Report of a meeting of the TDR/OCP/OCT subcommittee for monitoring of community trials of ivermectin Ouagadougou, 25-27 January 1989

JOINT PROGRAMME COMMTTTEE Office of the Chairman Onchocerciasis Control Programme in West Africa Programme de Luttc contre I'Onchocercose en Afrique de l,Ouest. JPC .CCP COMITE CONJOINT DU PROGITAMMEBureau du Pr€sident JOI},IT PROGRAMME COMMITTEE Tenth session The Haque. 4-7 December 1989 JPC1o/rNF /DOC.L ( rDR/ocP/ocr/ rvERMEcrrN/8g . 3 ) September 1!8t REPoRT OF A MEETTNG 0F THE TDR/oCP/oCT SLIBCoMMITIEE FOR MONITORING OF COMMT'NITY TRIALS OF IVERMECTIN t f WORLD HEALTH ORGANIZATION ORGANISATTON MONDIALE DE LA SANTE TDR/OCP /OCTITVERMECTTN/89 . 3 ENGLISH ONLY UNOP/WORLD BANK/WHO SPECIAL PROGRAMME FOR RESEARCH AND TRAINING IN TROPICAL DISEASES Ouagadougou. Burkina Faso. 25-27 January 1989 REPORT OF A MEETING OF THE TDR/OCP/OCT SUBCOMMITTEE FOR MONITORING OF COMMUNITY TRIALS OF ]VERMECTIN CONTENTS lNTRODUCT]ON REPORT FROM OCP REPORT FRO},I MERCK SHARP & DOHME COMMUNITY- BASED STUDIES Page I 2 3 4 2 3 3 4 4 4 5 6 6 7 7 7 8 8 9 9 9 4.L 4.2 4.3 4.4 i.1 5.2 5.3 Liberia (reported by Dr H.R. Taylor). Mali (reported by Dr G. Soula) OCP (reported by Drs G. de SoIe, J.H. Cameroon (reported by Dr J. Prod'hon) Remme & Y Dadzi-e) t 4.4.1 Cameroon (reported by Dr R. Moyou) 4.5 Ma1awi (reported by Dr G. Burnham) .... 4.6 cuatemala (reported by Dr E.W. Cupp) 4.7 Nigeria (reported by Drs A. Abiose and C. Vajime) 4.8 Sierra Leone (reported by Dr J. Whitworth) 5. SUMMARY: ADVERSE REACTIONS Exclusion Criteria Monitoring Research Priorities SUMMARY: EFFECT OF IVERMECTIN ON MICROFIIARIAL LOADS AND TRANSMISSION 6.1 The Effect on Microfilarial Loads 6.2 Transmission 6.3 Research Priorities . . SUMMARY: IVERMECTIN AND ITS IMPACT ON MORBIDITY AND THE PREVENT]ON OF MORBIDITY IN ONCHOCERCIASIS 6 10 10 10 12 7 Thrs report contatns the collective views of an lnternational group of experts convened by the UNDP/W0HLD BANK/ WHO SPECtAL PROGRAMME FOR RESEARCH AND TRAINING IN TROPICAL 0ISEASES (T0B). lt does not necessarily reflect the views of T0R/WH0. ln the interests of raprd communication it has been submrtted to only minimal edrtorial revisron. Moreover, any geo. graphrcal designatrons used rn the report do not imply the expres- sion of any optnion whatsoever on the part of TDR or WHO concerning the legal status of any country, territory, ctty or area or of rts authorities concerning the delimitation of rts Irontrers or bo u nd aries. L2 Ce rapport exprime les vues collectves d'un groupe internatronal d'experts rdunr par le PR0GRAMME SPECTAL PNUD/BAN0UE MONDIALE/OMS DE RECHEHCHE ET OE FOBMATION C0NCEHNANT LES MALADIES TR0PICALES (TDB) il ne reprdsente pas ndcessairement les vues du TDB/0MS et, en vue d'une diffusion acc6l6r6e, rl n'a pas dtC l'oblet d'une mrse en forme partrculrdrement soignde. En outre, les noms gdographiques utilts6s dans le prdsent rapport n'rmpliquent, oe la part du TDR ou de l'0MS, aucune prise de posrtion quant au statut luridique de tel ou tel pays, lerritorre, ville ou zone, ou de ses autorrtds, ni quant au trac6 de ses frontrdres. TDR/OCP /OCTITVERMECTTN/8 9 . 3 page 2 7.1 Features that Contribute to Morbidity in Onchocerciasis and their Monitoring .... 7.2 Assessment of impact on morbidity . . . . . . 7.3 Research Priorities . . PARTICTPANTS ABSTRACT Community-based studies on the use of ivermectin against onchocerciasis in over 70 000 people in 14 countries in Africa and Latin America showed that it is an effective and extremely safe microfilaricidal agent when given as a single oral dose. Depending on the intensity of infection, 10-30t of people experienced certain adverse reactions (the llazzotti reaction) at the time of first treatment. In most cases , these reactions resolved spontaneously. These side-effects were much less intense and occurred in fewer patients following subsequent re - treatment. it was recommended that current exclusion criteria, mainly involving \romen of childbearing age and young children, should be retained until further information becomes available, and that an experienced health care worker should be available to onchocerciasis patients for at least 36 hours following the first administration of ivermectin. The impact of ivermectin on disease morbidity in the treated population requires further detailed studies over a longer period, but early lesions in the anterior regions of the eye have already been known to be reversible. And, the substantial reduction of microfilariae from the skin (sustained for at least six months following treatment) gives relief from itching and facilitates improvement of superficial lesions. Research priorities include determining 1) the frequency of retreatment required in areas of differing endemicity, 2) the necessity to retain currently applied exclusion criteria, and 3) optimization of drug delivery systems to provide cost-effective rnethods for identifying and treating those infected with onchocerciasis. To ful1y evaluate the impact of ivermectin on disease transmission it r+i11 be essential to apply new mole,:ular identification techniques to differentiate animal Onchocerca species occurri-ng in the blackfly vector, and to use computer modelling techniques to predict the Iong-term effects of widespread use of the drug. 1. TNTRODUCTION A meeting of the TDR/OCP/OCT Subcommittee for monitoring of community trials of ivermectin was held in Ouagadougou, Burkina Faso on 25-?7 Januaty lgSg . The meeting !/as chaired by Professor J. F. i^Iil1iams (Chairman of SC/TDR/FIL) , and had two main obj ectives : (1) to review progless in the community-based trials; (2) to make recommendations for the use of ivermectin, and for further research. Dr E.M. Samba, Director of the Onchocerciasis Control Programme (OCP), welcomed participants and expressed optimism about the potential of ivermectin in onchocerciasis control, noting the appreciation of OCP for the gift of ivermectin made by Merck and Company (Dr Roy Vagelos, President). 13 13 t4 T4 f , tTDR/OCPIOCTlTVERMECTTN/8 9 . 3 page 3 REPORTS FROM COMMUNITY TRIALS 2. REPORT FROM OCP Dr B. philippon (OCP) reviewed the status of larviciding activities, noting the recommendations of the Expert Advisory Committee (EAC) and JPC that these activities should continue. In the Past year, aerial larwiciding had been extended to the south of Togo and Benin and into western !Ial-i, as well as selective and seasonal larviciding in eastern Guinea. In 1989, rivers in northern Sierra Leone, central Guinea, and Senegal will also be treated' Recent developments in OCP vector control activities include the following: a Development of temephos resistance affecting most five larvicidal compounds are now used in rotation' under control. This has increased oPerational impact on the efficacy of transmi-ssion control. The southern extension was well-controlled in 1988 southeastern margin of the OCP area was controlled the history of the Programme. of the Programme area; and resistance is now costs but has had no and reinvasion of the for the first time in a a a In 8Ot of the original .area, Onchocerca transmission is virtuallyinterrupted. In the remaining 20\, the major cause of residual transmission is reinvasion by savanna flies and local treatment failures. I The western extension is more complex, with very intense areas of transmission, especially in Guinea. The southern movement of savanna flies is particularly imPortant in southern Sierra Leone. Important questions to be considered are: (1) when to terminate larvi- ciding in areas under control for L2-L4 years, (2) what role ivermecEin may play 1n preventing recrudescence when vector control is interrupted, and (3) how ,to proceed in the western extension area in which the nine years remaining to OCP are inadequate to achieve vector control. Professor J.F. Williams ernphasized that the role of ivermectin ln controlling transmission of oncho- cerciasis remains a major question. 3. REPORT FROM MERCK SHARP & DOHME Dr K. Brown (Merck) reviewed ivermectin coxicity and pharmacology. The drug is fat-soluble but, due to lack of penetration of the blood-brain barrier, is not found in brain tj.ssue to any great extent. The therapeutlc index is high; for example, in dogs more than a 10-fold increase above therapeutic amounts can be given before mydriasis is seen as the first manlfestation of toxicity. Average peak serum concentration in humans occurs at four hours; the half-life is l-0 hours. Ivermectin appears in milk in lactating females and because of uncertain safety in newborns, should not be given to nursing mothers during the first three months after birth. The mechanism of action of ivermectin is unknown but may relate to its binding to GABA recePtors and effect on chloride channels. Resistance to ivermectin in Haemonchus contortus occurred after four passages in sheep receiving ivermectin treatment in the field, and has also been produced in the laboratory. The potential relevance ofthisobservationto@isunknown.Non-respondersinfie1d trials may simply rePresent non-compliance or poor absorption, since retreat- ment of ih"". patients is usually successful. However, measurement of serum levels has not been done in this setting. Idiosyncratic reactions relating to toxicity have been noted in dogs (collies), mice and cattle; any relationshiP to human resPonses is unknown. TDR/ OCP / OCTITVERMECTTN/8 9 . 3 PaEe 4 4. COMMUNITY-BASED STUDIES 4.L Liberia (reported by Dr H.R. Taylor) A study of community-based mass treatment of onchocerciasis with ivermectin continues at the Liberian Agricultural Company (I-AC) rubber plantation in the rain forest area of Liberia. The initial census and treat- ment of the population took place from September to December 1987 and this was repeated from September to December 1988. The censused population of the area during the second treatment vras 13 977. Alrogerher, 8062 people (97* of those eligible) were treated; 5629 people (40t of the population) were ineligible for treatment. Data on adverse reactions were collected by four different methods. These included: (a) a systematic house-to-house, fo11ow-up visit three days after treatment; (b) a year-round population surveillance system; (c) monitor- ing of the records of the plantation mobile clinic; ano (d) monitoring of LAC hoipital records. No severe adverse reactions were noted with retreatment, and .,o ."""" of postural hypotension, chest pain or haematoma were seen. With the second round of treatment, adverse reactions were even less common than during the first treatment. Only 37 people (0.3t) had a moderate reaction of che Irlazzoxt]- type, presumably related to the killing of microfilariae. No unusual or unexpected reactions were seen. No deaths could be related to ivermectin treatment. Of the 61 people who had moderate reactions after treatment in 1987 and were retreated this year, none had reactions in 1988. A11 675 infants were examined who were born on the plantation since the first round of treatment. 159 of the mothers took ivermectin either during pregnancy or in the three months preceding pregnancy. 96 mothers had taken ilreimectin during pregnancy, 83 of them during the first three months after conception. Only three infants with congenital malformations were seen and rhese could not te related to ivermectin treatment. In addition, 153 babies born in the hospital 9-11 months after the start of the first treatment round were examined at birth and showed no abnormalities. To monitor the efficacy of the community-based distribution of ivermectin to reduce microfilarial densities, a sample consisting of the population of five camps had skin snips taken before treatment, and again six and 12 months later. One year after the community-based distribution of ivermectin there was a 758 reduction of microfilarial density in those who were actually treated, and an overall 522 reduction in microfilarial load of the community in vshich treatment was distributed. I There was a 14.9* incidence of new infection (based on skin-snip tivity) in children 5-11 years of age during this year. fn this age onty ttritaren with positive skin snips urere treated with ivermectin. 4.2 Mali (rePorted bY Dr G. Soula) In an open phase IV clinical trial in non-hospitalized subjects living in separate va1Ieys, 855 Patients with onchocerciasis (Koba Va11ey) received an inirial dose of L5O nig/kg ivermectin in May 1987, while 507 (Dlaba Valley) vt/ere included as controls. This cohort was followed up seven and 12 months Iater. In June 1988, a second dose of ivermectin was administered Xo the 749 patients of the Koba Va1ley, while 511 patients of the Dlaba Va11ey received an initial dose. posi- grouP, I TDR/OCPlOCTlTVERMECTTN/8 9 . 3 Page 5 The tolerance to treatment with ivermectin was good and has improved after the second dose given one year later: 15.2* of patients treated for the first time in M"y 1987 reported side-effects, which were mostly mild or moderate, appearing early and quickly resolving. Only eight cases were impeded from carrying out their normal daily activities. The second dose, given one year after the first, produced mild side-effects only in 3.78 of cases. The intensity of the microfilarial infection constitutes a risk factor for side-effects to iverrnectin. The likelihood of side-effects also increases with age. Neither sex nor dosage varying from 100 to 200 ncg/kg seems to be related to the frequency of side-reactions, after controlling for the effects of age and dermal microfilarial load. The microfilaricidal effect of treatment appears to be more long-lasting on the ocular involvement than on dermal involvement. For example, there was 588 and 50t reduction in numbers of microfilariae in the anterior chamber at seven and 12 months post-treatment. After the decline in skin microfilariae observed at seven months after treatment (of che order of 80* of the initial load), the microfilarial count had a tendency to rise again one year later. Thus, one might expect that the improvement in the reversible ocular lesions may persist longer than any effect on transmission. 4.3 OCP (reported by Drs G Y. Dadzie) De Sole, K. Awadzi, J.H. Remme, R.H.A. Baker and Ivermectin has been distributed in eight sites throughout the each with specific epidemiological or disease control characEeristics people (60S of a population of 86 422) were treated with ivermectin, than half of those had already received a second treatment. OCP area, . 49 874 and more There wrs a correlation between the incidence of all recorded reactions to treatment and intensity of infection (with the exception of skin reactions). Adverse reactions did not correlate with dosage of ivermectin. Maximum reactions were recorded on the first day after treatment. Delayed reactions(swelling, abscess) seen at first treatment, were noE seen with retreatment. Several people who had severe hypotension (see report of this Sub- committee from the meeting held on 20 March 1988) after the first treatment were retreated and did not report such a reaction with retreatment. However, a significant number of people experiencing such severe reactions refused treatment on the second occasion. There were cases in the OCP area (and two cases in Malawi) in which administration of ivermectin appeared to precipitate a severe asthma attack in persons with pre-existing asthma. There were tv/o deaths in the OCP trials during the time of ivermectin administration. One occurred at second treatment in a one-year o1d epileptic whose family withheld the history of epilepsy, and a second in a person with pneumococcal meningitis. Neither could be attributed causally to ivermecti-n treatment. Effects of ivermectin on microfilarial counts were documented at 2, 4, L2 and 14 months post-treatment at Asubende -- an area of very high intensity of transmission. Following an initial fal1 in skin microfilariae, there was a major increase in microfilarial counts within L2 months (to over 40t of pretreatment leve1s). Sixteen people with a poor response to first treatment v/ere retreated. Twelve of these had a good response to the second treatment. The effect of i',rermectin treatment in the OCP area on transmission was examined in detail at six out of the eight trials. A substantial reduction(70-75*) in transmission was observed during the first three months after treatment at Asubende. A year 1ater, when vector control was agairr suspended aDR/ OCP / OCTITVERMECTT N/B 9 . 3 page 6 and before the second treatment, transmission returned to 50-50* of the pre-treatment level. This second treatment brought transmission down to a leveI si.milar to that observed after the first treatment. These observed changes in transmission leve1s correspond well with predictions based on observed changes in the microfilarial reservoir in the total human population and on estimates of the infective potential of the human hosts in relation to their microfilarial 1oad. Analysis was complicaced in other trials, either by tinguishable animal onchocerciasis transmission (Mali and control (Bui), differences in vector population dynamics post-ivermectin study Periods (Comoe and Dienkoa), or rapid the microfilarial loads (Dienkoa). Nevertheless, on the Bui mission indices were reduced by 50-70t and on the Dienkoa, reduced by 50-50* and Ll/Lz indices by 20-30*. high and indis- Senegal), vector between pre- and recrudescence in River all trans- L3 indices were Xenodiagnostics have been carried out to examine the relationship between microfilarial load in the skin and the number of infective larvae in the fly, and experiments are under !^/ay to examine the quantitative effect of ivermectin treatment on transmission. These data will be used in computer modelling to predict frequency of treatment required to control transmission in the OCP area. The effect of community-based treatment on ocular onchocerciasis was studied. 376 people were examined pre-treatment, and aE four and 12 months after treatment, and the results compared to a ncn- treated group of 49 ' Numbers of microfilariae in the anterior chamber and corneer decreased by about 80t at four months followed by a slight increase by 12 months Post-treatment. Twelve months after treatment, half the people with early sclerosing keratitis showed resolution, whereas advanced sclerosing keratitis was minimally responsive. Early iridocyclitis was even more responsive over a one-year period. In corltrast, choroidoretinitis showed no significant change. Similarly, ivermectin had no effect on visual acuity. 4.4 Cameroon (reported by Dr J. Prod'hon) Of 11 37L inhabitants of villages between Touboro and Vongna, 7780 were treated. Of these , 5153 received their first treatment with ivermectin, while 2027 received a second dose six months after original treatment. 20* of inhabitants of a hyperendemic zone and 12t from a meso-endemic zone shor^red a I,Iazzotti-type reacJion with first treatment. Only 98 of those treated for a second time showed any adverse reaction. Six months after treatment, there was a greater than 90t rlduction in skin microfilarial counts. In addition, in a ..rb-gro,rp of 1120 people aged 15-35, there was a 33*, 538 and 39t dec?ease in .r.r*f,".r- with punctate keratitis, iritis and optic nerve pa11or, respectively' The number of microfilariae in the anterior chamber fel1 sharply. Two people had hypotension below 100 mm systolic; chis appeared the first day after treatment, was asymptomatic, did not require therapy and resolved before the second day after treatment. The Cameroon study examined effects of treatment on fly infection' There was a 30t reduccion in infective larvae/1000 flies. The Parous rates were virtually the same before and after treatment' 4.4.L Cameroon (reported by Dr R. Moyou) Four villages were selected for a second study in cameroon, conducted in the Rumpi hills forest reserve . L76t of 3092 inhabitants were treated' The geometric mean microfilarial count before treatment was 5.29 (arithmetic mean 140) with a prevalence rate of 93*. Fifty-five Percent of Persons had microfilariae in the anterior chamber , 42* choroidoretinitis, 40t Punctate keratitis, 48 sclerosing keratitis, and 88 optic atrophy. Following treatment, TDR/OCPlOCTlTVERMECTTN/8 9 . 3 Page 7 fever occurred in 13,5t (much more frequently than in Ehe study in the Cameroon savanna) and pruritus in 8.58. Temporary incapacitation occurred in seven people (0.4t) due to Mazzotti-type reaction. Fo11ow-up cIinical, ophthalmo- 1ogical, and parasitological results are pending. 4.5 }lalawi (reported by Dr G. Burnham) This community-based trial in the Thyolo highlands has two main objectives: (1) to assess, in a placebo-control trial, the frequency of adverse reactions to i-vermectin; and (2) to examine the effect of i-vermectin on skin lesions. Registration of subjects corunenced during sulruner 1988 and ivermectin r^ras distributed to 274L people in September. Adverse reactions have been recorded and entered for computer analysis. 50* of people had some reaction, but it will not be known if these were related to the drug until the treatment code is broken. 18* of people had some type of cutaneous swelIing. One L9-year old boy had vesicular, bullous lesions on the forearm requiring steroid therapy. Two asthmatics had exacerbations following ivermectin therapy that responded to aminophylline. Overall, therapy was well tolerated and well accepted. Seventy pre-existing epilepcics were inadvertently treated with no apparent side effects. 4.6 Guatemala (reported by Dr E.W. Cupp) Five villages in Guatemala are under study. Four of these will receive ivermectin and continue to have nodulectomies performed. One village will have nodulectomy on1y. Prevalence of infection ranged from 42 to 80t and geometric mean microfilarial counts from 7.3 to 26.1. Ivermectin was given to 1045 persons in May 1988, and to 1018 in November 1988. In one village' many refused treatment so that coverage was very poor (20t of censused population). One 4O-year old woman with light infection developed headache eight days after treatment, which did not resolve and was associated with diplopia and ataxia; cerebral pseudotumour was diagnosed. Overall, 25.9* of treated Persons developed Mazzotti-type reactions following first treatment, and 9.9t after second treatment. The possible effect of ivermectin treatment on transmisslon 1s being examined. Preliminary evidence suggests a downward trend in Percentage of parous flies with larvae. In Guatemala, resistance to nodulectomy may adwersely influence the ivermectin distribution programme. It may be necessary to dissociate ivermectin treatment from nodulectomy. 4.7 Nigeria (reported by Drs A. Abiose and C. Vajime) The study in Kaduna State involves two areas: Saminaka (east of Kaduna) and Birnin-Gwari (west of Kaduna). Mapping, census, registration and skin snipping started in August 1988. Field teams were trained in ophthalmic and skin examinations during October-November and treatment began in December 1988. Alternate subjects receive ivermectin or placebo, allowing concurrent control for side effects of ivermectin and the effect of ivermectin on oPtic nerve disease. The total population is L2 702, with a total eligible popu- lation over age five of approximately 8000. Prevalence of infection is 41t and 45t in the two areas, with 1.2 and 1.5 microfilariae per mg (geometric mean). In the 34 communities to receive ivermectin, parasite density is 10.9 micro- filariae per snip in persons over 20 years old. Ocular examination will include visual examination by ophthalmic nurses, followed by for people with significant abnormalities. acuity, referral Detailed fields and basic eye to an ophthalmologist ophthalmic examination TDR/oCP /OCTITVERMECTTN/89 . 3 Page 8 will include fluorescein angiography. In addition to those referred, a random sample of 400 persons will receive complete examination. The effect on transmission will be monitored at a site that supports transmission year-round, where preliminary data are available. This is located on Galma River, 5 kn northeast of Kaduna. It is anticipated that this study will form the basis for future national programmes of ivermectin distribution. 4.8 Sierra Leone (reported by Dr J. Whitworth) A double-b1ind, placebo-controlled trial of ivermectin treatment is being undertaken in southern Sierra Leone. The population of L625 had a prevalence of 72* with a density of 4.4 microfilariae per mg skin; 530 received ivermectin and 522 placebo treatment. Some side effects were demonstrated by 23.4* of ivermectin recipients and by 9.8g of placebo recipients ; 4.22 of ivermectin recipients were disabled by side effects compared to 0.9t of placebo subjects. Six months after treatment, microfilarial counts fe11 from 4.6 to 0.8 microfilariae per mg. There was a tendency towards improvement in visual status in the ivermectin recipients when compared to placebo recipients. Six-monthly treatments will continue until March 1990. Seventeen people had no significant response to treatment; this included nine with low microfilarial counts, men as well as women. CONCLUSIONS AND RECOMMENDATIONS 5. SUMMARY: ADVERSE REACTIONS At this point, more than 70 000 people have been treated with iwermectin, many with more than one dose, giving a total of over l2O 000 treatments(Table 1). There are few, if any, drugs at present in use for the treatment of tropical diseases, that have undergone the scrutiny that ivermectin has had. The drug is extremely safe, and is without known pharmacological side-effects in humans. At present dosages, no deaths attributable to i-vermectin have been rePorted. TABLE ]". TOTAL IVERMECTIN TREATMENTS AS OF 27 JANUARY 1989 ocP MaI i Liberia Cameroon Malawi Nigeria Guatemala Sierra Leone Other 85 000 1 800 L6 9L2 9 761 2 74L 425 2 2t3 1 400 I 300 TOTAL 121 5s8 TDR/OCPlOCTlTvERMECTTN/8 9 . 3 Page 9 Treatment of Onchocerca volvulus infection is associated with a mild(Mazzotti-type) reaction in approximately l-0-30t of persons. This occurs within the first 2-3 days in most cases and resolves spontaneously. The major components of this reaction include pruritus, fever, rash, oedema, lymph-node swelling and pain, muscle pain and headache. More severe side-effects have occurred during ivermectin therapy, with a frequency of less than 1 in 1000. These include orthostatic hypotension and asthma attacks (in known asthmatics), both occurring within 36 hours of ingestion of ivermectin. In addition, bullous skin lesions occurring L-2 weeks post-therapy have been observed. 5.1 Exclusion Criteria At present, the following exclusion criteria apply to ivermectin distribution: o Pregnancy (further data forthcoming in the next 1-2 years may render this exclusion unnecessary). . Breastfeeding a child less than three months otd. o Age less than five, or weight less than 15 kg (unless there is a clear indication for therapy). o central nervous system disorders, especially meningitis and trypano- somiasis. Peak prevalence months for meningococcal meningitis should be avoided. ) o Severe concurrent illness 5.2 Monitorrng Although ivermectin appears an extremely safe drug, some of the possible adverse side-effects (e.g. hypotension, asthma) seen in onchocerciasis patients are readily managed with appropriate medical advice and simple treatment. Most cases of hyPotension will resolve with bed rest and oral fluids, and the asthma attacks have responded to aminophylline. Adverse reactions are more commonly seen with heawy infection. Furthermore, the most severe adverse events have occurred after the first dose of ivermectin. Reactions are less common and less severe with retreatment, presumably due to reduced microfilarial 1oads. Therefore, the following recommendations are made for monitoring after ivermectin treatment: With initial treatment, an experienced health-care worker (e.g. nurse or physician) should be readily available within rhe community for at least the first 35 hours following therapy. a The 1evel of monitoring for successive treatment can be determined based on the previous experience in the area. 5.3 Research Priorities Although ivermectin has been thoroughly investigated for use in oncho- cerciasi-s and is suitable for mass administration, certain important questions remain unanswered. These include the following, which have been separated into questions that are necessary for effective mass distribution of ivermectin, and those that are desirable to know, although not essential in the near future. Necessarv o Effect of ivermectin when taken during pregnancy, and with breastfeeding in children less than three months of age. o 'tDR/OCP /OCTIrVER-tIECTTN/89 . 3 page l0 Des irable Optimal drug delivery systems including strategies to optimize acceptability. o a a a a Causes of post-treatment fever and possible relationship to coexistent malaria. Interactions of ivermectin with other commonly used drugs (e.g malarials, compounds interacting with GABA receptors, and ethanol). anti - a a a Effect of coexistent Wuchereria bancrofti infection and implications for ivermectin dosage (note: ivermectin aPPears safe in Loa loa and Mansonella perstans infections) . Safety of ivermectin in children less than five years of age. Safety of ivermectin in persons with epilepsy' Cause of asthma attacks seen following ivermectin, and means of prevention. Lack of apparent antiparasitic effect of ivermectin in some persons, bioavailability and pharmacokinetics in various grouPs and effect of food intake. General health effect of ivermectin treatment of onchocerciasis. 6. SUMMARY: EFFECT OF IVERMECTIN ON MICROFIIARIAL LOADS AND TRANSMISSION 6.1 The Effect on Microfilarial Loads Immediate dramatic reductions in skin microfilarial loads in Patients were observed in all cases, but the repopulation dynamics in at least three of the comrnunity trials were faster than in the clinical trials (see Table 2) - This was observed at six and especially 12 months after ivermectin delivery. There were indications that the rate of microfilarial repopulation \^7as influenced by the intensity of transmission and vras more marked where the infection was recrudescing. As a result, the frequency of ivermectin delivery may have to be examined in certain areas. Recommendation Taking into account the increases in skin and ocular micofilarial loads with time since treatment, and the need to determine the optimal interval between drug deliveries in different areas, all trials should report uniformly on the dynamics of repopulation using standard age cohorts, as far as possible, both at six and 12 months after ivermectin treatment' 6.2 Transmission Results from 10 detailed sLudies \./ere available of the effect of ivermectin on vector transmission. Five different studies (Asubende in Ghana, Dienkoa in Burkina Faso, Guatemala, northern and western Cameroon) support the conclusion that community-based ivermectin treatment has reduced transmission' The maximum likely effect was that observed at Asubende with 70-75t reduction for the first thrle months after treatment in two consecutive years' However, TDR/OCP /OCTITVERMECTTN/89 . 3 Page 1t TABLE 2 TREND IN GEOMETRIC MEAN MICROFIIARIAL LOAD AFTER IVERMECTIN TREATMENT IN DIFFEP.ENT COMMUNITY TRIALS Study Area Age cohort Percentage of pre-treatment mean 4 months 6 months l-2 months \ Liberia Mali Asubende A11 ages Adults A11 ages Adults A11 ages Adults 25.0 27.0 2L.O ls .0 33.0 2L.O 43.0 30.0 7.O 4.5 Dienkoa A11 ages Adults Milo A11 ages Adults Cameroon A11 ages Adults Guatemala Cross-sectional data for 3 villages L7 .O Sierra Leone A11 ages t_8 .0 the transmission potential was stil1 over 10 times the tolerable }eve1. Accurate estimates of transmission reduction were frequently difficult to make due to the presence of indistinguishable animal Onchocerca, differences in the vector population dynamics before and after treatment, and vectbr invasion. Population coverage with ivernectin was also critical. At Asubende, there was a good relationship between transmission reduction and the change in microfilarial densities in the human population, but a poor relationship with disease prevalence. The ewidence is not yet sufficient to define optimal strategies for transmission control. The long-term impact of ivermectin on transmission is as yet uncertain. It is c1ear, however, that the best strategy to be adopted will depend on the objectives of the control prograrnme. Any attempt to control transmission v{ith ivermectin will require far greater resources and much more time than a Programme designed only to alleviate the ocular and skin manifes- tations of the disease. Recommendations Several additional studies are likely to yield good results during 1989 and, to facilitate comparisons, the following entomological transmission indices should be provided as standard: period of sampling, number of days collection, numbers of flies caught, numbers dissected, numbers parous, the MBR, MTP, number of flies with each parasite stage per 1000 parous and the number of each parasite stage per 1000 parous. The L1 and L2 data can be 0 0 33 2L 9.0 4.0 7.O 4.5 TDR/ OCP / OCTITVERMECTTN/8 9 . 3 Page L2 lumped together but head and body L3s should be distinguished in the calculations. l{here infection rates (especially L3 rates) are low or where vector populations are subject to substantial variations in parous rate, flies should be stained with Mayers Acid Haemalum to maximize the detection of L1s and L2s. Future studies of the effect of ivermectin on transmission should include accurate quantitative assessments of transmission reduction which can be related to the change in the microfilarial reservoir of the human population. Monitoring changing incidences in children may give an indirect measure of transmission reduction and should be included wherever appropriate. 5.3 Research Priorities It is virtually impossible by entomological methods to assess the impact of ivermectin on transmission in areas where animal Onchocerca are transmitted by human onchocerciasis vectors, because many species are morphologically indistinguishable. New molecular identification techniques should now be applied to field studies to assist identification. In order to predict the long-term impact of ivermectin delivery on microfilarial loads and transmission, mathematical models should be constructed and tested against the trial data. SUMMARY: IVERMECTIN AND ITS IMPACT ON MORBIDITY AND THE PREVENT]ON OF MORBIDITY IN ONCHOCERCIASlS Morbidity in onchocerciasis is usually a cumulative effect of the parasite and of parasite death in the eye, skin and elsewhere. Though morbidity may be associated with acute manifestations such as itching, the most severe effects such as poor vision, blindness and gross skin pathology, evolve over a period of many years. Monitoring the impact of ivermectin on morbidity therefore requires assessment of skin and ocular pathology before, soon after, and for many years after ivermectin administration. The prevention of morbidity will require the monitoring of new lesions or s)rmptoms that are associated with it. Data from Phase II and III trials provide compelling evidence that ivermectin treatment will ameliorate reversible onchocercal ocular disease. Preliminary results from the Phase IV community-based trials, though uncon- trolled, indicate improvement in reversible ocular and skin lesions. However, the data presented so far from the community-based studies do not yet provide sufficient detailed evidence on which to base firm conclusions on the effect of ivermectin on morbidity. This is either because the studies vrere not designed to address this question or because the fo1low-up has not proceeded long enough. Indirect evidence from the elimination of most of the skin and ocular microfilariae following single or repeated doses without any serious reactions clearly suggests that a beneficial effect on lesions and morbidity will be achieved. Ongoing studies, especially the placebo-controlled studies, which arre designed to investigate the impact of ivermectin on morbidity, should be encouraged to do this critically. The OCP studies, which include an ophthalmological monitoring element, will permit comparison of the effects of ivermectin treatment with information accumulated from areas with and without vector control. It is probably not necessary to design any further placebo-controlled studies to investigate this aspect. I 7 t7.1 TDR/OCP /OCTITVERMECTTN/89 . 3 page 13 Features that Contribute to Morbiditv in Onchocerciasis, and Their Monitorins Skin (Acute) itching papules pustules infection (Chronic) lichenification atrophy hanging groin Ocular intraocular microfilariae sclerosing keratitis iridocycl itis choro idoretinitis optic nerve disease defective ocular function, including blindness 7.2 Assessment of Impact on Morbidity 7 .2.L Skin manifestations Itching is a major cause of morbidity in onchocerciasis and any drug that can offer relief is of substantial benefit. Although severe manifestations canbe dramatic, lesser grades of itching are difficult to assess. To d.etermine the impact of ivermectin on this symptom, it will be necessary to conduct a simple survey before and at intervals after treatment. Monitoring of lesions may include records such diagrams. It is expected that acute lesions such aspustules will improve while chronic lesions such as and hanging groin may not show any change. as serial photographs or papules, excoriations and lichenification, atrophy 7 .2 . 2 Ocular lesions It is essential to monitor eye lesions before and ivermectin on a long-term basis in sorne studies, both for the occurrence of nehr ones. after treatment with existing lesions and As noted above, some of the OCP studies and other studies of the community-based distribution of ivermectin have shown a trend for regression in the anterior segment lesions within one year of treatment. These findings are consistent with the ocular findings of the controlled clinical trials. However, it will be necessary to monitor eye lesions and intraocular micro-filariae over longer periods using standardized methods, and giving due consideration to the factors of intra- and inter-observer variations. Such techniques as fundus photography and fluorescein angiography may be used to demonstrate changes which may occur in lesions of the posterior segment of the eye. Where specialized facilities are unavailable, function such as the visual acuity test need to be lar1y the incidence of blindness should be monitored. long-term tests of ocular carried out, and particu- 7.2.3 Improvement in general health As part of the general improvement in health microfilariae, it would be useful to monitor general height, especially in the younger generation and also age. due to the elimination of health such as weight and in women of child-bearing it TDR/ OCP / OCTIIVERMECT rN/8 9 . 3 page L4 7.2.4 The role of the primary health care worker in monitoring the impact on morbidity It is envisaged that ivermectin could be distributed and monitored by the physician, assistant nurses and primary health care workers. It would be useful to train personnel to recognize and record simple skin manifestations such as itching, papules and excoriations, and to determine visual acuity and assess the presence of blindness both at the initial stage and on a long-term basis. 7 .3 Research Priorities Although data are available upon which one can devise rational regimens for dosing r+ith ivermectin, many questions remain unanswered that may be necessary for optimal mass distribution to various populations with different patterns of intensity of infection, disease manifestations, primary health care systems, etc. Therefore, for optimal control of morbidity, research will be necessary in two major areas: (1) retreatment frequency, and (2) operational aspects of distribution. While these questions may be outside the mandate of this subcommittee, they will have to be addressed by those who propose to undertake mass distribution. 7 .3.L What is the optimal retreatment interval for each particular endemic focus? The interval may vary with level of endemieity. In some cases, yearly retreatment may be unnecessary and may not be cost-effective, while in others, twice-yearly treatment may be necessary for control of morbidity, The answer to these questions may require large-scale studies in the context of national control programmes. r- .3.2 In situations in which only some communities are at risk of onchocer- ciasis morbidity, how are those communities to be most cost-effectively identified? Are there simple ways to find such communities (e.g.surveys of skin signs or blindness)? Are parasite studies necessary and, if so, how are they best done? 7 .3.3 What is the most cost-effective method of delivering ivermectin to communities at risk of onchocerciasis morbidity? How should delivery be incorporated into primary health care? Should community mobilization for treatment be stimulated through schemes such as "national treatment days", as has been done successfully for child immunizations in some countries? Should delivery be through a "vertical" or "horizontal" organization? 1.3.4 trrlhat are the most cost-effective means to motivate communities for treatment with ivermecti-n and to ensure high compliance? What are the factors associated with non-compliance and how can these be overcome most effectively? 7 .3.5 What is the economic and social i-mpact of ivermectin mass therapy? Control of the morbidity associated with onchocerciasis will have both social and economic impacts (e.g. repopulation of endemic areas , elimination or reduction of onchocercal blindness with associated social and economic effects). Studies should be conducted to assess the nature and magnitude of such effects in order to evaluate the overall consequences of community-based distribution of ivermectin. 8. PARTICIPANTS Principal lnvestigators (other than OCP) ABIOSE,DT A., Guinness Ophthalmic Unit, Institute of Health, Ahmadu Bello University, P.M.B. 2016, Kaduna, Nigeria I t tTDR/ OCP / OCTITVERMECTTN/8 9 . 3 page 15 BURNHAM, Dr G., Malamulo Hospital, p.O. Makwasa, Malawi CUPP, Dr 8.W., Department of Entomology, College of Agriculture, The University of Arizona, Tucson, Arizona 85721, USA MOYOU OCHOA , Dr o., Division of Onchocerciasis, Ministry of pubrlc Health and socialAssistance, Direccion Generar de services de salud, 5A-Av. 11-40, zona11, Guatemala City, Guatemala oKoNKIno, Dr. P., Department of phamarcology and rherapeutics, college ofMedicine, University of Nigeria, Enugu Campus, Enugu, Nigeria PROD'HON, Dr J., Centre Pasteur, B.p. L274, yaound6, Cameroon soul^A, Dr G., Dept. d'Epid6miologie des Affections parasitaires EcoleNationare de M6decine et de pharmacie du Mali, B.p. 1g05, Bamako, Mali TAYLOR, Dr H., rnternational center for Epidemiorogic and preventiveOphthalmology, The Wilmer Institure, 500 worth Wolfe Street, Balrimore,Maryland 21205, USA VAJIME, Dr C., Department of Biological Sciences, Zaria, Kaduna State, Nigeria Ahmadu Bello University WHITE, Dr A., DePartment of Medicine, Case llestern Reserve and UniversityHospirals, Cleveland, Ohio 4410G, USA WHrTIJORTH, Dr J., The MRC Laboratory, p.o. Box gl-, Bo, sierra Leone OCP SAMBA, Dr E.M., Direcror, WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso AwADzr, Dr K., Director, ocRc, Hohoe Hospital, p.o. Box 144, Hohoe, Ghana BAKER, Dr R.H.A., WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso DADZIE, Dr Y., IJHO/OCP, B.p. 549, 0uagadougou, Burkina Faso DE SOLE, Dr G., WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso PHILIPPON, Dr B., WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso REMME, Dr J.H., WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso SOUMBEY, l,l.r A.E., WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso ZERBO, Mr c., WHO/OCP, B.p. 549, Ouagadougou, Burkina Faso Members of the Subcommittee FERNEX, Professor M., p.O. Box 158, 411_g Rodersdorf, Swirzerland GILLES, Professor H.M., Liverpool School of Tropical Medicirre, pembroke placeLiverpool, L3 5QA, England GREENE, Professor B.M., Director, Division of Geographic Medicine, Department of Medicine, University of Alabama at sirmingham, University Station,Birmingham, Alabama 35294, USA (Rapporteur) Dr R., Medical Research Station, Box 55, Kumba, Cameroon TDR/ OCP / OCTITVERMECTT N/8 9 . 3 Page 15 SMITH, Dr P., Head, Tropical Epidemiology Unit, London School of Hygiene and Tropical Medicine, Keppel Street (Gower Street), London WC1E 7HT, England I{ILLIAI,IS, Professor J., NIH-Sudan Medical Parasitology Research Project, Michigan State University, A.327 East Fee Hall, East Lanssing, Michigan 48824-L3L4, USA (Chairman) WHO Secretariat BRABIN, Dr L., WHO/TDR, Geneva GINCER, Dr C.D., WHO/OCT, Geneva RA],IACHANDRAN, Dr C.P., I"IHOITDR, Geneva RANQUE, Dr P., WHO/PDP, Geneva WURAPA, Dr F., I^rHOIAFRO Merck Sharp & Dohme BROWN, Dr K., Group Director, Clinical Research, Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., lJest Point, Pennsylvania 19486, USA NEU Clinical Research, Merck Sharp & Dohme Research Laboratories, Box 2000, Rahway, New Jersey 07055-0900, USA Observer MORGAN, Dr D., c/o Dr l"Ihitworth, The MRC Laboratory, P.O. Box 81, Bo Sierra Leone DrD P.O I