TRANSACTIONS OF THE ROYAL SOCIETY or TROPICAL MEDICINE AND HYGIENE (1992) 86, 537-540 537

Mass chemoprophylaxis of lymphatic filariasis with a single dose of ivermectin in a Polynesian community with a high Wuchereria bancrofiiinfection rate

J.-L. Cartel, N. L. Nguyen, J.-P. Moulia-Pelat, R. Plichart, P. M. V. Martin and A. Spiegel Institut Territorial de Recherches Medicales Louis Malard&, BP. 30, Papeete, Tahiti, Polynbie Francaise

Abstract In April 1991 supervised mass prophylaxis of lymphatic lilariasis with a single dose of ivermectin, 100 yg/kg, was carried out in a Polynesian village with a high infection rate of Wuchereria bancrofti in hu- mans and active transmission by the vector mosquito, Aedes polynesiensis. Of 876 inhabitants aged 3 years or more (pregnant women excluded), 864 (98.6%) were treated. Simultaneously, venous blood samples were collected from 577 (97.5%) of the 595 inhabitants aged 15 years or more, of whom 122 (21~4%) were found to be microtilaria (ml) carriers (86 males and 36 females). The geometric mean microfilariae (GMM) count was 358.7 mf/ml for the whole group, 387 mfiml for males (range l-8160 r&ml) and 280 mfiml for fe- males (range l-7769 mfiml). Following treatment, 33 (3.8%) of the 864 persons treated experienced some adverse reactions (21 with grade 1 and 12 with grade 2). Of the 33 with reactions, 29 were among the 122 (23.8%) mf carriers and 4 among the 831 (0.5%) non-microfilaraemic persons. Six months later, 123 (21.1%) of 584 inhabitants sampled were microfilaraemic: the GMM count for the whole group was 106 mfiml (l- 8177), with 29 mfiml (l-3740) in 35 female and 177 mf/ml (l-8177) in 88 male carriers. Of these 123, 15 (whose GMM count was 4.5 mfiml; range l-204) were amicrofilaraemic 6 months before, and 19 had a microfilaraemia level higher than that 6 months earlier, before treatment. 117 of the 122 carriers identified in April were resampled: comparison of their GMM counts before and 6 months after mass treatment indi- cated that treatment with a single dose of 100 pgikg ivermectin resulted in a reduction of microfilaraemia by 69%.

Introduction In French Polynesia, where lymphatic filariasis is due

to subperiodic Wuchereria bancrofti var. pacifica trans- mitted by the vector mosquito Aedespolynesiensis, several therapeutic trials on the efficacy and safety of single doses of ivermectin for treatment of microfilariae (mf) carriers were conducted between 1986 and 1991. The re- sults of those trials indicated that a single dose of 100 kg/kg of ivermectin was effective in reducing W. bancrofti microtilaraemia (CARTEL et al., 1990), and it was more effective when given twice-yearly than yearly (CARTEL et al.. 1991). Therefore. in 1991, a mass chemo- prophylaxis programme with single doses of 100 ug/kg of ivermectin administered twice-yearly was im- plemented in a village on an island near Tahiti, where both the mf carrier prevalence and transmission rate by the mosquito vector were known to be high (CARTEL et al., 1992). The aim of this paper is to report on the safety and acceptability of the first mass treatment and its effi- cacy evaluated by comparison of microfilaraemia pre- valence and levels in the population before, and 6 months after, treatment.

Materials and Methods In early 1991, a pre-trial study was carried out in the

coastal village of Opoa on one of the Leeward islands, near Tahiti. A team of one physician and one health worker visited each house of the village in order to up- date the 1988 census, to establish a house-by-house com- puterized list of inhabitants, to draw a map indicating the location of each house, and to collect venous blood samnles for further determination of microfilaraemia and evaluation of the mf carrier prevalence.

Two months later (April 1991), 2 teams, each with one physician and one health worker, visited every house of the village daily between 16:00 and 20:00 during 3 weeks. All inhabitants aged 3 years of more were identi- fied according to the pre-established computerized list in which were indicated the identification number of the house, and that of each person in the house, along with their names, sex and date of birth. They were then weighed and treated with a single dose of 100 ug/kg of ivermectin. Simultaneously, venous blood samples were collected from all treated persons aged 15 years or more and sent every day to the Institut Malarde in Tahiti, where 1 ml of blood was filtered through a nuclepore membrane which was then stained by the Giemsa method for counting mf (DESOWITZ et al., 1973). During

the preceding week, urine samples had been collected from all female inhabitants aged 14 to 50 years for deter- mination of pregnancy (HCG rapid test, Pasteur Diag- nostic); all pregnant women were excluded from the trial. Each morning following treatment, the ‘treated houses were visited for evaluation of side effects which were graded according to intensity: 1, mild to moderate (easily tolerated, does not interfere with daily activities) and 2, severe (subject unable to perform usual activities). Six months later (October 1991), mass treatment and blood collection were performed again using the same methods.

Pearson’s x2 test and analysis of variance were used to evaluate the efficacy of treatment (by comparison of ge- ometric mean microfilaraemia before and 6 months after treatment) and the correlation between adverse reactions and pretreatment microtilaraemia levels (SCHWARTZ, 1981).

Results At the time of the first mass treatment (April 1991),

the population of the village included 935 inhabitants liv- ing in 146 houses. Of these 935 (440 females and 495 males), 17 pregnant women, 41 children less than 3 years of age, and one person already participating in another therapeutic study were excluded from the trial. Thus, the population eligible for treatment was 876 persons of whom 864 (98.6%) were effectively treated. Of the 12 un- treated persons, 4 refused to accept treatment (2 males and 2 females) and 8 were temporarily out of the. village. Venous blood samnles were collected from 577 (97.5%) of the 595 inhabitants aged 15 years or more, of whom

Table 1. Adverse reactions according to pretreatment microlilaraemia levels in 864 inhabitants of a Polynesian village treated with a single dose of 100 &kg of ivermectin

ReaCtiOtl grade

Persons with adverse reaction Total Males Females

NO. mflml” NO. mflml” NO. mfiml”

0 830 (ts8160) . 441 $8160) 389 (&6:64) 1 21 723 14 707 7 756

(CL7616) (CL7616) (C-6954) 2 12 1785 6 795 6 4009

(O-7769) (O-7344) (748-7769)

‘Median number of microfilariae per ml (range in parentheses).

538

122 (21.4%) were found to be mf carriers (36 females and 86 males). The geometric mean microfilariae (GMM) count for the whole group was 358.7 mfiml; 387 mfiml (range l-8160) in the 86 males and 280 mfiml (range l- 776g) in the 36 females. Adverse reactions were bbs&ved in 33 (3.8%) of the 864 treated persons: grade 1 in 21 oersons and grade 2 in 12 others (Table 1). None of the Reactions wacconsidered serious; they disappeared in 6- 36 h, either spontaneously or after treatment with paracetamol when required. Asthenia (28 cases), fever 337.5”C (24 cases), myalgia (23 cases), headache (21 cases), arthralgia (20 cases), anorexia (17 cases), and chills (7 cases) were the most common symptoms and signs. Of the 33 patients with reactions, 29 were among the 122 (23.8%) with microfilaraemia and 4 among the 831 (0.5%) non-microfilaraemic inhabitants. In the latter 4 persons; adverse reactions were grade 1 in 3 cases (mainlv headache and asthenia) and grade 2 in the fourth case, whose reaction consisted’only if marked headache. In microfilaraemic persons, the intensity of reaction was correlated (ZVO.05) with the pre-treatment microfilarae- mia.

Six months later (October 1991), 949 persons (505 males and 444 females) were living in the village, of whom 603 were aeed 15 vears or more. Of the latter. 584 (96.8%) permittid venous blood collection and’ 123 (2 1.1%) were microfilaraemic; the GMM count for the 123 carriers was 106 mfiml (range l-8177), with 29 mfiml (range I-3740) in 35 females and 177 mfiml (range 1-8177) in 88 males. Of these 123 microtilaraemic persons, 15 (whose GMM count was 3.5 mfiml; range l- 476 mfiml) were amicrofilaraemic 6 months earlier. In 19 others,‘the GMM count was 221 mf/ml (range 5- 8177), higher than the 122 mfiml (range l-8160) ob- served 6 months earlier in the same persons, before treat- ment. Finally, of the 122 microtilaraemic persons identified in April 1991, 117 were blood sampled again, and 15 (whose GMM count was 4.5 mfiml; range l-204) were amicrofilaraemic 6 months after treatment. The GMM count for the whole group was 112.7 mfiml

raemia, which was nearly twice as high in male as in fe- male mf carriers. However, when 28 male and 28 female mf carriers were matched as to pretreatment microfila- raemia levels (Table 3), the reduction in females was not significantly different (P>O.O5) from that in males.

Discussion A reduction of microfilaraemia density of about 70%

(whether considering the whole microfilaraemic popula- tion or only the group of carriers examined before and after treatment), 6 months after a single dose of 100 pg/kg of ivermectin, may be considered an excellent result, consistent with those previously reported in small groups of carriers participating in controlled studies either in French Polynesia (CARTEL et al., 1990, 1991) or in other countries (KUMARASWAMI et al., 1988; OTTESEN et al., 1990). In those studies, amongst carriers treated with a sinale dose of ivermectin (at different dosages), the reduction of microfilaraemia‘ at 6 months ranged from 60 to 90%. Better results, in terms of sustained re- duction of microfilaraemia at 6 months and even at one year, have been recently reported in small groups of Hai- tian carriers (RICHARDS et al., 1991) treated with high doses of ivermectin (200-400 pgikg); but in these latter studies all carriers were first given a 1 mg dose of iver- mectin and, 5 d afterwards, a second, higher dose. Un- fortunately, such a strategy is not likely to be easily ac- cepted for mass treatments, given its evident lack of logistical simplicity. With respect to efficacy, 3 more facts should be emphasized. Firstly, no decrease in mf carrier prevalence rate was observed 6 months after mass treatment, a finding which indicates that prevalence rate should be used as an indicator of efficacy only after sev- eral treatments have been administered. Secondly, even though the difference was not significant, the reduction of microfilaraemia seemed to be higher in female than in male carriers; further results from our programme will permit assessment of the validity of that finding. Thirdly, 6 months after treatment, microfilaraemia was higher m 34 carriers of whom 15 had been amicrofila-

Table 2. Development of microfilaraemia levels in 117 Wuchereria bancrofti carriers sampled before and after mass treatment with a single dose of 100 pg/kg of ivermectin

Age group (years) and sex Carriers

Microfilaraemia”

Before treatment Six months after treatment

15-29 Male Female Total

30-49 Male ;; (q 665.5 (l-8160) Female 185.4 (l-6954) Total 39 (33I3$) 464.1 (l-8160)

1 -9 k e 31 (26.5%) 507.9 (2-7616) Female 19 (16.2%) 599.4 (5-7769) Total 50 (42.7%) 540.1 (2-7769)

Total Male 83 (70.9%) 400 (l-8 160) qemale 34 (29.1%) 275 (l-7769) ..‘otal 117 (100%) 358.7 (l-8160)

aGeometric mean number of microfilariae per ml (range in parentheses).

66.3 (O-4233) 14.5 (O-374) 53.4 (O-4233)

225.4 (O-8177) 17.2 (o-8177)

109.1 (0.8177)

255.9 (o-5610) 94.9 (o-3740)

175.5 (o-5610)

166 (O-8177) 44 (o-3740)

112.7 (CL8177)

(Table 2), significantly lower (EYO.05) than that of raemic 6 months earlier. This result is difficult to inter- 358 mfiml before treatment. The reduction of microtila- pret; a possible explanation could be the subperiodicity raemia evaluated on the comparison of these 2 GMM counts was 69% for the whole group. The GMM count

of W. buncrofti var. pucificu (ROSEN, 1955), which leads

was 44 mf/ml for females, significantly lower (P<O.O5) to the speculation that mf might have been detected, and

than that of 166 mfiml for males. The reduction of mf levels might have been higher, in several persons if

microfilaraemia was also significantly greater (P<O.O5) blood had been collected some hours or days earlier or

in females (84%) than in males (58.5%). This difference later. Whatever the explanation, the evolution of micro- filaraemia after a second treatment will have to be care-

was possibly due to the elevated pretreatment microfila- fully followed in these carriers.

539

Table 3. Microfilaraemia levels and corresponding reduction percentages 6 months after mass treatment with a single dose of 100 @kg of ivermectin in 56 Wuchereria bancrofti carriers, matched as to pretreatment microfilaraemia

Age group (years) and sex

15-19 Male Female

30-49 Male Female

No. of carriers

%

ii

Before treatment

18 (l-204) 20 (1-221)

116.6 (l-5987) 113.8 (l-5304)

Microfilaraemia” Six months

after treatment

3.8 (O-221) 14.5 (O-374)

35.7 (O-272) 22.6 (O-935)

Percentage reductionb

78.9 27.5

69.4 80.2

350 Male Female

Total Male Female

16 6566 (4-7616) 301 (o-5610) 46.8 16 600.9 (5-7769) 153.1 (o-3740) 74,5

220.2 (1-7616) 87.6 (o-5610) 60.2 229.7 (l-7769) 63.3 (O-3740) 72.5

aGeometric mean number of microfilaria per ml (range in parentheses). bPercentage reduction in microfilaraemia.

The percentage of carriers who experienced some ad- verse reactions (23%) was much lower than that usually observed in controlled therapeutic trials previously car- ried out in French Polynesia (CARTEL et al., 1990, 1991) or in other countries (KUMARASWAMI et al., 1988; SABRY et al., 1991). It must be kept in mind that this was a mass treatment, the first carried out on lymphatic filariasis using a single dose of ivermectin, and that an unknown number of treated persons with mild-to-moderate reac- tions most probably did not pay attention to side effects, carried on with their usual activities (fishing, working in coconut plantations, etc.) and were not at home when as- sessment of adverse reactions was carried out following treatment. Therefore, it is likely that adverse reactions were underestimated. In mass treatment campaigns? it is important to know the percentage of persons who ~111 ac- tually complain of reactions, and, far more important, the percentage of persons unable to perform their usual activities. In the present trial, they were 1.4 and 2.4% re- spectively; such low rates indicate that filariasis control programmes based on repeated administration of single doses of ivermectin should be very well tolerated. Finally, only 0.5% of non-microfilaraernic treated per- sons complained of any reaction, a percentage much lower than the 33% observed in non-microfilaraemic persons treated with single doses of diethylcarbamazine (DEC) (KIMURA et al., 1985).

With respect to acceptability, a rate of 0.5% who were definitely reluctant to accept treatment, and a total of 1.4% who could be neither found nor treated, may be considered very low. This suggests that a lymphatic fila- riasis control strategy based on the regular intake of a single treatment dose could be very popular, as reported previously by WIJERS (1988) in a Kenyan population treated with twice-yearly doses of 6 mgikg of DEC.

From our findings, it may be concluded that mass pro- phylactic treatment of W. bancrofti filariasis with a single dose of 100 pgikg of ivermectin has been shown to be safe and well accepted, and to result, after 6 months, in a significant reduction of microfilaraemia levels in the treated population. The results of a planned subsequent twice-yearly single dose treatment study should permit determination of whether such a strategy can reduce microfilaraemia to a level sufficiently low for trans- mission by the vector, A. polynesiensis, to be interrupted.

Acknowledgements This study received financial support from the UNDP/World

Bank/WHO Special Programme for Research and Training in

Tropical Diseases (TDR) and from Oeuvres Hospital&es Fran- qaises de 1’Ordre de Malte (France).

The drugs used in the trial were provided by Merck Sharp & Dohme (BP 62,78170 La Celle Saint-Cloud, France).

References Cartel, J.-L., Sechan, Y., Boutin, J.-P., Celerier, Ph., Plichart,

R. & Roux, J.-F. (1990). Ivermectin for treatment of bancrof- tian filariasis in French Polynesia: efficacy in man, effect on transmission by vector Aedes polynesiensis. Tropical Medicine and Parasitology, 41,241-244.

Cartel, J.-L., Spiegel, A., Nguyel, L., Martin, P. M. V., Gen- elle, B. & Roux, J.-F. (1991). Smgle versus repeated doses of ivermectin and diethvlcarbamazine for treatment of Wuchere- ria bancrofti var. paci$ca microfilaremia. Results at 12 months of a double-blind study. Tropical Medicine and Parasitology, 42,335-338.

Cartel, J.-L., Nguyen, N. L., Spiegel, A., Moulia-Pelat, J.-P., Plichart, R., Martin, I’. M. V., Manuellan, A. B. & Lardeux, F. (1992). Wuchereria bancrofti infection in human and mos- quito populations of a Polynesian village ten years after inter- ruption of mass chemoprophylaxis with diethylcarbamazine. Transactions of the Royal Society of Tropical Medicine and Hy- giene, 86, 414416.

Desowitz, R. S., Southgate, B. A. & Mataika, J. U. (1973). Study on filariasis in the Pacific. 3. Comparative efficacy of the stained blood-film, counting chamber and membrane fil- tration technique for the diagnosis of Wuchereria bancrofti microfilaraemia in untreated patients in areas of low ende- micity. Southeast AsianJournal of Tropical Medicine and Public Health, 4, 32%355.

Kimura, E., Penaia, L. & Spears, G. F. S. (1985). The efficacy of annual single-dose treatment with diethylcarbarnazine ci- trate against diurnally subperiodic bancroftian filariasis in Samoa. Bulletin of the World Health Organization, 63, 1097- 1106.

Kumaraswami, V:, Ottesen, E. A., Vijayasekara, V., Uma Devi, S., Swammathan, M. D., Aziz, M. A., Sarma, G. R., Prabhakar, R. & Tripathy, S. I’. (1988). Ivermectin for the treatment of Wuchereria bancrofti filariasis. Journal of the AmericanMedicalAssociation, 259,3150-3153.

Ottesen, E. A., Vijayasekara, V., Kumaraswami, V., Perumal Pillai, S. V., Sadanandam, M. A., Frederick, B. S,., Prabha- kar, R. & Tripathy, S. I’. (1990). A controlled trial of iver- mectin and diethylcarbamazine in lymphatic filariasis. Neu~ EnglandJournal of Medicine, 322, 1113-l 117.

Richards, F. O., jr, Eberhard, M. L., Bryan, R. T., McNeeley, D. F., Lanunie, P. J., McNeeley, M. B., Bernard, Y., Hightower, A. W. & Spencer, H. C. (1991). Comparison of high dose ivermectin and diethylcarbamazine for activity against bancroftian filariasis in Haiti. American 3ourmzl of Tropical Medicine and Hygiene, 44,3-10.

Rosen, L. (1955). Observations on the epidemiology of human tilariasis in French Oceania. AmericanJournal of Hygiene, 61, 219-284.

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Sabry, M., Gamal, H., El-Masry, N. & Kilpatrick, M. E. (1991). A placebo-controlled double-blind trial for the treat- ment of Bancroftian filariasis with ivermectin or dietbylcarba- mazine. Transactions of the Royal Society of Tropical Medicine and Hygiene, 85,640-643.

Schwartz, D. (1981). MCthodes Statistiques b PUsage des MJdecins et Biologistes, 3rd edition. Paris: Flammarion MCdecine Sciences.

Wijers, D. J. B:, Kaleli, N. & Ngindu, A. H. (1988). Di- etbylcarbamazme prophylaxis against bancroftian filariasis given by a member of the local community in Kenya. AnnaZs of Tropical Medicine and Parasitology, 82,411-412.

Received 16 January 1992; accepted for publication 31 March I992

TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1992) 86, 54C-541

A comparison of helminth infections in urban and rural areas of Addis Ababa

I. de Carneril, L. Di Matte01 and Shibru Tedlaz ‘Department of Preventive, Occupational and Community Medicine, University of Pavia, Italy; Vnstitute of Pathobiology, University of Addis Ababa, Ethiopia

Ethiopia, together with Eritrea, measures 1 251 282 km2 and lies between latitudes 3” and 18”N and longitudes 33” and 48”E. By mid-1990 it had 50.9 million inhabitants living between 100 m below sea level and at over 4000 m altitude in the mountains. With its broad variety of climate, and the general poverty of its inhabitants, this area appears tailor-made for studies on human hehnin- thology (ZEIN & KLOOS, 1988).

Worms are the main reason (TEKA, 1984), or the sec- ond one (TEDLA, 1989), why the people seek medical aid, and traditionally each village has its ‘kousso woman’ who uses herbal remedies for Taenia saginata infections. 89% of the population live in the countryside, but the population of Addis Ababa is rising at a rate of 4% a year, compared to 29% in the rest of the country. Be- tween November and January 1991 we started a study in Addis Ababa and its surroundings. From our experience in Italy since 1962 (see DE CARNERI, lVVO), we expected that in a homogeneous endemic area both the prevalence and the worm burden of geohehninthiases would be in- versely proportional to the socio-economic standard. Addis Ababa (2408 m above sea level) now officially has 1 917 900 inhabitants. We examined schoolchildren, mostly aged V-10 years, in 3 different parts of the city. Kolfe is a poor district on the western fringe of the city, built on red clay, with 13 583 inhabitants of various na- tionalities, mostly Christians, 2186 of them schoolchild- ren. Most of the inhabitants gave their occupation as ‘street merchants’, a euphemism that in most cases might be translated as ‘no specific profession’. Their homes are huts, with sanitary facilities consisting of defaecation fields between the houses. We examined 75 children aged V-10 years arid 9 aged eight years (total 84), attend- ing the local public school (public schools are at the same level as government schools and are set up when the gov- ernment schools have no room for all the children of a given borough). Kechene is a northern borough! again on red earth, with 8500 inhabitants, mostly Christians. Economica.lly it is one step up the scale from Kolfe. Many of the inhabitants are weavers, but there are also numerous ‘merchants’, as before. Excreta disposal is still based on defaecation fields. We examined 84 children aged V-10 years, from a public school. Bole is another suburb, built on volcanic black earth, to the south near the airport. It has 11 000 inhabitants of mixed nation- alities, mostly Christians, living in small, well-kept houses, each with a water closet, built 25 years ago by an American Company for government employees. We examined 84 children aged V-10 years, from a public school. In the countryside 30 km west of Addis Ababa,

at 2580 m above sea level on the road to Addis Alem, Menagesha is a village with about 3000 inhibitants, Christians of Amhara origin, mostly merchants, some government employees and a few farmers. We examined 87 children from the local government schools; 13 of them came from a small farming settlement, Kolobo, 500 m away. Collection of faecal samples and data was greatly facilitated by the co-operation of teachers and the children themselves. Examinations of faeces (Kato method on 20 mg and Ridley formol-ether sedimenta- tion on 1 g) were done, after storage at 4°C for not more than 48 h, at the Institute of Pathobiology in Addis Ababa.

The results showed that in Addis Ababa and its sur- rounding boroughs ascariasis was the main problem (Fig. 1). At Kolfe the prevalence was 83%. One-quarter of the

children had between 20 000 and 368 500 eggs/g. At Ke- chene (68% prevalence), 15% had between 20 000 and 60 000 eggs/g. In the more modern Bole borough (18% pre- valence), only 2 children had 20 000 and 45 000 eggs/g re- spectively. All the differences between pughs were highly significant (e.g., for pre_vglence, x =79.988; de- grees of freedom (df)=2; P<lO ).

In the village of Menagesha (59% prevalence), 9.2% of the children had between 20 000 and 168 500 eggs/g and the difference between the village itself and the Kolobo farms was not significant (x2=0.005; df=l; P=O941).

Excluding Bole, therefore, which is an exception in central Ethiopia, the helminthological differences be- tween the capital and the village 30 km away ye statisti- cally in favour of the village (for prevalence, x =7.0521; df=l; P=O.O08), probably on account of overcrowding and disruption of the traditional rules of hygiene in the Addis Ababa poverty belt (Fig. 2).

_-

1 12978 13098

10-- T 5553 1

0 8018 Mena~ePh~-KOiObO bsesnene KOI te

Fig. 2. Ascaris lumbricoides: arithmetic mean worm burden in Addis Ababa, with 95% confidence limits.