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TRANSACTIONS OFTHE ROYAL SOCIETY OFTROPICAL MEDICINE AND HYGIENE (1997) 91,592-593

Reduced Loa /oa microfilaria count ten to twelve months after a single dose of ivermectin

T. H. Duongl*, M. Kombilaz, A. Ferrer’, l? Bureau3, I? Gaxotte4 and D. Richard-Lenoblel ‘Fuculti de Mid- e&e, 37032 Tours Cedex, France; 2Faculti de M&&%te, B.l? 4009, Libreville, Gabon; 3Service des Grandes End&ties, Min- is&e de la San& Libreville, Gabon;4Laboratoz’re Merck Sharp & Dohme, B.l? 62, La-Celle-St-Cloud, France

Abstract The action of a single dose of ivermectin (200 l&kg) on 7 1 Gabonese patients with Loa Zoa microfilariae in the peripheral blood, and living in areas highly endemic for loiasis, has been evaluated. Ten to 12 months after treatment, 43 patients (63%) had no circulating microfilaria and the geometric mean peripheral blood microfilaria count had decreased by 886% (fiO.02). Thus, a single annual dose of ivermectin can markedly reduce loiasis transmission.

Keywords: loiasis, Loa Zoa, chemotherapy, ivermectin, Gabon

Introduction A single dose of 200400 l.tg/kg ivermectin has been

shown to result in an 82% decrease in Loa Zoa microfilaraemia in Gabon 7 d later (RICHARD-&NOBLE et al., 1988). PINDER et al. (1992) showed that a single dose of 300 @kg ivermectin decreased the microfilaraemia rate by91%afterlOdandby90%afterlOOdand~~N- J&BVEL et al. (1993a) reported that the plasma microfilaria (rnfl count decreased bv 90% 90 d after a single dose of 360 or 400 l&kg of>vermectin. Similarly,-in Congo, CARME et al. (1991) showed that microfilaraemia was decreased by 89% 14 d after a single dose of 200 l.@tg of ivermectin. CHIPPAUX et al. (1992) dem- onstrated that the reduction in microfilaraemia persist- ed for 6 months after 2 or 3 treatments (200 pg/kg) given at 3 months’ intervals. The present study was carried out to evaluate the changes in mf counts and the dura- tion of action after treatment with 200 @kg of ivermectin of patients from L. loa hyperendemic areas of Gabon.

Patients and Methods Seventy-one patients (40 women, 31 men; mean age

36 years, range 15-76) were recruited from several areas in Gabon where loiasis is endemic (RICHARD-LBNOBLE et al., 1980). They all had clinical symptoms of loiasis (pruritus, Calabar swelling, migration of adult worms to the subcutaneous tissues and eyes, pain and arthritis) but none was suffering from any other serious disease. Pregnant or nursing women and children less than 15 years old were excluded. All the patients consented to the treatment and each was given a single dose of ivermectin (200 @kg). Samples of venous blood (4 mL) were taken from the forearm into anticoagulant between 09:OO and 13:00, treated with saponin (Petithory & Ho Thi Sang, 1963), and centrifuged; the mf in the deposit were then counted. If necessary, due to pruritus, cutaneous rash, arthralgia or swelling, the ivermectin was ac- companied by an antihistamine Hl antagonist for 3 d. Blood samples were taken again 1 O-l 2 months later and the mf were counted similarly. Student’s paired t test was used to analyse the data.

Results Patients were examined l-3 d after ivermectin treat-

ment. In agreement with the findings of c&HPPAUX et al. (1994), 50% of them (36/71) had side effects from the drug in the 24 h following treatment: 36 had exacerba- tions of pruritus, 6 had cutaneous rash, 4 had arthralgia, and 7 patients had Calabar-like swellings. These patients were given antihistamine treatment, which rapidly reduced the side effects.

Address for correspondence: Dr T H. Duong, Parasitologie, Mycologic et Medecine Tropicale, Faculte de Medecine, 2 bis BoulevardTonnelle, 37032Tours Cedex, France.

The geometric mean mf count was 38.8 mUmL (range 0.25-35700) on the day of treatment, and 3.9 mfYmL (range zero-2800) lo-12 months after treatment, a decrease of 88.6% (fiO.02). Forty-five patients (63%) were amicrofilaraemic at the lo-12 months’ check-up.

Discussion MARTIN-PR&EL et aZ. (1993a, 1993b) found that a

single dose of ivermectin reduced L. loa microfilaraemia by over 90% 3 months after treatment. The present study showed that a single 200 pg/kg dose of ivermectin markedly decreased microfilaraemia 10 months after treatment, and over half of the patients treated were amicrofilaraemic. Moreover, we did not observe encephalopathy in any treated patients, even those with a high mf load. Repeated annual ivermectin mass treatments for onchocerciasis in areas where L. Zoa is endemic can therefore be considered to be safe (K~MBIU et al., 1995). These findings confirmed those described for Wuchereria bancrofti by EBERHARD et al. (1992) and for Brugtiz malayi by MAK et al. (1993). These authors showed that the mf counts remained low after single doses of ivermectin for 2 years with W. bancrojii and 6 months with B. malayi. This persistent decrease in microfilaraemia has led to the hope that a programme to prevent the transmission of loiasis could be successful using a single annual treatment with ivermectin. The re- sulting amicrofilaraemic subjects would be unable to in- fect the vectors, thus, partly at least, interrupting the transmission of the parasite.

There are 5 species of filaria in Gabon: Onchocerca volvulus, L. loa, Mansonella perstans, M. streptocerca and M. rhodaini. Only 0. volvulus and L. loa are sensitive to ivermectin. Treating the population of such areas with a single annual dose of ivermectin could form the basis of a simultaneous mass campaign against these 2 species, which are considered to be the most pathogenic filariae.

Acknowledgement The Programme Mectizan is supported by the Mission of As-

sistance and French Co-operation in Gabon and the Expert Mectizan Committee (Laboratory Merck Sharp & Dohme, La- Celle-St-Cloud, France).

References Carme, B., Ebikili, B., Mbitsi? A. & Copin, N. (1991). Essai

therapeutique de l’ivermectme au tours de la loase a moy- enne et forte microfilar&nie. Annales de la Sociiti Be&e de Mkiecim Tropicale, 71,47-50.

Chippaux, J.-P., Ernould, J.-C., Gardon, J., Gardon-Wendel, N., Chandre, F. & Barberi, N. (1992). Ivermectin treatment of loiasis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 86,289.

Chippaux, J.-P., Ducorps, M,., Ranque, S., Gardon, N., Bouss- inesq, M., Ndong, W., Fobi, G. Schneider, D., Cot, S. & Gar- cia, A. (1994). Adverse reactions following ivermectin treatment in patients with high Loa Zoa parasitaemia.Ametian jrournaZofZ+opicaZMedicine and Hygiene, 51, supplement, 132.

REDUCED LOA LOA MICROFILARAEMIA AFTER IVERMECTIN 593

Eberhard, M. L., Hightower, A. W., McNeeley, D. F. & Lam- nie, I? J. (1992). Long-term suppression of microfdaraemia following ivermectin treatment. Transactions of the Royal So- ciety ofTropical Medicine and Hygiene, 86,281-288.

Kombila, M., Duong, T. H. & Richard-Lenoblq, D. (1995). Safety of ivermectin for treating onchocerciasls in populations where loiasis is co-endemic (Central Africa: Gabon). American Journal of Tropical Medicine and Hygiene, 53, supplement, 260-26 1.

Mak, J. W., Navaramam, V., Grewel, J. S., Mansor, S. M. & Ambu, S. (1993). Treatment of subperiodic Brugia malayi infection with a single dose of ivermectin. American Journal of Tropical Medicine and Hygiene, 48, 591-596.

Martin-Prkvel, Y., Cosnefroy, J. Y., Ngari, P. & Pinder, M. (1993a). Reduction of microtiaraemia with single high-dose of ivermectin in loiasis. Lancet, 342,442.

Martin-P&e&Y., Cosnefroy, J. Y., Tshipamba, P., Ngari, P., Chodakewitz, J. A. & Finder, M. (1993b). Tolerance and ef- ficacy of single high-dose ivermectin for the treatment of loiasis. American Journal of Tropical Medicine and Hygiene, 48, 186-192.

Petithory, J. & Ho Thi Sang (1963). Techniques de concentra- tion des microfilaires sanguicoles. Bulletin de la So&% de Patholoffie Exotique, 56,197-206.

Pinder, M., Everaere, S., Luty, A., Chodakewitz, J. A. & Mar- tin-Pr&el,Y. (1992). Effect of treatment with a high dose of ivermectin on Loa loa microfilaremia and specific anti-fdarial immunoresponses. American Journal of Tropical Medicine and Hygiene, 41, supplement, 153-l 54.

Richard-Lenoble, D., Kombila, M., Carme, B., Gilles, J. C. & Delattre, P. Y. (1980). Prbvalence des filarioses humaines sanguicoles au Gabon. Bulletin de la Soci& de Patholoe’e Ex- otique, 73,192-199.

Richard-Lenoble, D., Kombila, M., Rupp, E. A., Papayliou, E. S., Gaxotte, P., Nguiri, C. & Azii, M. A. (1988). Ivermectin in loiasis and concomitant Onchocerca volvtdus and Man- sonella perstans infections. American Journal of Tropical Medi- cine and Hygiene, 39,480-483.

Received 3 March 1997; revised 2 April 1997; accepted for publication, 2 April 1997

TRANSACTIONS OFTHE ROYAL SOCIETY OFTROPICAL MEDICINE AND HYGIENE (1997) 91,593-594

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Marked decrease in Loa loa microfilaraemia six and twelve months after a single dose of ivermectin

J. Gardonl, J. Kamgno’ G. Folefack*, N. Gardon- Wendell, B. Boucl& and M. BoussinesqlJ 1 ORSTOM-&ntre Pasteur, YaoundE, Cameroon; 2Mbandjock Hospital, Mbandjock, Cameroon; 3~~~~~~ Commission Scient$que no. S, Pan’s, France

Keywords: loiasis, Loa Zoa, chemotherapy, ivermectin, Cameroon

Cases of encephalopathy have been recorded from Cameroon after ivermectin treatment for onchocerciasis in patients with very high coincident Loa loa microfilaraemia (BOUSSINESQ et al., in press). The threshold above which individuals are at risk of developing encephalopathy was estimated to be a microfilariai load of 30000 microfilariae (ti Der mL, of blood ((=HIPPAUX et al., 1996). Specific &o&ring strategies &us need to be developed when mass treatment with ivermectin for onchocerciasis control is implemented in areas where loiasis is co-endemic. As such procedures complicate the distribution of ivermectin, it is important to know whether they should be maintained during subsequent distribution& which are usually organized at annual intervals. The long-term effect of the standard dose of ivermectin (150 p&g) on the L. Zoa microtilaraemia of subjects with a very high initial microfilarial count has never been documented. This study aimed to assess whether patients with very high L. Zoa counts before their first dose of ivermectin were still at risk of developing encephalopathy when re-treated 6 or 12 months later.

The study took place in 2 districts, Elig-Mfomo and Sa’a (L&Z Division, Central Province of Cameroon). Capillary blood films (50 &) were taken between 10:00 and 16:00 from 5500 id&s-(aged 215 years), who then received their first dose of ivermectin (150 @kg). After Giemsa-staining, the L. Zoa mf in the blood films were

Address for correspondence: Dr M. Boussinesq, ORSTOM-CS no. 5,213 rue La Fayette, 75480 Paris Cedex 10, France.

counted. Within each district, the populations were di- vided into 7 strata according to their microfilarial counts per mL of blood: 0, l-100, 101-500, 501-2000, 2001-10000, 10001-30000 and >30000. Six months after dosing, 420 treated persons from Elig-Mfomo were selected for a second examination. The sampling was random within each stratum of microfilaraemia, 60 individuals being drawn from each stratum. Of the 420 persons selected, 255 agreed to be re-examined, including 35 with a pre-treatment count >30000 mf/mL. One vear after dosing, an identical sampling procedure was gpplied to the t&ted population of‘sa’;; bf the 420 persons selected. 278 orovided a second blood film. includ- , ing 33 with an in&al count >30000. The reduction in microfilaraemia within each stratum was calculated from the arithmetic mean microfilarial loads, not the geometric means because the latter give a disproportionate weight to zero and very low values and were thus considered inappropriate in the context of the present study which focused on high individual counts.

Before treatment, the prevalence of L. Zoa microfilaraemia and the average count (including zero counts) in the total populations examined were higher in Elig- Mfomo (32.9% and 3758 mE/mL, respectively) than in Sa’a (28.4% and 2876 mfYmL). The distribution of followed-up subjects according to their pre-treatment and post-treatment counts is given in the Table. Six months after treatment, the average microfilarial counts were reduced by more than 73% in all strata and no mf was found in 63 of the subjects who were microfilarae- mic before treatment (one of them having initially harboured 5260 mUmL). Amongst the 35 subjects who had microfilarial counts >30000 before treatment, only 2 had counts above this level 6 months after dosing; their counts were 141760 and 83780 mf/mL initially, and 7 1940 and 32280 mffmL 6 months after treatment. One year after treatment, the microfilarial count was zero in 79 of the subjects who were initially microfilarae- mic, including 5 who had > 10 000 mElmL before treatment; the rehuctions in all strata (except that of 101-500 mBmLj were 274%. Amonest the 33 subiects with pre-treatmknt counts >30000; only one had a count above this level one year after dosing (74 140 mfl mL before, and 34540 mffmL one year after, treatment) .

This study showed that a first single dose of ivermectin may bring about a striking reduction in L. Zoa microfilaraemia lasting for at least a year. The pre-treatment examination of 5550 persons allowed us to evaluate the effect of a first dose of ivermectin at 150 @kg on 68 individuals who harboured >30000 mE/mL. Onlv 3 of them had counts above this dangerous level at &e sec-