Report on visit to the Onchocerciasis Control Programme in the Volta River Bassin Area

IocP '76. I ORIGINAL: ENGLISH REPORT ON VISIT TO THE ONCHOCERCIASIS CONTROI, PROGRAi\I\IE IN TTIE VOLTA RIVER BASIN AREA by Professor !V. Peters Liverpool School of Tropical [\ledicine, Llverpool, UK lO - 16 June 1975 Objectives of visit. Itinerary and people contacted. Chenotherapy of onchocerciasis. Entomological problems. Oeneral comments. Summary of recommendations. 1. Objectives of visit The primary objectives of my visit to OCP Upper Volta were as follows (i) to discuss the value and limitations of existing drugs currently used in the treatment of onchocerciasisi (i.r.) to evaluate potential investrgators and institutes where clrnLcal trrals of antifilarial compounds could be carried out; (iii) to consider what, if any, facilities exist within the framework of OCP for basic chemotherapy research; (iv) to familiarize myself with the entomological and operational problems of OCP wlth a view to advising on possible gaps or deficiencies that have developed:-n the course of the Programme so far' 2. Itinerary and le contacted 05.oo Arrl.ve Ouagadougou, Briefrng by Dr ZiegLer t 2 3 4 5 6 [llonday, 9 June 15. OO a ocP ,/76 . I page 2 Tuesday, lO .Iune l(ednesday, 1l June Thursday, 12 June Friday, 13 June Saturday, 14 June Sunday, 15 .rune Illonday, 16 June all day Drscussron wrth Drs Prost, Pairault, Pons, l\,[r Presthus; brref vlsit to Dr Martin-Samos (IVHO Representatt.ve). f8.30 By arr to Bobo-Droulasso wlth Dr ZLegLer 07.OO Xleetrng w].th Drs Le Berre, Baldry, Srmaga 08. oo Vrs i t to OCCGE , Centre [\luraz . Discussl.on with Drs Prod'hon, Beaudourn, SelIin, SaIiou, Duvalhet , ColIette. Vrslt to Dr Cheick Sow (Secretary General of OCCCE). p. m. Vrsrt by helicopter to part of Sector wrth Drs Zregler and Baldry. 07. oo By Porter aircraft to Tamale with Messrs Baldry, Henderickx and Scho11. Discussron at Tamale Hospital with Dr Steffen (t\lO rn charge) and Dr Awadzi (Consultant physician). 15.OO Return by arr to Ouagadougou. 07. oo Return by Porter aircraft to Bobo-Droulasso. Vrsit to OCCGE Centre Muraz. olr. oo Discussion on chemotherapy with Director. M6decin-General i\{assacrier, Drs Prod'hon, Beaudouln and Collette. Visi.t to Bobo-Droulasso Hospital (Drs Le Bourthe, Pierreson, Lagadec ) . Dlscussion with Drs Challier and Brun of ORSTOL. Vr.srt to Glossina Centre of IEMVT, Dr Clair. Working drnner with Drs Cheick Sow, Brunhes (ORSTOIII, Bouak6) Particrpation rn briefing meeting, Bobo Sector. By air to Ouagadougou. Tsetse prospection at edge of Ouagadougou towyl. Frnal drscussion with Drs Zregler, Prost, Baldry. Depart Ouagadougou for Parrs and Geneva. tl.oo t 15. OO 16.oo Evening 07. oo 14.OO a. m. 07. oo ro. oo 3. Chemotherapy of onchocerciasis 3.1 Exrstrng drugs The only two drugs currerrtly in use, namelv suramrn and dlethl.lcarbamazine (d.e.c. ) were considered by membels of a I!.HO panel rn 1972 lsee WHO,/OCp/13.t, Annex 11-1) and agaln reviewed by the SAPrworkrng group on chemotherap),rn 1(-)74 (see OCP,/SAP/75.1). These documents provide an excellent review of the status of these compounds t.n relation to the chemotherapy of onchocercj-asis, but unfortunately were not ar",arlable to the wri.ter prior to his return from Upper VoIta, I Scientific Advisory Panel ocP f76.L page 3 Nevertheless dlscussions with members of the OCP and OCCGE conflrm the well--known limitations of both drugs in relat].on to thelr lnherent toxic1.ty, the side-effects they induce 1n parallel wr.th their activity, and especrally their potenttal role in mass drug admInl- stration as glven in classical dosage regimens. Several polnts however merit further cons idera tion. Suramin The SAP report recommends that the llterature on suramin should be reviewed and analyzed It is also recommended that clrnico-pharmacologrcal research facilitres should be established in the OCP area for the study of this and other drugs, such facllrties to include those requrred for, e.g. renal biopsy (although thl.s is not specified rn the report). A preliminary study by Dr Prost (OCP) and Dr Rolland suggests that, In a village community where transmission has been interrupted for 5 years, suraEin therapy has not produced a significant faIl in infection rates compared with untreated controls. Prelimrnary results of a trial of the possible prophylactrc effect of a single dose of I g suramin to immigrants into an onchocerclasis area are negative. The subSecr of renal biopsy studies to investr-gate the cause of suramin nephrotoxicity was discussed with both OCP and OCCGE physicians. It was felt that such a study would be impractl.cal (1n Upper Volta at least) for two principal reasons, (a) the difficulty of obtaining suitable subjects under approprlate hospital conditions and, (b) the danger of provoking adverse public sentiment in the OCP area in the (unlikely) case of accident. In the Bobo-Dioulasso general hospital it was quite clear that clinical research is out of the questlon, essentially because the medical staff of the hospital are already grossly overworked. On the other hand, Dr Awadzi of the Tamale Hospital appeared very interested in the possibitity of Lrndertaking a clinical research project in association with OCP if so requested. He is a young, dynamic Ghanaian with good postgraduate specialist qualificatlons obtained in UK, and appears to be inclined towards the academic side of clinrcal medicine. The facilities at the new Tamale Hospital are excellent and good nursi.ng staff are available there. The laboratories however would probably need additional support both in terms of technical staff and materials. An average of 20 to 30 onchocerciasls patients are referred each month to Drs Steffen and Awadzi for consultation, and these probably represent only a fractron of those arriving at the hospital OP departments. D.E.C \ trial of d.e.c. in small weekly doses as a long-term suppressant of microfilaraemia is supposed to have been carried out by Dr Laureal at Bamako, but all attempts to date by Dr Prost to obtain data from this project have fai.led. I\leanwhile Drs Rolland and prost have been studying the value of two dosage regimens of d.e.c. in 2 villages, with cutaneous and ophthalmological follow up. The dosage schedules were as follows In village A (2O7 cases) 20 x lOO mg d.e.c grven r.n I days (with corticords or phenergan) once weekly for 26 weeks.then 50 mg d.e.c ocP /?6. r page 4 In vrllage B (2I4 cases) 20 x lOO mg d.e.c. given rn $ days dosage repeated 6 months later then 50 mg d.e.c. once weekly for 26 weeks Quantitatlve skin snlps before and I year after end of treatment rn each village Better results were obtained in village B (details below) but Dr Prost attrlbutes this to the closer personal contact that was obtained with the residents of the village, rather' than to the treatment schedule 1.tself. Posltive at start Negat1. ve at start Became neBa t 1 ve I\IF decreased MF same MF increased VrlIage A Vrllage B 34 76 2550 30 t362 15 i-.e vrllage A 84 /13$ fotlowed up j"mproved vrllage B 138/i166 followed up :.mproved Dr Rolland who carried out the ophthalmological control of these and other similar studies observed a decrease of punctate keratrti.s in the patients who received treatment and an arrest of other progressive eye changes. Drs Ziegler and Prost emphasized the polnt that OCP is essentially an operational pro3ect and underlrned the necessrty for pro;ect personnel to avoid dl.recting their time and energy to research projects such as clinical trials, while at the same time showinB a full realiz.atron of the important place for such trials in the overall OCP strategy as outlined in OCP,/S-A.P/75.1 and other basic docunents. Small clinical studies with d.e.c. (? and suramin) are in hand based on five other centres(including the Centre i\luraz). Dr Prost hopes to call a meeting of the physicians concerned next octobe^ to drscuss their progress and attempt to coordinate their efforts. The writer advised him against setting up a multi-centre trial of new compounds (e.9. metrifonate) at this stage, and to await the result of Phase I trials (see below)' The Long-term use of d.e.c. from the experiences in OCP and elsewhere does seem to be of value rn reducing microfilarial levals and eye damaBe due to O.volvulus. It would seem most desirable to develop a formulation of d.e.c. such as an inJectable repository form (cf. cycloguanil embonate tried in malaria prophylaxis) that could be adminrstered at infrequent intervals for mass chemotherapy, since the long-term administration of the standard formulation by mouth over a long period of time is not_ a practical proposrtion under fi-eld conditions.(This point has already been noted in OCP/SAP,/lS.t). 4 ocP /76 .r page 5 3.2 New drugs already used or tested for other indications l.n man In the SAP report several compounds were specifred that merit clinical trial in patients with onchocerciasis. M6decin-General l\{assacrier and Dr Prod'hon are eager to undertake such studies, starting with metrifonate and levamrsole. Once the concept of clinical trials carried out in progresslve phases was made clear to them they agreed to draw up a protocol for submission to OCP for a Phase I trial, of metrr- fonate in onchocerciasis patients kept under strict observation in the small hospital attached to the Centre l\luraz. Details wl.ll be provided shortly to Dr Ziegler for consideration. The phasing of clinical studies with new drugs (such as metrifonate) that the writer discussed in Upper Votta is virtually the same as that outtined in Annex 2 of OCPf73.L Annex 1l-1, the difference being that the safety of such drugs will already have been established in earlier trials conducted in non-onchocercal patients. Since such compounds, if effective, may produce entirely new side-effects in patients infected with O. volvulus it was enphasized that strict precautions must be taken until the safety of the trial drug is assured in a Phase I study. The selection of cases is particularly important in this respect since, for example, unforeseen nicrofilaricidal activity might induce dangerous secondary effects in the eye or elsewhere. It seems fron present evidence that the compounds listed rn OCe/See/tS.t are unlikely to produce dramatic macro- or nicrofilaricidal effects against O.volvulus. If the Centre Muraz trial of metrifonate materializes, and satisfactory data (positive or negative) are obtained in this first clinical study, it would seem reasonable to support this centre in conducting further Phase I studies of other compounds (e.g. nebendazole, levamisole. niridazole). A positive result in Phase I at this centre could be followed by the establishnent of a multi- centre study (Phase II) using a dosage regi.men based on Phase I data, along the lines already envisaged (but in a soEewtrat different context) by Dr Prost. However. it would then be advisable to caLl on the services of a clinical trials adviser (see 5.1.3. below) to obtain expert statistical advice from the planning stage onward. 3.3 New drugs not yet tested in nan Clinical studies on completely new drugs discovered in the course of experimental work on animal models cannot be made by personnel of OCP but demand the attention of a specialist in clinical pharmacology, with adequate parasitological support. All the precautions sulmar- ized in @Pf73.1 Annex 11-1 and in other WHO documents concerning drug trials must be followed. It is possible that such studies could be made at Tama1e Hospital in collaboration with Dr Awadzi but the following conditions would have to be met: - (a) agreement obtained from the Ministry of Health of Ghana (b) support provided to the clinical (? and parasitological) laboratories (c) expertise provided by a specialist consultant provided by 1VHO (d) prior assurance of drug safety obtained by studies in healthy hunan volunteers following standard preclinical safety studies (e) ethical safeguards imposed accordrng to internatlonally accepted standards ocP,/76.r page 6 3.4. Basic research on onchocerciasis chemotherapy The disinterest of the pharmaceutical industry :.n general in the search for and develop- ment of new drugs for use in parasltic diseases is a well-known and currently much mooted problem needing no further emphasis here. Clearly much basic work needs to be done both to clarify the mode of action of compounds (experimental or otherwise) already known to exert an action against adult or larval filaria, and to study the biology and physiology of the worms themselves, in a search for points at which they may be attacked. Most of this work will have to be carried out in animal models of which several exist, all far from adequate. It is the writer's belief that this aspect of the problem, basic chemotherapy research, should be tackled by the Filariasis Task Force of the WHO Special Programme for Research and Training in Tropical DiseaseJand not by OCP, although it may be considered desirable for OCP to contribute funds for this purpose from its own budget. The testinB of new drugs(section 3.3) might also be considered to fall within the purview of the Task Force, rather than of OCP, although it is obvious that a closer inter-divisional liaison and coordination of effort will be required at all stages. 4. Entomological problems 4.1. Simulium taxonomy One of the most striking and urgent entomological problems experienced by OCP at the present time is the determination of the source of adult S,damnosr.m that reinvade controlled areas of the proJect. While cytotaxonomic techniques are now being used to analyze larval populations, no technique is available for the adult flies. Isoenzyme analysis has proved a useful taxonomic tool in the analysis of populations of other groups of Diptera (e.g. Drosophila, Culicidae) although the procedures are still at a relatively early stage of development. The writer understands that isoenzyme analysis has been attempted i" Sig"lf* (e.g. Coker in Accra), so far with little success. However, in this little explored field there is good reason to believe that, given adequate impetus, advances can be made within a reasonably limited time and it is strongly reconrmended that further support should be provided to encourage workers experienced in isoenzyme techniques to apply themselves to the study of Simulium populations. While much of the preliminary work could be carried out on other species of Simuli.um, e.g. in Europe or North Ameri.ca, the main problem finally would have to be investigated in the field with S.damnosum itself in paraltel with cytotaxonomic analysis of larvae produced by individual female flies. This matter is of great urgency. 4.2. Can rnsecticides used for Simulium control influence anophel ine populations? In drscussion with several entomologists I.n the OCP area 1t was suggested that Abate used for Simulium control by OCP might incidentally exert a beneficial reduction of malaria transmission over a period of time by producing a small but significant reduction in the densities of certain anopheline vectors. Dr Jacques Hamon of the Division of Vector Biology and Control, WHO Headquarters (VBC) in discussion with the writer however has pointed out that, on the basis of his long and unique experience of malaria epidemiology and anopheline bionomics in Upper Volta, there is very little likelihood that insectrcides in the dosage employed by OCP would have any influence on anophelines and malaria in this reBion of highly stable, holoendemic transmission. lrr* Divr.sion ocPh6.L page 7 5. General Comments 5. I Chemotherapy 5.1.1 Study of the excellent OCP master plan (OCP/73.1) reveals that insufficrent consideration has been given to the chemotherapeutic aspects of onchocerclasis, especially in the event that any delays might occur in the interruption of transmission by vector control. Ultimately it is the effect of the Programme on their own wellbeing that will ensure a continuing cooperation of the peoples of the Volta River basin area for the necessary time, and not Just the destruction of Simulir.rm damnosum. Experience r.n other frelds has shown how high is the risk of the population losrng interest in, or e'.'en becoming antaBonistic towards a vector control progranme, as it contj.nues over a period of years. 5.L.2 It is essential therefore, that the populatlon see, r-n themselves, thelr families and the.I.r neighbours, a positive benefit from the control of onchocerciasis trans- missron, and health education propaganda alone r.s probably not golng to suffrce in the OCP area. Successful treatment of high risk patients, improvement of vision in those with early Iesions, and an evident failure of infants, children, and new immigrants to acquire infection, are more Iikely to assure continuing support by the indigenous population. Mass chemotherapy should therefore receive a higher degree of priorlty within the overall framework of OCP than it has done to date. However, it is vital (a) that any chetrotherapeutic measure that is applied on a large scale should produce an absolute minimum of side-effects, and preferably none, and (b) any preliminary clinical trials of new drugs should be conducted in such a way and in such places that any adverse effects of treatment do not cause undue alarm among the populace. There are notable examples where, incidents of this nature having occurred (in fact or fancyi ), treatment has been thereafter refused by sigrrificant nuobers of the people most at risk (e.g. preliminary trials of antlmalarials, trypanocides, schistosooicides and antifilarials I ) 5.1.3 The planning, surveillance and conduct of ctinical trials during aIt their phases (e.g. as laid down L^ OCPf73.1 Annex 11-1) today demands the servlces of a specialized physician and an appropriate supporting team, Individual portions of a trial may be, and usually are allocated to specific working units (see for example 3.2 above). The coordination of the work and the evaluation of data constitute a fuIl-time job demanding an intimate knowledge and experience of clinical pharracology, drug monitoring and, in the case of anti- parasitic aBents for tropical use, tropical medicine, parasitology and the way of life of man in the developing world. This job cannot be performed by physicians of the present OCP organization, all of whom already have ful1-time operational duties to perform within the existing progranme. 5.1.4 It is therefore in the writer's oprnion, essentral to establish an additional post of "Clinical trials adviser" (CTA) with appropriate supporting staff. The first of these should be a senior laboratory technician with experlence of biochemical monitoring, capable of supervising junior (preferably national) laboratory staff, and the second a technician to assi.st in field studies, with experience in parasitological procedures. Unless the CTA has personal experience of ophthalmology he, in his turn, will need the expert advice of a specialist ophthalmologlst, possible one of the OCP team. 5.I.5 The CTA might be recruited from the ranks of medr.cal advisers in the pharntaceutical industry, or from among the fairly numerous physicians who, in recent years, have been concerned in the tropics with clinical trlals of antimalarrals, schistosomicides, etc. (Advice on this point should be available from the Division of }lalaria and other Parasitic Diseases (ll{PD) and TDR). ocPf 76.L page 8 5.1.6 The only medical centre seen by the writer on to which a clinical trials team could be grafted would be the new hospital at Tama1e, but other potentially suitable centres may exist within the OCP area, e.g. Bamako or in non-OCP onchocerciasis regions, e.g. Zaria (Ahnadu BelIo University). 5.I.7 Basic drug research up to and including the stage of clinical pharmacology in uninfected volunteers, cannot be carried out under the direction of OCP personnel , and probably not within the OCP area. (The possible exception is that some basic research night be carried out in appropriate university departments within some of the OCP countries. and indeed this would be a most desirable development). At this point we encounter the current problem of drug development for the control of parasitic diseases with which the TDR division is attempting to cope through the new Task Force proBramme. The most logical action for OCP to take in relation to basic drug research is to allocate funds through the TDR Filariasis Task Force, while ensuring that OCP has representation on this Task Force to guide its efforts in the directron of onchocerciasis chemotherapy. 5.1.8 New macro- and microfilaricidal drugs are urgently needed. It does not seem that much progress will be made with the large-scale application of suramin or d.e.c. However, further studies do need to be nade in the field with these compounds (as indi.cated in ocefSlOflS. l), and in the laboratory (a iob to be camied out via the Task Force). 5.I.9 Drugs currently in clinical use for other indications could readily be studied within the OCP under the direction of the CTA with the precautions already stressed above. Completely new drugs must however be sought. US Army experience over the last decade in the antimalarial field shows how difficult it is, even after nobilizing the resources of a great global network of research workers in the pharmaceutical and chemical industries as wetl as the uni.versiti.es, to find and develop to the stage of clinical field trials, even one drug. Of some 25O,OOO compounds screened, only one antimalarial is likely to find general acceptance for the specific purpose for which it was sought, nanely the treatment of chloroquine-resistant falciparum malaria. At the same time however it must be remembered that at least several hundred compounds emerged from the screen that were highly active against Plasmodium, if not against models of drug-resistant malaria, and that for this reason many were not followed up to the stage of clinical studies. 5.1.10 The screening machinery set up by the US Army was the biggest ever evolved to discover and develop an anti-parasitic drug. Much can be learned from this experience and it would not seem beyond the realms of possibillty, given the impetus and financial backing, to set up a mass-screen for the developoent of anti-filaria1 drugs. The experience of those intimately concerned with the US Army project could be called upon, possibly by setting up a joint ad hoc "Study group on the screenlng of potential anti-filarial compounds" :n addition, to the antimalarial experts, invitations should be extended to investigators fron the pharmaceutical industry experienced in anti-filarial drug screening, and experts In the nass screening of other agents, €.8. anti-bacterial, anti-viral and anti-cancer drugs. 5.1.11 Serious consideration should be given to establishing a "Special fund for the development of anti-filarial drugs, with special reference to onchocerciasrs". It must be envisaged that it may cost between 10 and 20 million US dollars to develop the next drug for the successful treatment of onchocerciasis. Much of thrs fund may have to be used to provide support to the pharmaceutical industry which is ultinately the best equipped to deal with new drug development. 5.2 Anti-vector oPerations The. writer was very favourably impressed during his brief visit by two fundamental aspects of the operations. a tocPf 76.r page !) The success or failure of every field progranme hangs on the personalrties, energy and esprit de corps of the team carrying it out. From this point of view, rf the situation contlnues as it appears to be doing at present, OCP has every chance of making rapid headway with the eradication of S.damnosum. The team, under the dynamic guidance of the Chief of Simutiun control operati6frIllEfrs to be working extremely welI together in spite of inevitable setbacks, both technical and personal, the growing pains that must be expected to accompany the evolution of such an ambitious programme as that of OCP. The writer was frankly amazed at the efficient and rapid headway that has been made rn the operational programme during the short life-time of this project. The immaculate attention to detail, intimate knowledge of the area and appreciation of its problems dispLayed by the OCP staff members was outstandrng. Deficiencres in the attention to chemo- therapy in this Programme are deficiencies due not to the physicians of OCP but to the fallure to appreciate the importance of this aspect of the operation in the basic OCP plan. The Programme Director has stressed qurte correctly throughout that, as laid down, this is an operational programme, and att staff members must devote aIl their energies to carrying out the operational plan. It muso however be agreed that this itself is still to a large degree, a plan of operational research. In the writer's opinion it is still premature to asstrme as has been done, that all the technicat problems have been foreseen and studied, and that the operations as plannecl-can go ahead without any maJor interruptions for the next 20 years. Phase I of the operation, at least in its first year, should rn the writer's opinion be considered as a phase of operational research, without moclifying anything except the philosophical approach to the obtaining and the evaluation of data from the fie1d. The total exclusion of the idea of research from OCP can perhaps be taken too far, with the result that the team becomes too rnftexible in its assessment of its own work. 6. Summa of recommerdations 6. 1. Chemothe rapy (i) A post of "Clinical Trials Adviser" should be created with, init:.aILy, two taboratory technician assistants. (ii) Phase I studies should be made of metrifonate, Ievamisole and other drugs in human use, in hospitalized patients, The Centre Muraz could undertake such stuclles. (iii)Additional Phase II studies are still required to explore the role of suramin and d.e.c i-n mass -chemotherapy. (iv) Basic research on new antl-filarral drugs should be coordinated throuBh the lrlartasis Task Force. (v) A "Study Broup on the screening of potential antt.-filarial compounds" should be organized, especially to benefit from recent US experience l.n the antlmalarlal fielcl. (vi) New drugs (other than those referred to in Section (ti) above) in their flrst clinical trials i" 9"9!""etcg infected patients should preferably be tested outslde the OCp area. (vii)Consideration should be given to establishing a "Special fund for the development of anti-filarial drugs, with special reference to onchocerclasrs". 6.2 Entomology (viii)A short-term consultant should be appointed or contract allocated to an appropriate institute to work out techniques for the biochemical taxonomic determination of strains cf S.damnosum in adult flies, for(see section 4.1 above) comparison with cytotypes based on larval chromosomal analysis a ocP /76 . L page 10 6.3 Operations (ix) Flexibility should be retarned rn the assessment of phase I operations on the under- standing this is stitl, in a sense, operational research, and that long-term plans may strllhave to be modified if necessary in the light of this programme. The writer wishes to thank Dr BeLlerive, Director-Consultant OCP, for making his visit to Upper Volta possible, and Dr Zregler. Programme Director OCP Ouagadougou and his Programme staff for their warm reception, ready cooperatt.on and frank discussions. a