British Journal of Ophthalmology, 1988, 72, 561-569

Effect of single-dose invermectin therapy on humanOnchocerca volvulus infection with onchocercal ocularinvolvementHENRY S NEWLAND,' ALBERT T WHITE,2 BRUCH M GREENE,2SALVATORE A D'ANNA,' EZATOLLAH KEYVAN-LARIJANI,'MOHAMMED A AZIZ,' P NOEL WILLIAMS, AND HUGH R TAYLOR'

From the 'Ocular Onchocerciasis Research Unit, International Centre for Epidemiologic and PreventiveOphthalmology, the Wilmer Institute, Johns Hopkins University, Baltimore, Maryland; the 2Division ofGeographic Medicine, Department of Medicine, Case Western Reserve University and University Hospitals,Cleveland, Ohio; 3Merck, Sharp and Dohme Research Laboratories; Rahway, New Jersey, USA; and UniroyalLiberian Agricultural Company, Grand Bassa County, Liberia

SUMMARY Ivermectin has shown promise as a potentially safe and effective microfilaricidal drugfor the treatment of onchocerciasis. Several limited studies have shown it to have fewer side effects,especially ocular complications, than the currently available drug, diethylcarbamazine. Thedetailed ocular findings in 200 moderately to heavily infected Liberians who were enrolled in asafety and dose-finding study are presented. They received either 0, 100, 150, or 200 [tg/kg ofivermectin and were followed up for 12 months. In clinical studies so far carried out ivermectin in adose of 100, 150, or 200 jig/kg has not been associated with any major adverse reactions nor werethere any sight-threatening effects even in the presence of severe ocular disease. Each of thesedoses significantly reduced the ocular microfilaria load for at least 12 months when compared witheither the placebo (p<005) or pretreatment values (p<0.001). However, the 100 and 150 [tg/kgdoses caused fewer minor side effects than the higher dose. These results confirm that ivermectin ina single oral dose may be a safe and effective microfilaricidal drug for the treatment ofonchocerciasis and that it appears to be free of major ocular side effects.

No appropriate treatment is available for widespreaduse against onchocerciasis. The two drugs used,diethylcarbamazine (DEC) and suramin, are associ-ated with severe systemic and ocular side effects. Theocular side effects of DEC are well known andinclude permanent sight-threatening changes andsometimes blindness. ' DEC is therefore recom-mended only for patients with severe disease, especi-ally those whose sight is severely threatened withouttreatment." Suramin, which is inherently toxic,' alsocauses similar ocular changes. "' Invermectin, asemisynthetic macrocyclic lactone widely used inveterinary medicine, shows promise as a micro-filaricidal drug that has been better tolerated than

Correspondence to Hugh R Taylor, MD, 116 Wilmer Building,Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore,Maryland 21205, USA.

DEC and has fewer ocular complications in thestudies conducted so far."...

Studies of invermectin treatment in man that havebeen reported so far are limited to fewer than 100patients, most of whom had either relatively milddisease or incomplete follow-up. We report here thedetailed ocular findings of a double masked study ofdosage and efficacy in which 200 patients withmoderate to severe onchocerciasis were treated withone of three different doses of invermectin orplacebo. The detailed systemic findings in this groupof patients are being reported separately.'9

Subjects and methods

SUBJECTSEight hundred patients, aged 12-60 years, werescreened clinically and parasitologically. The 200

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patients with heaviest infection by microfilaria skincount who were otherwise apparently healthy andwho had given consent were selected for inclusion inthis study. All patients had screening skin-snipmicrofilaria counts of greater than 15 microfilaria permg of skin. Pregnant and lactating females and anysubject who had received an antifilaricidal within oneyear were excluded.' They were residents of theLiberian Agricultural Company rubber plantation inGrand Bassa County, Liberia, an area hyperendemicfor the rain forest type of onchocerciasis.

CLINICAL EVALUATION

The patients underwent detailed ocular, physical,and parasitological examination before the start oftreatment." The ocular examination included thetesting of visual acuity with an illiterate E chart andvisual fields with a clear dome perimeter using a 2 mmfibreoptic target (Goodlite Company, Forest Park,Illinois).The anterior chamber and cornea were examined

with a Topcon SL5D slit-lamp at 25x after thesubjects were placed in the head down position for atleast two minutes. The microfilariae in the corneaand the anterior chamber of each eye were counted.Limbitis was diagnosed by the presence of limbalvessel dilatation, limbal oedema, and white globularopacities, and each sign was graded as absent, mild,moderate, or severe. Anterior uveitis was diagnosedby the presence of anterior chamber cells and flare;each sign was graded as absent, mild, moderate, orsevere. Sclerosing keratitis was graded according tothe presence of limbal haze, the extent of character-istic corneal involvement starting in the nasal ortemporal periphery, being confluent inferiorly,or covering the pupil. Intraocular pressure wasmeasured by applanation tonometry.The fundus was examined by direct and indirect

ophthalmoscopy after pupil dilatation with 1%tropicamide and 10% phenylephrine hydrochloride.Fundus photography was performed with a TopconFE fundus camera; the photographs were graded in amasked fashion with the patient's identity, treat-ment, and date of examination obscured. Thesephotographs were graded for the presence and extentof intraretinal deposits, intraretinal pigment (IRP),atrophy of the retinal pigment epithelium (RPEA),retinitis, haemorrhage, optic neuropathy, and sub-retinal fibrosis.7 Intraretinal deposits are either smallwhite or glistening deposits found in the neuroretina.They could be clearly distinguished in stereo photo-graphs from drusen, which occur at the level of theretinal pigment epithelium. They had a differentappearance from intraretinal microfilariae and in ourexperience do not occur in people living outside areaswhere onchocerciasis is endemic.

After treatment the detailed ocular examinatiollwas repeated at day 3, and at three, six, and 12months; physical and parasitological examinationswere also repeated at these times. In order toquantify the ocular changes due to onchocerciasisand due to therapy an ocular reaction index wascalculated." This index is based on the intraocularmicrofilaria load and the severity of punctatekeratitis, limbitis, and anterior uveitis.

All subjects were admitted to hospital during thefirst four days of the study. Olle hundred and thirty-two patients attended all follow-up examinations.The patients that missed one or more follow-upexaminations included eight from the 100()g/kg,17 from the 150 ig/kg, 16 from the 200( tg/kgivermectin groups, and 17 from the placebo group.There were 177 subjects present at three months, 162at six months, and 176 at 12 months. At 12 months allpatients not examined were accounted for as follows:14 had moved to the interior of the country; six hadmoved to urban areas and could not be found; thewhereabouts of one was unknown; and two refusedexamination. One patient in the 150 [tg/kg groupdied of undetermined causes between the six- and 12-month examination.

TREATMENT PROTOCOLSubjects were randomly assigned to receive either 0(placebo), 100, 150, or 200 Rg/kg of ivermectin. Thedosage was adjusted for weight, with 5 kg incre-ments. The drug was provided in coded packagescontaining five identical capsules; each patient wastreated individually and closely observed to ensurecompliance. Additional medication was available ondemand and included aspirin for pain or fever andantihistamine for pruritus or insomnia.

DATA ANALYSISData were gathered in a double-masked fashion andentered for computer analysis prior to breaking thetreatment code at six months. The patients wereexamined at 12 months without reference to thetreatment code. Statistical analyses were based onanalysis of covariance (to adjust for differences atbaseline), with the two-tailed t test for multiplecomparisons when means for treatment were com-pared. In addition the mean differences betweengroups over time were compared by simple t test forindependent samples. Other analyses were per-formed with Student's t test or Fisher's exact test.The data analysis to be presented was performed ondata available for all those patients present at anexamination, regardless or their presence at otherexaminations. Restricting the analysis to only thosepatients present at every examination (132 or 66%)did not alter the findings.

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Results

PRETREATMENT FINDINGS

Random assignment of the subjects into four groupsresulted in similar distributions with regard to age,skin microfilaria count, and ocular findings (Table 1).Similarly, weight, number of palpable onchocercalnodules, and skin changes due to onchocerciasis werealso evenly distributed.'5

Thirty-two patients entered the study with visualacuity in one or both eyes of 6/12 or less. Of these, 17had visual impairment (vision of less than 6/18 in theworse eye). Eight subjects had abnormal visualfields. Their distribution was likewise similar amongthe treatment groups. Four patients, two in the 100and one each in the 150 and 200 [tg/kg groups, hadunilateral optic atrophy.One patient, a 13-year-old girl in the 200 [tg/kg

group, had active retinitis and optic neuritis in heronly seeing eye, with severe bilateral anterior uveitisand raised intraocular pressure (34 mmH in eacheye). This was associated with a massive intraocularmicrofilaria load (over 100 microfilariae in eachanterior chamber). No evidence for other causes ofsevere intraocular inflammation, such as old toxo-plasmosis lesions, could be seen.

CHANGES AFTER THERAPYThe mean skin microfilaria density in the threeinvermectin treatment groups was significantlyreduced at all follow-up examinations in comparisonwith the placebo group (p<0-01, Table 2). The rapidlowering of skin microfilariae in the first three days

Table 1 Pretreatment characteristics andprevalence ofocularfindings

Finding Ivermectin treatment groups

Placebo 100 gglkg 150 [glkg 200 [glkg(n =48) (n =49) (n=52) (n=51)

Mean age (years) 30 5 29 3 29-3 30(3Microfilaria

skincounts 21-0 17-9 21 2 20 8(geometric mean,mf/mg skin)

Punctate keratitis 21* 15 21 22(4388%) (30(6%) (4044%) (43 1%)

Microfilariae in 16 8 15 14cornea (33-3%) (16-3%) (2888%) (27 5%)

Microfilariae in 26 19 27 24anterior chamber (54-2%) (38-8% ) (51-9%) (471% )

Anterior uveitis 0 2 1 l(0.0%) (4I1%) (199%) (20%)

Limbitis 5 6 5 7(10-4%) (1222%) (966%) (13 7%)

Sclerosing keratitis 1 1 2 3(211%) (2-0%) (3-8%) (5-9%)

*Number affected (percentage).

Table 2 Microfilaria skin denisities before and aftertreatment

Microfilaria skin count

Placebo 100 figlkg 150 kglkg 200 tg/kg(n= 48) ( =49) (n= 52) (n =Si)

Pretreatment 21-0 17 9 21.2 20(83day 17-7 7-0 7(00 4-33months 16 5 0(93 0-65 0(556months 15 6 1 8 1-7 1 31 year 13 0 3 1 3 5 3-6

*Geometric mean for all those present at an examination (mf/mgskin). All treatment groups had significant reduction in microfilariadensities at every interval compared to both placebo and topretreatment levels (p<0.0I1).

after treatment was associated with only mildsystemic reactions. 9

All patients in the ivermectin groups eitherretained the same visual acuity or improved, but onepatient in the placebo group lost some vision in oneeye (6/6 to 6/9) when tested at three and 12 months.No cause could be ascribed to this loss of vision. Nopatient suffered further loss of visual field at any ofthe follow-up examinations. The 13-year-old girl withactive retinitis and neuritis at baseline was treatedwith intensive topical anti-inflammatory andpressure-lowering drugs in addition to ivermectin.She regained visual field, which enlarged from 100 atbaseline to 200 at three months. There was noprogression of optic atrophy in any patient in eitherthe ivermectin or the placebo treated groups, and nonew cases of optic neuritis or optic atrophy were seenat any follow-up examination.The number of microfilariae in the anterior

chamber in all treatment groups fell rapidly duringthe three days following treatment. At three monthsthe difference between the ivermectin treated groupsand the placebo group was significant, and itremained significant at the six- and 12-month exami-nations (p<005, Fig. 1). The motility of micro-filariae in the anterior chamber was observed to beabnormal for the first three days after ivermectintreatment. This abnormal motility consisted of acharacteristic extended configuration, periodicimmobility, and an occasional unusual motion inwhich the microfilariae bent only in the middle,suggestive of a spastic paralysis.The number of corneal microfilariae in all treat-

ment groups tended to increase by day 3 but hadsignificantly decreased in the ivermectin treatedgroups at three months in comparison to the placebogroup (p<0-01). As with the microfilariae counts inthe skin, there was a gradual increase in the numberof corneal microfilariae in the ivermectin treatedgroups between both the three- and six-month

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Fig. 1 Geometric mean number ofmicrofilariae in anterior chamber ineach treatment group. Asterisks

indicate counts significantlydifferentfrom those in placebogroup (single asterisks, p<O005;double asterisks, p<OOl (t test)).

0 3 3 6

Days Months

examinations and the twelve-month examination.Though not statistically significant, this was more

marked in the 200 [tg/kg group (Fig. 2). Similarchanges were seen in the number of punctate cornealopacities; the 200 [tg/kg group showed a smalldecrease at day three and a more marked (thoughnot statistically significant) increase than the otherinvermectin groups at both the six- and 12-monthexaminations (Fig. 3).

In all three ivermectin groups there was a signifi-cant decrease in the ocular reaction index in compari-son with the placebo group at three, six, and 12

Fig. 2 Geometric mean number ofcorneal microfilariae in eachtreatment group. Asterisks indicatecounts significantly different thanthose in placebo group (singleasterisks, p<OO.5; double asterisks,p<00J (t test)).

4,,a

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months. There was no significant difference betweenthe three ivermectin groups (Fig. 4).

Chorioretinal abnormalities were noted beforeand after treatment in patients in all treatment groups(Table 3). Patients were classified by their worse eye.In all instances the chorioretinal changes after treat-ment were noted to have occurred between the three-and 12-month examination. There was no change inthe amount or distribution of IRP in patients withIRP from the ivermectin groups except in one patientin the 100 ,ug/kg group, in whom progressive IRPclumping was noted (Figs. 5A, B). All those with

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12

Fig. 3 Geometric mean number ofpunctate corneal opacities in eachtreatment group. Asterisks indicatecounts significantly differentfromthose in placebo group (singleasterisks, p<005; double asterisks,p<001 (t test)).

RPEA in the ivermectin-treated groups remainedunchanged (Fig. 6). In contrast, in the placebo grouppatients with either IRP or RPEA showed progres-sion in 18-2% (four patients) and 23-1% (threepatients) of cases respectively. Of patients initiallywithout RPEA none of the ivermectin and 11-4%(four patients) of the placebo patients developedthese changes. Nineteen patients with normal fundibefore treatment developed retinal deposits, andthey were from all four treatment groups. Theproportion of patients who developed retinaldeposits in the placebo group (seven patients) was

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significantly greater than that (one patient) in the 200[tg/kg group (p<005). In two patients-a placebopatient and one from the 200 [tg/kg group-with pre-existing retinal deposits the number of depositsdecreased after treatment.The one patient with active retinitis and optic

neuritis from the 200 [tg/kg group (the 13-year-oldgirl mentioned above) showed some improvementclinically when seen at three days and three months,after which she was lost to further follow-up. Onepatient in the placebo group had a small area of mildretinitis which remained unchanged throughout the

Fig. 4 Ocular reaction index ineach treatmentgroup. Asterisksindicate scores significantlydifferentfrom those in placebo

group (single asterisks, p<005;double asterisks, p<001 (t test)).

Months

1.2

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100Ig/Kgo 150,w9g/Kgo 200pfg/Kg

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Fio. nA Fig. 6 Fundus photograph of19-year-old male patient inthe 100 ptglkg group showing retinalpigment epithelialatrophx and white retinal depo.sit.s (arrows below dhi~v). Notestudy (Fig. 7). A retinal haemorrhage appeared at also intrarettinalpiglentt cluopingsuperonasal to disc.

tree months in a placebo patient but had resolved bythe six-month assessment (Fig. 8), while a smallparamacular area of active retinitis in another patienton placebo remained unchanged during the study.

Fig. 5BFig. 5 Fundus photograph of28-year-oldfemale patient inthe 100 [tglkg group before treatment (A) and six monthsafter treatment (B) in whom there was progressiveintraretinalpigment clumping.

Discussion

This report presents the detailed ocular findings in adouble-masked study of the safety and dosage ofivermectin comparing three different doses with

Fig. 7 Fundus photograph ofa 48-year-old maleplacebopatient who receivedplacebo showing a small area ofmildretinitis which did not progress during the study.

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Table 3 Alteration infundusfindings according topretreatment status during one-yearfollow-up

Abnormality Pretreatment statusTreatmentgroup Abnormality Abnormality present

absent

No. % No. % % %Worse Improved No change Worse

IntraretinalpigmentPlacebo 26 0-0 22 0-0 81-8 18-2100 Rg/kg 32 0-0 17 0-0 100-0 0 0150 Rg/kg 33 3-0 16 0-0 100-0 0.0200 Rg/kg 30 3-3 20 5 0 95 0 0.0Retinalpigment epithelium atrophyPlacebo 35 11-4 13 0-0 76-9 23-1100 tsg/kg 36 0-0 13 0-0 100-0 0.0150 jsg/kg 30 0-0 19 0-0 100-0 0.0200 sg/kg 37 0-0 13 0-0 100-0 0-0Retinal depositsPlacebo 36 19-4 12 8-3 83-3 8-3100 pg/kg 41 12-2 8 0-0 100-0 0-0150 ,ug/kg 43 14-0 6 0-0 83-3 16-7200,ug/kg 44 2-3 6 16-7 83-3 0.0

Note: Three cases in the 150 tLg/kg and one case in the 200 [ug/kggroup did not have photographs before being treated and wereexcluded. They had no fundus abnormalities on clinicalexamination.

placebo in 200 patients with moderate to severeonchocerciasis from a forest area. The detailedsystemic findings are presented in another report,'9which concluded that the acute systemic reactionswere less with the 100 and 150 [tg/kg than with

Fig. 8 Fundusphotograph of12-year-old malepatientwho receivedplacebo showing a retinal haemorrhage at threemonths which had resolved at the six-month examination.

the 200 Rg/kg dose. Overall the reduction in skinmicrofilariae counts in each treatment group wascomparable, though at three months there were moreskin-snip positive patients in the 100 Rg/kg group.'9From these observations it would appear that 150ptg/kg is the preferred dosage in terms of both safetyand microfilaricidal effect. No direct macrofilaricidaleffect has been observed with ivermectin.'5 16 18 19

In the studies reported so far information on a totalof fewer than 100 patients treated with ivermectin hasbeen presented, and patients with severe oculardisease have not been treated. In our study 200patients were selected on the basis of moderate tosevere levels of infection; all had skin-snip countsgreater than 12 and ranging up to 158 microfilariaeper mg. Moreover, in this study 42 patients hadsevere ocular disease by criteria suggested by theWorld Health Organisation.2223 Of these, 30 weretreated with ivermectin and none showed deteriora-tion of their ocular status. Significantly there were nonew cases of optic neuritis or optic atrophy in anyperson in any treatment group throughout the study.A single patient with optic neuritis was treated withivermectin, and she improved clinically, though ofcourse she also received intensive topical treatment.It was not possible to document a change on eitherfundus photographs or fluorescein angiography forthis patient because of the media opacities associatedwith her severe uvietis.New chorioretinal changes were seen in colour

fundal photographs of patients from all four groupsduring the study. It is assumed that these are in factnew lesions, though it is possible that some may havebeen overlooked at one or other of the examinations.It is in part because of the frequent occurrence ofthese chorioretinal changes, observed in previoustrials,5'7 that it was considered necessary to include aplacebo treated control group. Previous trials hadalso included fluorescein angiography to compare thechorioretinal changes after treatment with DEC,ivermectin, and with placebo. 724 25 While fluoresceinangiographic changes were seen in patients treatedwith ivermectin, similar changes were also noted inthe DEC and placebo treated patients. However, nofunctional ocular deficiency occurred in ivermectintreated patients. It was therefore decided not toinclude fluorescein angiography in the present studybecause of the logistic problems associated withexamining and treating 200 patients under fieldconditions.

It is noteworthy that pre-existing intraretinal pig-ment and retinal pigment epithelial abnormalitiesbecame worse during the study in a number ofplacebo patients. In addition, in a small number ofplacebo patients with normal fundi on entry into thestudy RPEA changes appeared during the study. The

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aetiology of these pigmentary and atrophic changes isstill not clear, though they may be related eitherdirectly or indirectly to the presence of intraocularmicrofilariae.25 The reduction of intraocular micro-filariae with ivermectin treatment would be expectedto reduce, if not prevent, the appearance of newchorioretinal changes, and those that involve apermanent structural change should not improve.Retinal deposits appeared in a number of patientswho had normal fundi on entry into the study. Inaddition, in a small number of patients pre-existingretinal deposits disappeared. These changes occur-red in both placebo and ivermectin treated patients.We do not know if this appearance and disappear-ance of deposits represents the effect on the retinawhich results from passage of microfilariae throughthe retina or focal areas of inflammation akin tocorneal punctate opacities around a dead micro-filaria.

Overall the incidence and severity of the inflam-matory reaction which could be ascribed to treatmentwith ivermectin were less than would be expectedwith the other microfilaricidal drugs such asDEC.'1S27 The reason for this is unknown. One factormay be that ivermectin treatment does not mobilisemicrofilariae in the way that DEC does.' 7Ivermectinclearly has a direct effect on microfilariae, producinga spastic paralysis as shown by the altered motility ofmicrofilariae in the anterior chamber and in vitro.25This is consistent with its Gaba agonist-likeactivity.29

In this study ivermectin did not precipitate majorocular complications and may in fact have decreasedthe rate of progression of ocular onchocerciasis.Further, this study suggests that the drug can be usedin patients with severe ocular disease without dangerof the sight threatening complications associated withtreatment with diethylcarbamazine. Although theresults of other clinical trials in areas of savannaonchocerciasis are needed, the results of the presentstudy in a rain forest area clearly suggest thativermectin may ultimately prove to be sufficientlysafe for use in community based mass treatmentprogrammes.

This study was supported by grants from the OnchocerciasisChemotherapy Project of the FAO/UNDP/World Bank/WHOOnchocerciasis Control Programme in the Volta River Basin area;by Merck Sharp and Dohme Research Laboratories, Rahway, NJ;by Uniroyal Inc., Middlebury, CT; and by NIH grants EY 03318 andAI 15351.We thank the following persons for their assistance: John

Boateng, MB BS, and the staff of the Liberian AgriculturalCompany, Grand Bassa County, under the direction of Kenneth DGerhart; S Vaani Freeman, MD, J Maxwell, MD, 0 V Cassell, andthe staff of the LAMCO Hospital, Buchanan, Liberia; Aloysius PHanson, PhD, and Betsy Brotman, the Liberian Institute forBiomedical Research, Robertsfield; Shirley Johnson, AliceFlumbaum, and Inga Jackman, the Johns Hopkins University,

Baltimore; Theo Greene, Ngawai White. Mark Wieland. MD, andPatrick S Moore, MD, the Divison of Geographic Medicine.Department of Medicine, Case Western Reserve University,University Ilospitals. Cleveland.

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2 Ikejiani 0. Studies in onchoecrcilsis (111). The combined use otHetrazan and Antrypol (suramin BP) in the treatment of Africanonchocerciasis. West Afr Med 11954; 3: 166-8.

3 Anderson J. Fuglsang H, Marshall TFdeC. Effects of diethyl-carbamazine on onchocerciasis. Tropenmned Parasitol 1976; 27:263-78.

4 Anderson J. Fuglsang H. Further studies on the treatment ofocular onchocerciasis with diethylcarbamazine and suramin. BrJOphthalmol 1978; 62: 45t)-7.

5 Bird AC, El Sheikh H., Anderson J, Fuglsang H. Changes invisual function and in the posterior segment of the eye duringtreatment of onchocerciasis with dicthylcarbamazine citratc. BrJOphthalmol 1980; 64: 191-2t)().

6 Taylor HR, Greene BM, Langham ME. Controlled clinical trialof oral and topical diethylcarbamazine in treatment ofonchocerciasis. Lancet 198t); i: 943-6.

7 Goodwin LG. Recent advances in research on filariasis: chemo-therapy. Trans R Soc Trop Med Hyg 1984; 78 (suppl): 1-8.

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11 Aziz MA, Diop IM, Diallo S, Lariviere M, Porta M. Efficacy andtolerance of ivermectin in human onehocerciasis. Lancet 1982; ii:171-3.

12 Aziz MA, Diallo S, Lariviere M, Diop IM, Porta M, Gaxotte P.Ivermectin in onchocerciasis. Lancet 1982; ii: 1456-7.

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14 Couland JP, Lariviere M, Aziz MA, et al. Ivermectin inonchocerciasis. Lancet 1984; ii: 526-7.

15 Lariviere M, Vingtain P, Aziz MA, et al. Double-blind study ofivermectin and diethylcarbamazine in African onchocerciasispatients with ocular involvement. Lancet 1985; ii: 174-7.

16 Greene BM, Taylor HR, Cupp EW, et al. Comparison ofivermectin and diethylcarbamazine in the treatment ofonchocerciasis. N EnglJ Med 1985; 313: 133-8.

17 Taylor HR, Murphy RP, Newland HS, et al. Treatment ofonchocerciasis. The ocular effects of ivermectin and diethyl-carbamazine. Arch Ophthalmol 1986; 104: 863-70.

18 Diallo S, Aziz MA, Lariviere M, Diallo JS, et al. A double-blindcomparison of the efficacy and safety of ivermectin and diethyl-carbamazine in a placebo controlled study of Senegalese patientswith onchocerciasis. Trans R Soc Trop Med 1986; 80: 927-34.

19 White AT, Newland HS, Taylor HR, et al. Controlled trial anddose-finding study of ivermectin for treatment of onchocerciasis.J Infect Dio 1987; 156: 463-70.

2t) Keyvan-Larijani E, Newland HS, Taylor HR. An ocularreaction index for use in the study of onchocerciasis. Trop MedParasitol 1985; 36: 241.

21 Armitage P. Statistical methods in medical research. Oxford:Blackwell, 1971: 116-26.

22 Report of WHO Expert Committee. Epidemiology ofonchocerciasis. Techn Rep Ser 1976; 597: 18.

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Accepted for publication 4 June 1987.

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