 lvfarch I a 12 I. INTRODUCTION At the invitation ofthe Programme Director, the meeting on operational research and strategies was held in Ouagadougou from 1l to 13 March 1997 in the Programme's conference room under the chairmanship ofthe Chief of the Vector Control Unit (VCU). The list of the participants is as in the annexe. The session was opened by Dr K. Yankum Dadzie, the Programme Director. After welcoming the participants, especially the external guests (see list of participants), Dr Dadzie stressed the importance the meeting which would be to address the issue of defining the best possible strategies for the conduct of the remaining operations. He also informed the meeting that the JPC had approved the budget for the phasing-out period at its last meeting held in Cotonou in December 1996 and had recommended that an independent committee be set up to evaluate OCP activities so as to make recommendations on the new approach to be adopted from now on the year till 2002. ln introducing the important points of the meeting the chief of the VCU emphasized the particular nature ofthis y@r's meeting which would consist of in-depth reflexion on the different activities of the Programme in the worhng groups after an informative briefing in a plenary session. The different items to be discussed in the group work were. Group A : Attitude when faced with recrudescence of infection Group B : Timetable for the cessation of larviciding operations - situationby 2002 Group C : Transfer of OCP residual activities and assets schedule. details of implementation and After the adoption of the agenda, the participants reviewed the recommendations of the 1996 meeting which, on the whole, were found to have been correctly implemented. 2. BRIEFING REPORTS ON RESEARCII IN OCP 2.1 Research on macrofilaricides Following a very well conducted trial using amocarzine at the dosage optimised by Ciba-Geigy in Latin American, it was concluded that, at the maximum tolerated dose, amocarzine showed no macrofilaricidal activity against onchocerciasis in West Africa. The drug was absorbed, cleared microfilariae from the skin of infected patients, and induced a heavy Mazzotti reaction. It was therefore the decision of a WHO Clinical Group that no further work on amocarzine for onchocerciasis in Africa was justified. However, TDR would fund planned phase II clinical trials of amocarzine against lymphatic filariasis in India, as clinical adverse effects were not a limiting factor. Ongoing preclinical development of the benzimidazole drug UNIF078 was discussed. UlvIF078 is active by both the oral and intramuscular routes, but whereas a single intramuscular injection in oil is effective, multiple oral treatments are necessary. Thus, like amocarzine, a 3 day, bid, treatment may result in a systematic non compliance in the community. I3 Efticacy studies, and associated pharmacokinetics, are being carried out using the Brugia phangt I dog, and Onchocerca ochengi I cattle models to optimise dosing regimens, and obtain the best drug formulations. Preclinicat toxicology in rodents is underway, with special attention being paid to bone marrow and gut epithelial cell toxicity. Detailed studies on the intramuscular injection route are being carried out in rabbits, to assess irritancy. Further synthesis of UMF078 and its hydroctrloride salt (UMF289) to GMP standards is urgently required as remaining stocks of drug are limited. Day-to-day administration of the UMF Development Project is now in the hands of a small development team with a part-time project leader, and this should enable momentum of the project to be maintained. The target date for clinical trials is 1998, and that for possible submission of a regulatory package in the year 2002. 2.2 Molecular biology of ivermectin resistance Following EAC's request that Macrofil address the problem of possible resistance to ivermectin n Onchoceru volwtlus, eight projects (of which six are still in operation) have been supported, with the objective of generating molecular "probes" which could detect resistance genes in the O. volvulus population at an early stage. While early work utilised the free living nematode Caenorhabditis elegans (whose entire genome has been cloned, and a large part of it sequenced), work has now progressed to four parasitic nematodes which have shown ivermectin resistance. These are: Haemonchus contortus Oste rtagia c i rcumcincta Tr i chostrongtlu s co lu br dorm i s and Oesophagoslomum dentatum Tlree genes which can mutate to give ivermectin resistance in these worrns of the gastrointestinal tract have been identified. These mutations occur at the ivermectin receptor (a sub-unit of the glutamate-controlled Cl-channel), in the axoneme of the sensory amphids (axonemal dynein), and at a membrane drug transporter (the P-glycoprotein). Homologues of these genes will be sought in Onchocerca and Brugia genomes. Additionally, initially unidentified gene mutations are being detected by use of the Random Amplified Polymorphic DNA Technique (RAPD) on individuals or populations, of drug-sensitive and resistant worrns. Whenever a mutant gene is identified and cloned, a probe can be generated which can be applied to O. wlwlus, andany gene mutations monitored over time. Such work could easily be carried out in the Bouak6 DNA laboratory ofOCP, as it is essentially similar to the DNA probes used to identify sub-populations of Onchocerca or Simulium. Fig.1 a Fig.1 b Fig.1 c E o a 100 80 60 40 20 4 Annual treatment, cov = 650/o (holo-endemic area, Prev. > 80o/o) Mf-prevalence 1S6 2@7 2018 Calendar year Annualtreatment, cov = 65% recessive resistance mutation, p=0. 1 Mf-prevalence CMFL 2flo7 m18 20xt Calonda. year Annualtreatment, cov = 650/o trend in % of resis{ant microfilariae 2007 2016 2929 2W ooo o * 100 EO 60 .() m 1996 fr4 1@ 60 a, .rc N NN1990 CMFL Cal€nda. !€ar 20lo a6 6 E E c a 'a a t s5 2.3 Model simulation of ivermectin resistance In order to investigate the likelihood of spread of resistance in areas where long periods of regular ivermectin treatment are being carried out or considered, the ONCHOSM model has been extended with a sub-model for the genetics of such resistance. In all simulations presented to the meeting, the following assumptions were made: (i) resistance is the result of mutation of a single gene, (ii) resistance is complete, i.e. genetically resistant microfi- lariae (m0 do not at all respond to ivermectin, (iii) there is no selective disadvantage (resistant mf or worrns are as viable as wildtype). One important feature of the transmission of O.volwtlas is the non-linear saturated relationship between the microfilarial density in the skin and the number of larvae that will appear in biting flies. The relatively higher efficiency of flies to transmit at low Mf-densities may have important implications for the spread of resistance in situations where the low post-treatment residual number of Mf are all resistant. The first scenario shown was a situation of continuous annual treatment in a holo-endemic situation (prevalence of mf > 80%). In the absence of resistance and with a coverage level of on average 657o, this will likely lead to elimination of the parasite within a period of 25-30 years (fig.la). However, if in this same situation at the start of the treatment strategy the initial allele frequency of a recessive resistance mutation is l0% (which implies that-lo/o of microfilariae is resistant), then etimination will completely fail (fig.1b). Initially, the spread of resistance will not be apparent in that the CMFL reaches very low values after 20 years of control. After this period of control, however, it willbecome increasingly difticult to bring down the prevalence of infection and the trend starts to reverse. An important observation in this respect is that while mf-levels are very low after 20 years of control, fig.lc shows that the percentage of resistant microfrlariae starts to rise rapidly. These observations also apply to strategies based on 6-monthly treatment, which, in the absence of resistance witl lead to an earlier etimination of the infection (probably within 10-15 years). A dif[erence is that, as a result of a higher selection pressure, the percentage of resistant Mf rises more rapidly than with annual treatment. However, while the selection pressure is higher, the more intense stratery also results in a faster decrease ofldf-levels. Several simulations showed that the elimination of the parasite was achieved before resistance started to become a real threat. This also becomes apparent when we plot the risk of spread of resistance as a function of the initial allele frequency. At an allele frequency of 0.1, spread of resistance is almost certain during annual treatment at a coverage level of 65%. However at a six-monthly schedule it will occur only seldomly (fi9.2a). The idea of eliminating the problem before resistance starts to become a problem also applies to the coverage level: high coverage levels, though representing a higher selection pressure, give a relatively lower risk of resistance spread. Particularly dangerous are those scenario's where intense treatment (e.g. six-monthly during l0 year$ is fotlowed by a period of waning awareness during which the predominantly resistant parasite population may build up again (fi9.2b & fi9.2c). !5 2.3 Model simulation of ivermectin resistance In order to investigate the likelihood of spread of resistance in areas where long periods of regular ivermectin treatment are being carried out or considered, the ONCHOSIM model has been extended with a sub-model for the genetics of such resistance. In all simulations presented to the meeting, the following assumptions were made: (i) resistance is the rezult of mutation of a single gene, (ii) resistance is complete, i.e. genetically resistant microfi- lariae (rn| do not at all respond to ivermectin, (iii) there is no selective disadvantage (resistant mf or worrns are as viable as wildtype). One important feature of the transmission of O.volwlzs is the non-linear saturated relationship between the microfilarial density in the skin and the number of larvae that will appear in biting flies. The relatively higher efficiency of flies to transmit at low Mf-densities may have important implications for the spread of resistance in situations where the low post-treatment residual number of Mf are all resistant. The first scenario shown was a situation of continuous annual treatment in a holo-endemic situation (prevalence of mf > 80%). In the absence of resistance and with a coverage levelof on average 65%, this will likely lead to elimination of the parasite within a period of 25-30 years (fig.la). However, if in this same situation at the start of the treatment strategy the initial allele frequency of a recessive resistance mutation is l0% (which implies that-lo/o of microfilariae is resistant), then elimination will completely fail (fig.lb). Initially, the spread of resistance will not be apparent in that the CMFL reaches very low values after 20 years of control. After this period of control, however, it willbecome increasingly diffrcult to bring down the prevalence of infection and the trend starts to reverse. An important observation in this respect is that while mf-levels are very low after 20 years ofcontrol, fig.lc shows that the percentage of resistant microfilariae starts to rise rapidly. These observations also apply to strategies based on 6-monthly treatment, whiclr, in the absence of resistance will lead to an earlier elimination of the infection (probably within 10-15 years). A difference is that, as a rezult of a higher selection pressure, the percentage of resistant Mf rises more rapidly than with annual treatment. Howeveq while the selection pressure is higher, the more intense strategy also results in a faster decrease of Mf-levels. Several simulations showed that the elimination of the parasite was achieved before resistance started to become a real threat. This also becomes apparent when we plot the risk of spread of resistance as a function of the initial allele frequency. At an allele frequency ofO.l, spread ofresistance is almost certain during annual treatment at a coverage level of 65%. However at a six-monthly schedule it will occur only seldomly (fig.2a). The idea of eliminating the problem before resistance starts to become a problem also applies to the coverage level: high coverage levels, though representing a higher selection pressure, give a relatively lower risk of resistance spread. Particulady dangerous are those scenario's where intense treatment (e.g. six-monthly during 10 year, is followed by a period of waning awareness during which the predominantly resistant parasite population may build up again (fig.2b & fig.2c). 6 Risk ol spread o[ recessive resistance Various reglmcns - cov. '65% Fig.2a Fig.2b Fig.2c 1.00 0.80 0.60 0.40 0.20 Annually 6-monthly I .1. : ,,!g. .Y .,2 E, I I .1. I I t... 't 0.00 0.05 0.10 lnitial allele frequency (p) 0.15 6-monthly treatment, cov = 650/o recessive resistance mutration, p=0. 1 1990 2000 2010 2020 Calendar year 2030 2040 Risk ol spread ol recessive resistance o-monlhly trcatmcnl - cov. . 65% './ ., l ...--..r., Wth 10 lears 1 iirterruption / ..----/.-., :lt1 . :. . . . . . . . J. . . .it :t Continuous 0.05 0.10 lnitial allele frequency (p) 100 80 oE60 o a40 20 0 1.00 0.80 0.60 0.40 o.20 I"t' I lrtfarevalence CMFL 0.00 0.15 t I : 7 Though the simulations for a recessive mutation are highly informative in that they highlight a number of principles and indicate which strategies are safe or not, they are unrealistic in their assumption of an allele frequency of LUoh. Therefore, the potential danger of dominant resistance mutations was also looked at. The simulations done under this assumption showed that if dominant (complete and single gene) resistance really exists, it will cause serious problems if one or two adult parasites in an entire endemic village are heterorygous for this mutation. A plot of the risk of spread of resistance as a function of the allele frequency shows that considerable risks (>l%) occur at allele frequencies between 10'5 and t0{ (annual treatment, coverage 65%). These are frequencies which are more close to values found in the model nematode C.elegans. In conclusion 1. Recessive resistance mutation is probably not important in the endemic situatioq but could be dangerous in previously treated populations. 2. Dominant mutations will be dangerous; one or two heterozygous worrns may be serious 3. Shift from sensitive to resistant occurs when Mf-density is low. This has consequences for detection strategies. 4. lntensive treatment (high coverage or frequency of treatment) will not always lead to higher risks of resistance spread (in spite of the high selection pressure). 2.4 Clinical protocol to examine the prophylactic activity of ivermectin Following the demonstration that monthly ivermectin treatments (200 frdkg) showed full prophylactic activity in the O. uhengi / cattle model, using new born calves exposed to two seasons of natural infection, EAC asked Macrofil to examine a possible protocol for a similar clinical study in man. Such a protocol has been developed, and will be submitted to EAC for consideration in June, 1997. However it should be noted that if a population of children aged 3 years and above could be identified, and an incidence of 2-3 Yo new infections per year anticipated, such a study would need to be multicentre, using 700-1000 children per centre, and run for 3 years. This would allow for comparison between an untreated control group, a group treated monthly, and a further group treated quarterly. Placebo tablets would be used in the control group, and in the group treated quarterly when ivermectin was not given. Detection of new infections in the naive population would be done by PCR of circulating DNA or by detection of a specific adult antigen. Because of the need for a high transmission level such a study could not be carried out in the OCP area. 2.5. Diagnostic tools for detecting onchocerciasis infection 2.5.1. Diagnostic tests for epidemiological surveillance The search for an alternative test to the classic skin snip method for detecting onchocerciasis infection was continued with studies on the topical diethylcarbamazine (DEC) patch test which had been retained for field trials. Results from studies on the possible allergic reaction of the skin to the "Nivea cream" which is used as "carier" for the DEC, and the sensitivity of the DEC patch test compared to the other tests (skin snip and serolory based on the tri-cocktail antigens) were presented at the meeting. 8In a sample of I 12 children from the village of Gbletia in the basin of the Sassandra in C6te d'lvoire, the apptication of the Nivea Cream alone without the DEC caused no skin reaction. However, the application of the Nivea cream mixed with DEC showed skin reactionsin29.4o/o of the cases among the same children after a 48 hours reading time; the prevalence rate by the skin snip method in the same group of children was 8oZ. A comparison of three test methods carried out in a sample of 553 people in 6 villages of the Bougouriba basin is shown in Table I below: Table l: Comparison of three methods for detecting onchocerciasis infection t The result of the DEC patch test being the best reading after 48 hours Conclusion: The results show that the DEC patch test has reasonable sensitivity and can detect, a higher prevalence than the skin snip method. The prevalence shown by the serology and the DEC patch tests are not statistically different. The DEC patch test remains more acceptable by the population than the other tests. Nevertheless, the studies must be pursued in order to resolve the issue of species specificity with regards to Mansonella perstans and streptocerca. 2.5.2. Detecting infective larvae in a crushed mass of blackflies. This method is to be used mainly after the cessation of OCP activities. The "crushed mass" method therefore, has to be simple, cheap, quick to apply, feasible and applicable on a large scale to verify or compare the infectivity level of blackflies to what it was just at the time o(, or after, the cessation ofcontrol activities. It is a method which should be able to give the signal for undertaking more in-depth investigations in order to better assess the epidemiological situation of the zone being considered. It would in fact serve as a first step, a phase in the approach of early detection of a possible recrudescence. It would be applied first and foremost in the zones which presented a high level of endemicity before control operations started. Skin mip (a) versas (vs) Serolog (b) Serolog (b) ys DEC patch test* (c) Skin snip (a) ys DEC patch test* (c) Sampling size 553 492 481 Prevalence (a) 1.5.60/o O) 20.1o/o (P: 0.05 ) o) 23.2% @) 2s.a% (NS ) (a) 16.6% (c) 23.9% (P:0.005) Sensitivity 76.7Yo 7t.t% 63.8% Specificity 90.4% 88.4% 84.0% Positive predictive index 0.56 0.61 0.42 Negative predictive index 0.95 0.91 0.92 9The method allows for the use of only the heads of undissected blackflies divided into batches of 50 or 100 heads. The total number ofblacldlies caught and preserved in alcohol per catching point could be from 2000-15000. The possibility of identifying blackflies and the infective larvae of O.volwlus by DNA probes, and especially, the possibility of determining the levelof infectivity of blacldies tkough the crushing ofbatches ofblacldly heads, allow for a reasonable approach to using the entomological tool as one phase in the detection of any recrudescence of onchocerciasis. The trials continued this year at two catching points on the Baoul6 basin in Mali. The results of the identification by the PCR revealed O. Ochengi species. No specific conclusion could be drawn at the moment in view of the small sample size. The meeting recommended the continuation of the studies scheduled from July 1997 onthe Marahou6 at Kongasso. It also suggested a continuation of the trials at the same time, with the use ofcrushed whole fly instead of the head only with specimens from some catching points. 2.6. Research on B.a H-14 2.6.1. Improving the techniques for the evaluation of experimental formulations and operational batches ln 1994, the mini-gutter trials were replaced by the orbital shaker systems. At the moment, the magnetic multi-stirrer system is used for the biotrials intended to test the efficacy of the B.t.H-14 samples. [n order to limit the risk of delivery of defective B.t.H-14 batches, many pre-samples are tested at OCP using the orbital shaker to identi$ the batches which meet the efficacy criteria retained for the vector control operations of the Programme (CL50>90mg/Vs). Similar tests are conducted to monitor the stability of operational batches. An acceptable stability is expressed by CL 50s not exceeding 135 mg/Vs during the first four months after delivery. Several experimental samples have been tested in this way in connection with the actions undertaken in collaboration with Abbott to improve the formulations of Vectobac 12 AS. Biotrials and tests were carried out in rivers to assess the effectiveness and stability of the formulations of an experimental batch of Tecknar HPD from Sandoz. Taking into account'the satisfactory results obtained 10 months after delivery, it may be concluded that this batch was satisfactory both in terrns of effectiveness and stability. 2.6.2. Research on the recombinant strains of.B.l. H-14 Collaboration between OCP and the Pasteur Institute is ongoing in the field of research on the recombinant strains of B.t. H-14. It is centered on the study of the insecticide activity of8.r. H-14 resulting from the combined action of 4 toxins 135 Kda, 125 Kda, 68 Da and 28 Kda. Only 28KDa appears to have a hemolytic effect. The objective of this study is to confirm the major role of the hemolytic protein on the larvae of Simulium damnosum s'./. and to develop a simple protocol for a correct proportioning by hemolysis allowing for a laboratory evaluation of the effectiveness of8.r. H-14 formulations htended for the control of blacldies. This study should make it possible to (i) test the formulations on the very site of production, (ii) improve the methods of production of the formulations through the correct proportioning of the toxin 28KDa at the different stages of fermentation, (iii) improve the effectiveness and sensitivity of the formulations so as to allow their use at discharges above 15 m3/s. 2.7. Research at the DNA probe laboratory 2.7.L. The Southern blot method The southern blot is a technique based on the amplification of the DNA and its transfer from an l0 electrophoresis gel onto a nylon membrane which is then hybridized to specific probes. Four probes are currently available : two are specific to O. wlwtlzs and O. ochengi species ; they are respectively OVS-2 and OCH, and the other two are specific to the forest and savanna strains of O. volvulus ; they are respectively PFS-l and PSS-IBT. This technique is used for: - the identification of the parasites collected tkoughout the entomological evaluation network, during epidemiological evaluations and during special studies. In 1996, 593 infective females with larvae stage 3 in the head (L3FI), were collected throughout the entomological evaluation network ; 218 females carried animal origin larvae, 109 females were infected with forest O. volwlus and 266 with savanna O. Volwtlzs (Map la et lb). During the special studies canied out in 1996 on the Bougouribq in southern Ghana and on the lower Como6, on the Tinkisso and in the south-east region of Guinea, the L3H of 299 infective females were identified. 157 carried animal origin larvae, 59 were infected with forest O. volvulus and 98 with savannaO. volwtlus (Map. 2). - the early detection of a resumption of the transmission through the evaluation for the prevalence of the infection by O. volvulus in a crushed mass of blacldlies. - support to the detection of onchocerciasis through the use of DNA probes on skin desquamations (scratch test) or skin snips. 2.7.2. The Heteroduplex method The principle of this technique is based on the matching of the DNA strands of the samples to be identified with a reference DNA strand. During an electrophoretic migration, the quality of the matching brings about some differences which are characteristic. Six species of the S.damnosum complex are identifiable: S. damnosum s.l. ; S. sirbanum ; S. leonense ; S. sanctipauli ; S. yahense and S. squamosum. The technique can be applied to the identification of vectors both at the larval and adult stages. As a result, it allows for a fine-tuned discrimination which can specify the species, strains and hybrids between these strains. Two approaches are still being experimented : the mitochondrial approach and the nuclear approach. The investigations are ongoing and conclusions are expected in the next two years. This technique could allow for a determination of the pathogenicity levels due to the different strains. 2.7.3. The ELISA test The ELISA test method is cheap, faster and it allows for the treatment of a great number of samples. It is an immunodiagnostic test based on the amplification of the DNA by PCR, the attachment ofthe products of the amplification to the probes ; the complex thus formed is detected through dyeing in a microtitration plate. The ELISA test is available and used for the identification of parasites as well as for immunodiagnosis. The improvement of the test is under way. It will soon be available for use in the treatment of crushed masses of blackflies as a diagnostic tool for the detection of onchocerciasis, which would thus allow for the analysis of a great number of samples. 2.7.4. Microsatellites Mcrosatellites are short sequences ofDNA repeated in tandem which are present in the genome of eucaryotes; they are highly polymorphic. Some primers are already marked out and the amplification products can be detected both for O. volwlus blackflies and parasites. This research is carried out in collaboration with ORSTOM and the university of Alabama at Birmingham. 11 Mop lo \-; \,ul" EpARTITION DES ESPEces D'oNcHocEReuES ONCHOCERCA SPECIES OISTRIBUTION IN THE OCP AREA MALI ,IIAU BURKINA FASO+ BAOOE{ GUINEE rurcenouruee/ff t KOLENTE SEU ' }IAUT SANI(ARANI G--mlrou , BAS G OTI' }IAUT ,ff onrSAscOre o'votRe , HAUT a BANOAIiA, BAs VOLTA NOIRE ' 8A8 t-Ac voLTA MONO' G N.z a DISTRIEUTION OF'ONCHOC€RCA SPECIES 1997 SEWA T , BAS , BAS Rdualon & Recherches Op,ndorurelles ct Stral6g/es 97 97 4t, 91 J .OdrqrctwhrOtrc p{..f. Mop lb' BENIN ( (?\ I N DES SOUCHES D'O.VOLVULUS O.VOLVULUS STRAINS DISTRIBUTION IN THE OCP MALIF, I I F I t<- I i" I rflihlHh NIGER ' MAU + BAGOE coTE D'tvotRE Nzl BURKINA FASO VOLTA , BAE on HAUT ,&- ON'BA:t I MONO ' TIAUT, GUINEE nNK880 NI6ER OUINEE . e KOLENTE SEU ' HAUT SANI(ARANI ,HAUT 6 , BAS , BAS R0utbn & Roctlp,tchot Opdniomeiles ct Stat6gilos 97 ,84.8 @ 8EWA + P J& BANOAI{A ' BA8 BENIN OlSTRlEUTION OF O. volvulus STRAIIS E o 1t ,7' 7t O.Elrlu&Eno O rclwhr fqaat lACVOLTA' +ll* M R^Houg + ll* tiARAHOUg c, uJ3oJ € z -(9 lr o Fo ul + -F =oo 9qhl IrJ al,o tr € z (9 Fo IIJ =Io =U' ul o =oo og C'to ot .l o c, atI o o l2 /'\. ff I$t UJ G z o @ etr =o of o @ I 8a da IogItI Tot toatto; EGl o of o @ 5 ulo zIo u.lG@oo z o F =otFLo o IIJ o ulG U' <o o trJGO uJ3()FooE -.ro< =o\J uJ\.8 U'O u.l OoE IIJUJJosoo - IIJoo.2u,Oobq oHUJEfii! o. U' UJ @ UJo z o F tr tr, o. UJg, \ \f) \ r'-]-- ( I $J CLo =(l, oo u.l UJ =Do Fo Hofo =f(, ll. o th F =E-= l3 3. GENERAL INFORMATION 3.1. Control of blackfly nuisance The cessation of larviciding results in the reappearance of non infective blackflies whose bites may, beyond a certain density, constitute a limiting factor to the optimal development of the oncho- freed areas. Being aware of this problem and of the ever increasing number of sites favourable for resettlement, the Programme at first encouraged the implementation of localized control actions against the blackflies through ground larviciding with non polluting insecticides. Technical guides have been prepared. Ground larviciding shoutd be applied in sites of socio-economic interest, agro- industrial complexes, (sugarcane, pineapple, palm oil, cotton plantations etc.). Such industrial units are able to pay for the insecticides and train their own technicians for ground larviciding with assistance from OCP. However, after reviewing the problems that too great a multiplication of ground treatments might lead to, it was recommended that their use be limited to those areas where the means of ensuring their efficient and durable management exist. In more deprived communities where the technical and financial means are lacking, the only alternative remaining is individual protection by the use of repulsive products or protective clothing. Research is under way and a document on antiblackfly repulsive products is to be prepared by OCP. 3.2. Geographical Information System (GIS) The Geographical lnformation System (GIS) is a package made up of computer, software, digitized geographic maps and data banks. It is a tool which allows for data to be entered, processed, analysed and visualized in the form of maps. It thus permits a spatial analysis of the data in the context of a multi-sector approach. The two main parts of the system are the collection of digitized maps and the data banks whose sites are geographically referenced by coordinates which can be easily located on the maps. The greatest part of the time must be devoted to the checking of the data banks in the use of this tool. The system allows the integrated analysis of epidemiological and entomological data as well as those concerning the control methods set up, and makes it possible to quickly get these data in order to assist in decision-making. The data collected by OCP have been integrated into the GIS and a trial was carried out during the meeting, especially in connection with the work of Group B for the review of the epidemiological situation (see paragraph 5.3). It will be used in the framework of the transfer of the data to the Participating Countries. 3.3. Performance indicators for Phase V and the post-OCP period The indicators to be used for monitoring performance during the Programme's phasing-out and post-OCP period wilt be based on the objectives and strategies set up in the fields of vector control ihrough the use of larvicides, control of morbidity through ivermectin distribution, personnel training in the countries in order to enable them to take over the residual activities of the Programme i.e. detection and control of any recrudescence of the infection, transfer to the countries of the tools, expertise and data accumulated by OCP. A distinction is to be made between the indicators used for measuring the output of each of the strategies used by OCP and those used to assess their impact. Some of these indicators will be valid only during the phasing-out period while others may be progressive, extending beyond the termination of OCP. The meeting was informed about these performance indicators which are described in detail in document OCPA/CU-PET/DOCl00ll97.The main performance indicators that should be monitored during the phasing-out and post-OCP periods are enumerated below. t4 a) Phasing out Period Indicators of impact during the period of larviciding - Annual Biting Rate (ABR)and the Annual Transmission Potential (ATP) - the incidence of infection - change in the prevalence of infection - changes in ophthalmological indices Indicators of impact after cessation of larviciding - The number of infective simulium per 1000 parous females Ou tput indicators for vector control - mean cost per kilometre of river treated - number of areas with resistance to temephos - level of intensity of resistance to temephos - level of advancement in the research for vector and parasite identification - number and severity of cases of accidental pollution with insecticide Output indicators for mor bidi ty control - ivermectin treatment coverage (populatioq village, and continuation rate) - advancement in the installation of Community Directed Treatment with Ivermectin (CDTI) - level of adherence to prescribed methods of treatment - level of adherence to planned frequency for treatment Ou tpu t indi cators for Staff - presence and number of trained staff (medical ofticers, nurse technicians, entomology technicians, village distributors) - level of expertise of trained staff Output indicatorsfor tools and methods - presence of appropriate tools and methods for defined activities - state of transfer of OCP data to countries b) Post OCP period Output indicators - presence and number of trained stafffor recrudescence detection and control - presence and number of trained stafffor epidemiological evaluation - plan for epidemiological surveillancdevaluation - presence ofthe right, adequate tools and logistics for epidemiological surveillance / evaluation I l5 Impact indicators - speed of recrudescence detection and the establishment of its control - the presence or absence of new infections (incidence) in the treatment area 3.4. Brieling on APOC In 1996, six projects were submitted by three APOC countries to the second Technical Consultative Committee (TCC) for review and recommendation to the Joint Action Forum (JAF). Only the Malawi project and the two projects submitted by Ugandq one of which concems elimination of the vector, were retained by the second JAF for financing by APOC. The two projects submitted by Nigeria (Kog, and Cross-Rivers States) which had been recommended by the TCC srbject to some modifications could not be considered by the second JAF but will be examined after correction by the Committee for Sponsoring Agencies at its next session. The rapid epidemiological mapping of onchocerciasis (REMO) was carried out in several APOC countries and integrated into the GIS. It has been completed for Nigeria and Cameroon. The multi- country studies on the economic impact of the skin diseases caused by onchocerciasis have confirmed their importance. The multi-centre studies on the effect of ivermectin on the skin manifestations of onchocerciasis are ongoing and the results witl be available soon. The results of the operational research on community directed treatment with ivermectin have clearly shown the feasibility, acceptability, reproducibility and effectiveness of this intervention method. Research is continuing to ascertain the validity of the durability criteria. 4. ATTITUDE WHEN FACED WITH A RECRUDESCENCE OF INFECTION Before it engaged in the discussion about the attitude to be adopted in the face of a recrudescence of infectioq gfoup A reviewed the principal factors likely to favor such a situation. General guidelines were then suggested"in order to limit the risks of appearance of recrudescence, and facilitate the task of the national teams should such situations occur before, and especially, after the end of OCP. The group paid particular attention to the Bougouriba basin which had been the subject of numerous studies, surveys and interventions of all kinds. 4.1. Study on migratory itinerary of the positive individuals in the Bougouriba basin A study on the migratory itinerary of 874 positive individuals from 14 villages with more than l0% prevalence in the Bougouriba basin was carried out in 1996. From the survey datao it emerges that the individuals with positive skin snips, among which were children of less than 10 years old, in the Bougouriba basin were mainly non-migrants who had not left the area for the past twelve years (including the group of individuals having high mioofilarial loads i.e., more than 50 microfilariae). Their movements had generally been within the same zone. The population surveyed was found to have even beeq more stable in its present place of residence during the past seven years. The study showed that the increase in the prevalence of onchocerciasis in the village was likely to be as a result of an endogenous transmission. The majority of the individuals surveyed had their working place (fields) in the vicinity of watercourses not far from the Bougouriba and the P6 rivers. The majority claimed to have received blackfly bites particularly during the farming season. Blacldly nuisance is sometimes felt inside the houses in some villages. It can therefore be assumed that they may constitute active foci of transmission of the disease. tFig.3a Fig.3b Fig.3c 90 80 70 60 50 40 30 20 10 16 Partially effective vector contsol (first lwo years 75o,6 efiectve) &%, .bxI s 60 70 60 50 rO a) n 10 8! 5At r-Zqrlo - -.35% 1975 1980 1985 1990 1995 2000 2005 2010 Calendar year lmmigrants 198$1991 (36 adults, PoP={S) o<-Zoulo 1975 1960 1S5 1S0 1995 Calcndar year 2(xD 2CXr5 2010 Fly re-invasion 1986-1996 mbet9o; 0.05 L3 pcr bi6ng lly re-inrasion t 1965 1990 1995 Calcndar yaar 90 EO 70 60 50 ,lO 30 20 10 ooc!!o a * o+Boulo \ \' r\ 100 Mouvielo / r I I I I I I control o o 1975 19tO 2000 2005 2010 t s t7 The history of some infected people shows that there are some factors favoring the origin of the infection in the zone itself Among those with a positive skin snip, there was a paralytic (who had never left his village), some children most of whom were keepers of the frelds from depredators (birds, animals...) and who looked after other children. Some children were the only positive individuals in their families. The results of the study show then that the hypothesis of population movements as a cause of the deterioration ofthe epidemiological situation is unlikely to be plausible. Nevertheless, it must be noted that by its nature, the strrvey could only focus on the positive individuals present. Those who had lived in the zone for the past twelve years but who had definitively left the area could not be included in the survey. 4.2. Epidemiological modelling of recrudescence in the Bougouriba valley During the discussions in group d an analysis ofthe simulation of recrudescence in the Bougouriba valley was presented and discussed. The first logical step considered whether the rising trend of th prevalence observed in this area after 1994 confirms the hypothesis that vector control had not bee^. carried to its term. Figure 3a shows the dynamics of the recrudescence projected from different hypotheses taking into account the effectiveness ofvector control. Such effectiveness is represented as the percentage of the decrease of the biting rate compared to the situation prior to vector control operations. In addition to the levels of effectiveness shown on the Efaph (figures between 80 and 100% reduction of the biting rate) , all the simulations presented suppose that during the first two years of vector control, the effectiveness reached 75Yo. All the projections were compared to the prevalence trends observed in the villages of Mouvielo and Zoulo. Figure 3a shows that the trend during vector control is in accordance with that observed at Mouvielo if we start from the hypothesis that the effectiveness of vector control ranged from 95 to 100%. However, none of the projected trends of recrudescence conforms with that observed at Taulo where a very rapid increase of the prevalence was observed. Figures 3b and 3c illustrate two attempts at explaining the trend at Zoulo on the basis of two external factors whose levels were set through several simulations: immigration of infected individuals (fig.3b) or invasion by infective blackflies (fig.3c): a) In figure 3b, the simulations have led to assuming that during the 1989-1992 period, thirty eigl adult migrants arrived in the village whose total population would be around 400 people. Th- migrants are presumed to have settled in the village of Zoulo and to have created a zone with very high endemicity (similar to Mouvielo before the beginning of control operations). With such an important in flow of the infection, we can adjust the trend observed at Zoulo. b) Figure 3c supposes that from 1986 to 1996 the village was reinvaded by infective blacldlies reaching a monthly biting rate of about 190. If this scenario had actually taken place, it would have meant the existence of an unknown or new simulium breeding site, and that the blacldlies originating from that breeding site had been feeding in a village up to now undetected with an unknown epidemiological situatioq where the infective loads were very high (for instance in the ONAT villages) and from where these blackflies had carried their L3 Larvae (0.05 L3 per infective bite) up to Zoulo. The sociological as well as entomological studies carried out have shown how difficult it is to believe the extreme hypotheses made in the simulations in order to adjust the observed trends. As a result, we also explored other causes which might be linked to the ONCHOSM model itself: could there be some hypotheses which we have always accepted (probably rightly, given the available data) but which needed to be revised in the light of the present situation? One such attempt was made in the simulations offigure 4a where we supposed that the individuals who carry 40 worns are l0 times less !Fig.4a Fig.4b 90 80 70 60 50 40 30 20 10 IC ]PIo o = 18 Density dependence 40 worms = susceptibility 10olo Zoulo 1975 1980 1985 1990 1995 Calendar year 2000 2005 2010 Fly r+invasion 1 986-1 996 (rSF19O: 0.05 L3 p€r blthS M lvermec{in trsatnent in July and Dec€mb€f Corerage 72% 1975 1980 lgEti lgso 190{r ZnO mGt 2010 2015 tm Cabndaa yea. Density dependence (40 woms. susoepllbilty 10%) lv€rm€din tr€dme.t in July and December CwetageT2% 1975 t980 1985 1900 1905 aDo 2005 m10 rc15 2020 Calenda. y€a] c) &) 70 60 e) 4 30 xt 10 oocI tso a = Fig.4c 90 60 70 60 50 4 30 20 10 ooco 3o a = Mouvielo V€ctor contol Veclor coartaol I i 19 likely to be reinfected than those who are not infected. According to this model, this situations would mean that the rate of success (i.e. the probability that an inoculated L3 larva become an adult male or female worm) is a function of the worrn load of the individual. This supposes that when the worm load has been reduced to almost zero through v@tor control, upon their return the blackflies draw their food from extremely susceptible people and can thus rapidly create a new endemic situation from even a residual and derisory reservoir ofthe infection. Figure 4a shows the hypothesis of the existence of such a reservoir assuming that vector control was97o/o effective. The increasing variation of one of these factors is also likely to favor recrudescence as shown by the trends projected on the basis of other simulations. However, none of these factors could alone, explain the trend predicted during vector control. Based on the different simulations, it is clear that one should not rely only on a single factor, but rather should investigate a whole set of causes, preferably while continuing an in-depth study of the available data from the Bougouriba region. Figures 4b and 4c show in two different simulations the impact of the introduction of ivermectin on a six-monthly basis from 1996 to the end of OCP tn2002 to control any recrudescence of the infectio In these t\ryo cases, none of the simulations is projecting the elimination of the problem before that ter--" and the distribution of ivermectin at least must be continued for longer than 10 to 15 years on a six- monthly basis. 4.3 Factors likely to favor recrudescence of infection Based on these studies, the group attempted to find possible explanations for the phenomenon of recrudescence observed in the Bougouriba basin. It concluded that some factors are more likely to favor a recrudescence ofinfection in a basin : (i) migration, (ii) larval breeding sites and their proximity to the villages, iii) epidemiological situation at the cessation of control operations. 4.4. Decision-making on the cessation of larviciding Taking into account the experience from the Bougouriba where studies were carried out to understand the appearance of recrudescence of infection 3-4 years after the cessation of larviciding despite epidemiological and entomological result which had been deemed to be acceptable, the grou^ recommended that for the basins where a decision to stop larviciding is to be made, the following ste^ be followed from now on: a) At the mesological level That prospecting and human population migration surveys be conducted in order to detect - any new blackfly larvalbreeding site - any new village located near the breeding site - the population movements which are likely to have an effect on the transmission of the infection. b) At the entomological level That in addition to the post-treatment studies carried out on some well known catching points, some rapid supplementary studies be initiated in the zones suspected as being likely to be dangerous on the basis of the mesological data gathered according to the guidelines in point (a) above. 20 c) At the epidemiological level That in addition to the studies canied out in the sentinel villages, supplementary surveys be initiated in some selected villagis taking into account the results of the mesological studies carried out in (a). Besides the usual epidemiological er/aluation criteria, other factors such as the existence of a residual load or reinvasion by infective blackflies should also be considered. In any case, the interpretation of the results for making the final decision would have to take into account not only the history of the parameters studied but also any discordances between for example the prevalence and the number of microfilariae per skin snip in certain individuals. 4.5. Early detection of recrudescence in the areas no longer under larviciding To make possible the early detection of any recrudescence of the infection in a basin and to avoid in this way its taking hold, the group recommended the national teams continue the periodic (every ttree years) epidemiological evaluation of the sentinel villages as well as of other villages to be chosen on the basis of the following criteria: a) the location of the villages with respect to the blackfly larval breeding sites (old and possibly new), which supposes adequate knowledge of the environment; b) the population movements in the area c) the information provided by the populations on blackfly nuisance in the area. In addition to the epidemiological studies, the group suggested the use of the entomological tool for the early detection of recrudescence after it has been validated and the practical method of its use has been established. 4.6. Actions to be taken In summary, the. group recommended the following actions to the national teams once a recrudescence has been detected: - Immediately undertake epidemiological and entomological investigations in the neighboring villages in order to delimit the zone concerned. - Undertakesocio-demographicstudies - Promptly make a decision based on the results of the different studies and if necessary, start the community-based bi-monthly treatment without delay. In this @ntext, and on the basis ofthe actions taken on the Bougouriba to control the recrudescence of the onchocercal infection, the group analysed the epidemiological situation currently prevailing on the Oti-Pendjari in northern Togo and Benin in the original Programme area and which was raising some concern after the cessation of larviciding. The prevalence recorded in northern Togo ranged from 0.5% to 13.9lo/o, those in Benin reach up to 40yo in some villages in 1996. The group recommended to the national teams of i) Benin to speed up the community-based distribution of ivermectin, ii) Togo to undertake complementary epidemiological investigations in order to immediately institute community- based distribution of ivermectin. 2t 5. TIMETABLE FOR TIIE CESSATION OF LARVICIDING. Relying on the predictions of the epidemiological trends, group B reviewed the current epidemiological situation in all the basins under larviciding with a view to planning the definitive cessation of vector control operations between now and the end of the prograrnme. The basins principally examined were the Kankelaba and the Niger in Mali, the Marahoue and the Sassandra in southern C6te d'Ivoire. On this occasion the group used the possibilities offered by the Geographical Information System and prepared a first draft timetable for the post-treatment entomological studies for which the crushed mass of blackflies technique will be used. Beforehand, the group had developed an epidemiological evaluation protocol for the zones under community-based treatment with ivermectin. Institution of an epidemiological evaluation protocol for the zones under ivermectin treatment 5.1. One consequence of the impact of the distribution of ivermectin on the reservoir of the parasite is that it masks epidemiological results. It then becomes difficult after several cycles of treatment to accurately determine the individuals who are actually positive. The principles laid down below will make it possible to determine the number of individuals really positive in a population and to better assess the state of the reservoir of parasites after several cycles of treatment with ivermectin. Specific objectives To study the recolonization dynamics of the microfilariae after the suspension of treatment in positive individuals who have been treated several times with ivermectin. To determine the false negative individuals in a village where the distribution of ivermectin has been suspended after several cycles oftreatment. Principles The principle is to suspend, in some villages, the distribution of ivermectin for two consecutivL years after more than four to five cycles of annual treatment in the zones where: i) vector control and ivermectin distribution are ongoing, ii) vector control was stopped and replaced by ivermectin distribution. This is to determine the recolonization dynamics of the microfilariae and the false negative individuals. Study areas and actions to be taken Among the areas that lend themselves well to such studies, two basins in southern extension C6te d'Ivoire and the basin of the Kankelaba in Mali were retained. l. The Marahoue basin has been under larvicide spraying since 1979. The villages of this basin have been put under annual ivermectin treatment since l992.This treatment has been temporarily suspended since 1995, the date of the last treatment. [n 1992,the epidemiological trends began to fall in the indicator villages of Kavaka and Bagozra. The cessation of larviciding is scheduled for 1997, hence the urgency of having reliable epidemiological data. The entomological data show that the Annual Transmission Potentials (ATP) have been less than 100 in most of the catching points since 1992 (fig.sb). 22 Actions to be taken: Cessation of vector control and maintenance of the temporary suspension of ivermectin distribution until the end of 1997. Intensification of post-larviciding entomological studies and the conduct of two series ofepidemiologicalevaluation surveys in 1997. A first series of evaluation will be conducted in May 1997 after l5 months oftemporary suspension of ivermectin distribution. This suspension will be maintained in order to carry out a second series of epidemiological evaluation 6 months later (the exact date will be subject to the analysis of the data from Asubende on the Pru in Ghana in order to set the time interval between the two evaluations). At the conclusion of these two evaluations, and after the analysis of the data is made, it will be possible to make a decision on a definitive cessation of vector control combined with ivermectin distribution. 2. The Sassandra basin has also been under larviciding since 1979 and under ivermectin treatment since 1992. The distribution of ivermectin has been temporarily suspended since 1995, the year of the last treatment. Contrary to the Marahoue basin, the epidemiological trends were not very good and vector control is scheduled to cease at the end of 1998 subject to improved epidemiological results. Actions to be taken: Continuation of larviciding until the end of 1998. Suspension of ivermectin distribution in the indicator villages retained for two years till the beginning of 1998. Routine epidemiological evaluation in the concept of an incidence study using a placebo for the cohort of negative individuals in the villages retained for the study. Three epidemiological evaluations are to be carried out in these villages starting in 1997, at six months time intervals. 3. The Kankelaba basin has been under larviciding since 1977. Ivermectin distribution was carried out from 1992to 1995. The epidemiological evaluation protocol which was instituted has allowed the gathering of reliable data in the two indicator villages as well as four other villages evaluated in 1996 and 1997. Actions to be taken: Cessation of vector control n 1997. Resumption of ivermectin distribution in all villages except those of Kankela and Ouroumpana where only the positive individuals will be treated. Conduct post-treatment entomological studies at the Kankela catching point. Monitoring of the cohort of negative,individuals in an'incidence study carried out through two epidemiological evaluation surveys in 1998 and 1999. Conclusion The group recommended that these studies be conducted in close collaboration with the national teams of C6te d'Ivoire and Mali. These studies are to be combined with sensitization meetings in the uillages with the assistance of a sociologist. It was also suggested that those not receiving ivermectin (after the information and sensitization of the population) be given a beneficial drug rather than a plain placebo. The results of these studies will make it possible to determine the recolonization dynamics of the microfilariae based on a minimum suspension time, to fine-tune the projections of epidemiological trends using ONCHOSM and to plan the epidemiological evaluations to be carried out in the extension zones of the Programme. 5.2. Overall epidemiological situation and strategies On the basis of the latest epidemiological results, the VCU plan of operations for 1998 and 1999- 2002 was adjusted (IvIaps 3a & 3b). The main recommendations and strategies to be applied from now on till the year 2002 and beyond are given in table 2.
23 Mop 3o vcu PI-AN oF OPERATIONS FoR 1998 / Pl-Al.l D'OPERATIONS oE vCU POUR 1g9O Lfirrib du - - . OrtgimlPJoearfilrr.alaAL.ii!.t duprcerumr \rF Rh..O!.d, Rhr$r !.1U. q r_ I TtWnolrt fflnil.b.l r^nal (l.llniu lib.ndt Mop 3b VCU PI.AN OF OPERANONS FOR 1B2M / Pt^N OOPERANONS DE VCU POUR IS2@ -PIIa.l IJflb - . orrgttdPloetrlnnl.aar A.r!-thb(fu ftogortnr \F Rti,r.t d,Rh/taotru. tI q C Tr-neibfirirfrdrAnldaliniEtrtribm.nt II 24 FQ.5r: Trcndr ln thc crudc ATP ln thc Kenldebe brln frorn tOZ to 1006 Gts I ra r@ E @ {D m o ra! tao ta rqD & t! @ fr o lm rot rtt t6 tit tGl rGt rla tGt tlt re ts t3t rll t*t rL r*t r8 Flg.6c Tnndr lnOEGrudcATPd Tlcnhh ln thc NlgGrbdn tuonr iCZ to lg0e tli t5, Vm a I rtaa rE rg, t9r tEl tgt rL rG rct Flg5b: Trcnd. h Orc G.uda AIP ln thc ilentrcuc brrln ltan lCZg to lCOa a I to o ra tq, E m {@ 2gl rm tg,l to rat ttn tGt rra trE t6 te tE la,t tl:l r*! lL tglt tgrtr? rltYn t,tfl rg,l rc,i rQ tat t&r rGt rec. tGt 16 rs7 Vm l+n-er.l t 25 Kankelaba basin: the epidemiological results obtained in January 1997 remain satisfactory in the six villages retained since 1996. There was no new infections in the indigenous population. A total of l0 subjects with positive skin snips was detected: four at Kankela, one at Fininko and five at Warakana. All l0 subjects were former positive cases or migrants having sojourned in southern C6te d'Ivoire. They were all more than 20 years ofage with the exception of a young migrant girl aged 8 at Warakana who was born in the village and had been living in that village for a year after a stay of 7 years in C6te d'Ivoire, and a girl 14 years old at Kankela who was previously positive and with no history of migration. Microfilarial loads were low on the whole. Prevalence rates ranged between 0Yo and4Yo The fuinualTransmission Potentials (ATP) remained virtually nil except in December 1996 when the monthly potential rose to 26 (fig.sa). The simulations (fig.7a) show that if both vector control and ivermectin distribution were stopped in 1997 as planned, the projected trends remained satisfactory. After taking these results into consideration and noting the strong demographic pressure in the zone due to he migrants coming from C6te d'Ivoire, the group recommended that the distribution of ivermectin be continued in the zone until the end of the Programme. It also recommended that the studies planned in the villages of Kankela and Ouroumpana go ahead as indicated in 5.1. Dienkoa basin: the results for this were analysed during the OCP zone meeting in 1996. The strategy of ground larviciding combined with ivermectin distribution which started in 1990 should be continued till the end of the Programme in 2002. The epidemiological trends predicted for Pendie Hameaux confirm this strategy (fig.6a & 6b). Basins in the southern extension COte d'Ivoire '. see paragraph 5.5 Basins in the south-eastern andwestern extensions. The larviciding coverage of the basins in the south-eastern extension will remain unchanged in 1997. In the western extension, ground larviciding on the Niger and its tributaries in the Bamako area will continue to be ensured as in 1996 by the national team of Mali with the technical assistance from the VCU. The entomological results show that the crude ATP were high in 1995 and 1996 (fig. 5c). The results of the identification of parasites by DNA probes conducted from November 1992 to December 1996 show that only l3Yo of the parasites were O.volvulus. Furthermore, the group noted that only 7 years of vector control had been properly executed in this basin. The group suggested maintaining the current strategy till the end of 1998 and conducting reliable epidemiological evaluations in this basin before taking any decision with regards to the cessation of larviciding planned for the end of 1998. The intensification of ivermectin distribution is to be pursued. The trends predicted for the basins in the south-eastern extension (fig.7b) show that by continuing larviciding on these basins until2002, ivermectin distribution could be suspended around the year 2000 in order to allow for the conduct of reliable epidemiological evaluations. Basins in the origirwl uea: The group briefly reviewed the epidemiological situation in the original Programme area and recommended that the poor epidemiological results recently obtained in the Sissili basin in Ghana despite the distribution of ivermectin around the village of Kayoro Baliu be investigated. In this connection, in order to facilitate the transfer of the residual activities of the Programme to the Participating countries, the group recommended that general evaluation to assess the epidemiological situation in the original Programme area be conducted. A first series of surveys could be carried out as of 1997 while a second series could be made around the year 2000 before the complete cessation of the Programme's activities. oE II =o *' o(E o E o ooc o, G o G Fig. 6a 120 110 100 90 80 70 60 50 40 30 20 10 0 26 lmpact of the Control in the Dienkoa basin Predicted trends using the endemicity level of Pendie Badala. 1970 1980 1990 2000 2010 2020 2030 lmpact of the Control in the Dienkoa basin Predicted trends using the endemicity level of Pendie Hameaux. Fig 6b 120 110 100 90 80 70 60 50 40 30 20 10 0 ah g II =o Ji o6 an E o o C)co(l q, o- HtDodnhd crlwffith Prev. CMFL Observed A a Predicted re$. HElnatcd aroo o, lrcdheI .ad l99t A Prev. Observed A a Predicted hco.iorn Gtq otl c lmlt$. th. ro .roc o, n 2OO2 l4uf \ \a/w rr CMFL ( / 1 970 1980 1990 2000 2010 2020 2030 {ctd harr@tild ram. ra{t. h tlta ..rd tgtt. CllHm CodDr..d Cm.d ffid h !0ta ..{ lett. {cu 27 Table 2. strategy recommendations t Basins in Guinea-Bissau Senegal, Western Mali No change planned from now, till 2002. Ivermectin distribution to be continued Set up an ad hoc committee of APOC, TDR and OCP to determine length of ivermectin treatments after 2002, this committee is to work on the basis of different scenario having frst been the subject of epidemiological modeling. Based on the 1997 epidemiological results of the villages of the Rio Geba in Guinea-Bissau with prevalence virtually znro ,it is recommended that only the former positive individuals detected in these villages be treated through the "advanced sfategy". Evaluation of the community-directed treatment with ivennectin taking advantage of APOC's experience after 3 years of operations. 2. Basins in Guinea Norttrern S ierra l.eone South-eastern Extension Togo South-eastern Extension Benin South-eastern Extension Ghana Dienkoa (Burkina) No change of strategy ptanned from now till 2002. Continuation of incidence studies in Benin, Guinea, Sierra Leone and Togo The practical approaches to the incidence studies in the context of community-based treatnent will be elaborated on the basis of the results of the protocol mentioned in 5.1. 3. Sassandra/lowerNzi- Bandama/lower Comoe (C6te d'Ivoire) Cessation of vector control planned before 2002. For each basin, the final decision will have to be made on ttre basis of an epidemiological evaluation. This evaluation will have 0o be carried out before the end of l99Tlbeglnning of 1998 so that a decision !o slop EeaEnents can be made at the appropriate time. The practical approaches to this evaluation are defined in section 5.1. 4. Kankelaba (Mali) Marahoue (C6te d'Ivoire) Niger at Bamako (Mali) Cessation of larviciding treatments on tlrc Kankelaba in Mali and ttre Marahoue in COte d'lvoire at the end of May 1997 and planning of post-treahrent studies as from June 1997 Cessation of larvicide treatments at ttre end of 1998 on the Niger at Bamako subject 0o acceptable epidemiological results. 5. Baoule-Bagoe (Mali) Planning of an epidemiological evaluation to ascertain the appropriateness of the suspension of ivermectin trearnent'from now till 2002. The practical approaches to these evaluations in the context of community-based trearnent will be elaborated taking into account the results of the protocol mentioned in 5. l. 6. Bui (Ghana) Bougouriba @urkina) Kulpawn-Mole (Ghana) Sota-Alibori (Benin) Oti-Pendj ari (Togo-Benin) Southern Sierra Leone No change of strategy planned from now till 2002. lntensification of ivermectin distribution. Distribution !o be canied on beyond 2002. t : ZB Fis. 7a lmpact of the Control in the Kankelaba basin in Mali 110 100 90 80 70 20 10 0 2030 60 50 40 30 vt E J lJ- =o s il,6j o o- 1 970 1 990 201 0 lmpact of the Control in the Eastern Extension Asubende 2050 Fig. 7b o E Jll. =o s o oj o o- 130 120 110 100 90 80 70 60 50 40 30 20 10 0 Vector Control rev a Observed a Predicted rmectin ^tA C Prev. Control (VC) + lvermectin (lV) Observed Predicted . lV :1987-2000 VC: 1988 - 2002 a ^. 1 970 1 990 2010 2030 2050 29 5.3. Use of the Geographical Information System (GIS) as a tool to assist in decision- making. In the discussions of group B, the GIS was used to facilitate the analysis of the situation in the various basins. The GIS made it possible to quickly visualize the most recent epidemiological situation in the basins of the Kankelaba, Marahoue and Sassandra. The consultation of the prevalence data base at a given point allowed one to visualize the overall results from l97l to 1997. A number of computerized data is available on the whole OCP area: maps of the rivers and of the territorial limits of the countries the geographic location of some epidemiological evaluation villages prevalence data for these villages from l97l to 1997 the geographic location of some catching points the entomological data (ATP) from the catching points the location of some villages under ivermectin treatment in the Bougouriba basin. In its present state, the GIS does not permit answering all the questions that arise at the time of making decisions about stopping larvicide treatments. The three main limitations of the system are: the absence of coordinates for a great number of villages the need to be able to integrate the analysis of the trends arrived at from the modelling based on the epidemiological data the need to be able to visualize the chronology oftreatment sequences (larvicide and ivermectin) at a given point. Considering the advantages of the GlS, the group recommended that: the use of the GIS be encouraged, all the epidemiological evaluation villages currently in the data base have a record of their geographic coordinates. These coordinates will at first be taken from the existing maps. During a field $N€y, the exact coordinates must be taken using the Global Positioning system (GPS) a data base integrating the chronology of the different treatments (larvicide and/or ivermectin) at a given point should be prepared, it be made possible to consult the longitudinal analysis of the data and the incidence situation simultaneously. The programmes already used for decision making @picros and Monthly) should be made accessible from the GIS. The trends in a given village, as provided by ONCHOSM, should also be made accessible. To do so, it is necessary to set up a general structure of access to the data bases and programmes which is based on geographic information. From a given village on the map, it should be possible to have not only the most recent epidemiological and entomological situation of the catching point nearest to this village, but also all the data provided by the other programmes. To provide an answer to this precise aspect, the group recommended that in the framework of the collaboration between OCP and CTD/HealthMap, HealttMap be given the responsibility of creating such a system. At first, all the data on the Bougouriba as well as the current different programmes of consultation of these data will be provided to HealthMap in order to test the product on this basin. 30 6. TRANSFER OF OCP RESIDUAL ACTIVITIES AND ASSETS: DETAILS OF IMPLEMENTATION AND TIMETABLE The general objective in assuring a successful transfer of the residual activities of the Programme to the countries is to strengthen the capacities of the countries to carry out (i) epidemiological evaluation and sr.rrveillance in order to detect and control recrudescence ; (ii) the residual entomological activities which would remain after 2002 through to a successful conclusion. The control activities directed against morbidity as well as those aimed at detecting and controlling recrudescence will then have to be integrated into the national system of multi-disease epidemiological surveillance. One of OCP's major roles is to see to it that this transfer of the residual activities of the Programme is carried out in the best possible way. To that effect, OCP, backed by WHO/AFRO and all the other development organizations willing to be involved in these activities, will lend its technical, logistic and financial support to the countries. The group studied the requirements for the transfer and made suggestions for the future of the various services and tools currently used by the Programme @NA laboratory, documentation centrg hydrological networh communication networlg management of programme data, buildings etc.). The goup also paid particular attention to the valorisation of the Programme's activities with a view to making them better known and in general the available services likely to be transferred. 6.1 Transfer of residual activities These activities have both the epidemiological and vector control components. Table 3 shows the activities to be transferred, the reasons for the transfer and the time frames for the transfer. After reviewing these activities, the group recommended that: epidemiological surveillance and evaluation, ivermectin treatment and diagnosis be transferred as of now to the countries. 6.2 ground larviciding and entomological evaluation be transferred as of now to the countries, entomological surveillance be transferred'to the countries as soon as the methods to be used are mastered, hydrological monitoring be transferred to the countries after further training of the existing staff; transfer of hydrobiological monitoring of the rivers be made at the end of the Programme; the transfer of research on biological insecticides, should take place at the end of the Programme. Reflexions on training The group reviewed the training activities and noted that for VCU activities, training was under way in the different fields likely to be transferred. For epidemiological activities, teams have already been constituted and are operational. Furthermore, the manuals and training materials are available. The group recommended therefore that: - an evaluation of training activities in entomology be undertaken, an action plan elaborated and that this be followed by an intensification of the activities so as to be in line with the time frames of the Programme; 3l - as training for epidemiological activities has involved only the central level units of the countries, it should be extended to the peripheral units as well; - the current manuals used for epidemiological surveillance should be revised to include the new diagnostic methods; - IEC being an important component of all these training programmes and given that OCP does not have the necessary specialists in this field, external expertise should be sought for IEC training . Table 3. Activities to be transferred 6,3 Reflexions on the activities of the DNA probe laboratory (DNA laboratory). The DNA laboratory is an important support unit for the entomological activities. [n the prospect of its use for surveillance for the detection of recrudescence, the group noted that training for the collection and preservation of samples can be easily carried out. It recommended however, that a task force be set up to make proposals on the means oftransportation of the samples to the laboratory and on the forwarding of the results of the analyses to the recipients. Type of activity Reasons Timetable PET t. Epidemiological evaluation 2. Epidemiological surveillance 3. Ivermectin treatment 4. Diagnostic For the follow-up of onchocerciasis control activities For the detection of recrudescence For the control of morbidity For I and 2 Now Now Now As soon as possible VCU l. Ground larviciding 2. Entomological evaluation/surveillance 3. Hydrological monitoring 4. Hydrobiological monitoring 5. Research on biological insecticides For nuisance control For follow-up of ground larviciding, post-treatment studies and detection of recrudescence For ground treatment in some areas For ground treatment and impact study of the development of the oncho-freed areas For ground treatment Now Now As soon as possible. Some communities trained and used in the context of ground treatment for nuisance control As soon as possible. National stafftrained and used to do the work now. Need for financial resourc€s [n2002 The DNA laboratory is equipped to carry out molecular biology tests which could be applied to other 32 diseases. The group recommended that investigations be undertaken in collaboration with WHO/AFRO in order to determine the feasibility of such a project. In accordance with the JPCIT recommendations and the Executive Board Resolution EB97A4, the group recommended that WHO investigate the possibility of using the OCP premises in Ouagadougou to house the DNA laboratory and some WHO services. 6.4 Transfer of physical assets and seruices The transfer ofthe physical assets of OCP were considered as being governed by Paragraph l0 of fuinex I oftheMemorandum of Agreement which is attached to the Onchocerciasis Fund Agreement 1992-1997. This states that : "Prior to the completion of the Programme, the Participating Governments and the Executing Agency shall consult as to the disposition of all project equipment provided by the Programme. Title to such equipment shall normally be transferred to the Participating Governments or to entities nominated by them, when it is required for the continued operation of the Programme, or for activities followin directly therefrom. The Executing Agency may however at its discretion, retain title to part or all of such equipment." The assets listed by the Working group were A - Human resources made available to the Programme by secondment from Participating Governments. B - Physical assets and services l. Real Estate 2. Vehicles, and Garage Equipment 3. Radio System 4. Informatics and Office Equipment 5. TechnicalDocumentation in the Documentation Centre 6. Field Archives and Administrative Documentation 7. The DNA Laboratory in Bouak6 8. The Argos System 9. Insecticides in stock at the end of the Programme 10. Miscellaneous. The Group recommended as follows l. That staff members seconded to the Programme by governments be formally returned to the goverrunents giving due notice to all parties concerned and settling all WHO's liabilities to the staff member. 2. (a) That WHO retains title to all real estate and to use same appropriately. (b) Specifically in relation to the office complex at Ouagadougou, the group proposed that in accordance with Executive Board resolution EB97 A4 paragraph Cl, (passed in January 1996), WHO should investigate the possibility of using these premises to house the DNA Laboratory and some services ofWHO. It further recommended to this effect that the Regional Director of WHO AFRICA Region propose that this idea be discussed at the next session of the Global a33 Programme Committee (GPC) of the WHO 3. (a) That WHO retains title to some vehicles, to meet the needs of its own work in the countries (WR's offices, projects, etc); (b) That WHO consults with the countries at JPC at least 3 years before the end of the Programme; and hand over the remaining vehicles to countries in accordance with the Fund Agreement cited above. (c) That OCP sets up a committee at least 6 months before the end of the Programme to oversee the transfer of title of these vehicles during the first 3 months of 2003. 4 (a) That OCP maintains title for the radio system for use by the intercountry co-ordinating mechanism which will exist, post OCP. (b) That OCP begins to stimulate the use ofthe radio system as an inter-country facility, say one half day per month for epidemiological information exchange. 5. That Informatics and Office equipment be treated together and disposed of in accordance with WHO's rules for disposal of surplus or obsolete property. It was noted that informatics technology was advancing rapidly and would make current equipment obsolete by 2O02.It was also noted that internal publication of equipment to be disposed of was permissible. 6. That the Documentation Centre be retained in Ouagadougou as part of the intercountry co- ordinating mechanism. 7. That equipment from various units (microscopes, slides etc...) be disposed of in accordance with WHO's rules which permits them to be passed on to institutions in the countries ( laboratories, universities, etc...). 8. That the OCP committee nominated at theZone Meeting in 1996, pursues its work vigorously, and that all field operations report to the committee on the number of pages of documentation which remain to be archived on computer or CD-ROM. Care should be taken not to record copies of information retained at sour@, and record the same information again at HQ where the original had been sent. 9. That OCP should consult with ORSTOM FIYDRO-MGER and project WHY/COM about their taking on board parts of our ARGOS system. The OCP real-time, sophisticated multi-country system was too expensive for any one country to maintain, especially since their needs in water supply and agriculture did not require "real-time" data monitoring. l0 (a) That OCP plans in advance to dispose of all toxic insecticides remaining unused at the end of the Programme in an environmentally responsible manner. (b) That OCP hands over to the government any non-toxic insecticides remaining in that country at the end of the Programme. I l. That any miscellaneous asset of the Programme remaining at the end of activities be retained by OCP and disposed of in accordance with the Fund Agreement and/or the WHO rules for disposal of surplus property. a 34 7. RECOMMENDATIONS 7.1. Reducing the risk of recrudescence (VCU/PET, National Teams (NT)) In order to reduce the risk of recrudescence of onchocercal infection after the cessation of larvicide tr@tments, and after having tried to work out the reasons for the recrudescence which occurred four years after vector control was stopped on the Bougouriba basiq the meeting recommended that in all the basins eligible for a definitive cessation of larvicide treatments, a number of additional studies be conducted on several fronts: - mesological: through entomological prospecting (detection of any new blacldly larvalbreeding sites and any new villages in the vicinity of the breeding site) and human population migration surveys; - entomological: through additional post-treatment studies in the areas suspected as being dangerous from the mesological point of view; - epidemiological: through additional epidemiological evaluations of the villages suspected as beiq dangerous in view of the mesological findings. This recommendation is to be implemented at first in the following basins: - the Kankelaba in Mali after larvicide treatments are stopped in April 1997; - the Marahoue in C6te d'Ivoire after the probable cessation of larvicide treatments in June 1997; - the Sassandra, lower Bandama and lower Comoe before and after the cessation of larvicide treatments scheduled for December 1998; - the Niger in the Bamako area and its tributaries the Dylamba, Faya and Fie before and after the cessation of larvicide treatments scheduled for December 1998. 7.2. Instituting the distribution of ivermectin in the Oti-Pendjari basin (PET/NT). Because ofthe worrying situation in the Oti/Pendjari basiq the meeting recommended that the national teams of: - Benin speed up the installation of community-based distribution of ivermectin; - Togo undertake additional epidemiological studies with a view to instituting community-based distribution of ivermectin without delay. 7.3. Early Detection of recrudescence (VCU/PET, NT) To allow for an even earlier detection of recrudescence of infection in the basins no longer under larvicide treatments, the meeting recommended that the use of the entomological tool for the detection of onchocercal infection through the crushed mass of blackflies and DNA probes be instituted as soon as possible. In this connection, a precise entomological threshold indicating recrudescence of onchocercal infection must be determined through ONCHOSM to facilitate the interpretation of the results. 7.4. Assessing epidemiological results in the original OCP area (PET/NT) To facilitate the transfer of the residual activities of the Programme to the participating countries, the meeting recommended that under OCP supervision, the epidemiological situation in the original Programme area be evaluated. A first series of surveys could be carried out from 1997 while a second series could take place around the year 2000 before the termination of the Programme's activities. t35 7.5. Facilitating the interpretation of epidemiological results in the basins under ivermectin treatment (VCU/PET, NT) To facilitate the interpretation of the results of epidemiological evaluations in the areas that have been under ivermectin treatment for several years, the meeting recommended that in close collaboration with the national teams, experimental studies be planned in order to monitor the evolution of microfilarial loads after the suspension of ivermectin treatments in the basins of the Sassandra and Marahoue in C6te d'Ivoire and Kankelaba in Mali. 7.6. Use of the Geographical Information System (BIS, CTD/Health Nap). To allow for a more productive use ofthe OCP software and data banks, the meeting recommended that a general computerized structure ofthese prograrnmes of data banks based on a geographical information system be set up andthat the development of such a structure be carried out in the framework of the collaboration between OCP and CTD/Health Map for a more productive use of the Geographical Information System (GIS). 7.7. Speeding up the transfer of skills in the tield of epidemiological and entomological surveillance to the countries (PET/VCU). Considering the increasing importance of surveillance, epidemiological and entomological evaluation activities in the phasing-out and post-OCP periods, the meeting recommended the immediate speeding up of the transfer of the whole of OCP experience, skills and tools necessary for these activities, to the Participating countries. 7.8. Transfer of the molecular biolory laboratory to oCP headquarters (DIR) With respect to the shared services of the Programme, the meeting first read paragraph l0 of Appendix I ofthe'?rotocol of agreement for the onchocerciasis control Programme" signed by the Donors and the Participating countries: "Before the completion ofthe Programme, the participating governments and the executing Agency shall consult one another to decide on the future of the equipment and infrastructures belonging to the Programme. The corresponding titles of property shall normally be transferred to the participating governments or to some legal entities designated by them when these equipment and infrastructures are deemed indispensable for the continuation of the Programme or for activities derived therefrom. Nonryithstanding, the executing Agency carL at its discretion, keep title of property to all or part of the material". Referring to this paragraph and to the terms of Resolution EB97A4 of the WHO Executive Council session of fanuary 1996, the meeting asked WHO to consider the possibility of transferring to the OCP headquarters in Ouagadougou, before 2002, the molecular biology laboratory as well as other shared services of the Programme. It also recommended that a proposal on the matter be addressed to the WHO/AFRO Regional Director who will submit it for the consideration of the next WHO "Global Programme Committee (GPC). a a I 36 Annexe 8. LIST OF PARTICIPANTS OCP / APOC 1. Dr. K.Y. Dadzie, DIR/OCP 2. Dr. H. Agouq CATA/CU, Kara (Co-rapporteur) 3. Mr A. Ak6, VCU, Odienne 4. Dr. L.K.B. Akpoboua, CATA/CU, Odienn6 (Co-rapporteur) 5. Dr. U. Amazigo, APOC, Ouaga 6. Dr. B. A. Boatiq CPET, Ouaga 7. Dr. Y. Bissaq VCU, Bouak6 8. Dr. O.W. Christensen, OCP, Geneva 9. Dr. N. Demb6l6, PET, Ouaga (Co-rapporteur) 10. Dr. A. K. Diallo, VCU, Kara 11. Dr. C. Gnger, Macrofil, Gendve 12.Dr. J.-M. Hougard, CVCU, Ouaga, (Chairman) 13. Dr A. Itondo, CMT, Ouaga 14. Mr V. K6r6, VCU, Ouaga 15. IvIr R. Meyer, VCU, Kara 16. Dr M. Nlandu, PET, Ouaga 17. hfr M. Ouedraogo, VCU, Bouak6 18. Ivtr M. Sarr, VCU, Odienn6 19. Dr. E. Soumbey-Alley, CBIS, Ouaga (Rapporteur) 20. IvIr S. Sowah, VCU, Bouake Zl.Dr. L. To6, VCU, Bouake 22.Dr. L. Yam6ogo, COORD ai, Ouaga Other Participants 23. Mr A.K. Asamoah, WHO, Geneva 24.Dr M. Banla, Ophthalmologist, Togo 25.Dr T. Diarra, Sociologist, Mali 26.Mr H.K. Larseq WHO, Copenhagen 27.Dr I. Nuttall, CTD, Gendve 28. Dr A. Plaisier, ERASMUS University, Rotterdam 29.Dr J.H.F. Remme, TDR/TDE, Geneva 30. Dr D. Sacko, Ophthalmologist, Mali I a a