Scientific and Technical Advisory committee eighth meeting, Geneva, 4 - 7 September 1979: treatment of onchocerciasis in a hyperendemic community by small doses of suramin (evaluation after three months)

WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE ocr/srace.a ORIGINAL: FRENCH ONCHOCERCIASIS CONTROL PROGRA},[{E IN THE VOLTA RIVER BASIN AREA SCIENTIFIC AND TECHNICAL ADVISORY COMMITTEE Eighth meeting Geneva. 4- 7 September L979 TRNATMENT OF ONCHOCERCIASIS IN A HYPERENDEMIC COMMUNITY BY SMALL DOSES OF SURAMIN (Evaluation after three months) by A. ROUGEMONT, M. HrEN, B. THYLEFORS, A. PROST & A. ROLLAND 1. ORIECTIVES To evaluate administered in the filaricidal efficacY for o.volvulus gradually increasing doses, the total not of suramin exceeding 4 g. a parasitological of severe ocuLar such as blindness, or intercurrent In the event of success, to define criteria for the selection of subjects likely to benefit from treatment. To draw up a standard protocol thaL can be applied by mobile teams headed by a speciaLLzed nurse. To deEermine the type, frequency and severity of adverse effects when the treatment is applied in a hyperendemic conmunity. To state precise rules for treating any adverse effects in the eyes, skin or generally. 2. SELECTION OF SUBJECTS Treatment was instituted in March I979 by the Mobile Ophthalmology Group of the Upper Volta Health Services and by the EPI unit of the Onchocerciasis Control Programme in the village of Bonga on the Red Volta, Ti6b616 sub-prefecture. Six hundred and ninety inhabitants were registered, of whom 319 (from 85 families) were examined; 235 of them, i.e. 73.7%, were found to be carriers of O.volvulus microfilariae (mf) . It is therefore def initely a hyperendemj-c conrmunity. Eighty-eight subjecLs were seLected on the basis of and ophthaLmological examination (high mf counts, onset lesions); certain exclusion criteria were also applied, age below L4 ot above 55 years, poor general status and/ disease, and visible pregnancy. The distribution by age and sex is shown in Fig. 1. The average age of the men is 36.6 + 4 years, that of Lhe hTomen 38.3 + 9.9 years. Ten subjects were exclude<i from treatment for the following reasons : non-aEtendance at the first sessions (3), selection for treatment with DEC (6), and incipient collapse following the first injection (1). 3. METHOD The individuals subjected to treatment underwent the examinations summarized in Fig. 2. 3 .1. Basic examinations Individual skin parasite infestation is expressed by the mf counted in two iliac snips after digestion by collagenase. fore the true number of mf present in the biopsy specimens. Ihe There is mean number of This is there- distribution of mf counts prior to treaEment is shovrn in Fig.3. a slight excess of counts above 600 and below 100 mf in women. 23.2. Qqpplelgntary examinations 3.2.L. Fif teen patients \^7ere given weekly venous punctures from the third week onward for the measurement of plasma suramin. The measurements were made one week after each injection. 3.2.2. One hundred and twenty nodules were excised from 30 patients in order to determine the viability and fecundity of females freed after digestion by collagenase. Ttre specimens were taken before treatment. and one month and three months after the end of treatment. This is an essential test for determining the lethal or sterilLzing effect of suramin on adult worms. 3,2.3. A certain number of skin snips were taken before and during the therapeutic tests for examination under the optical and electron microscope 3.2.4. An additional skin snip was taken weekly from five patients to demonstrate the activity of acid phosphatases in the microfilariae during treatment. 3.3. Treatment Suramin was injected intravenously in sixoweekly doses of a 1-:O% aqueous solution of the dry product (Bayer 205--) in accoldance with the following schedule for a subject weighing 60 kg or more. Week 1: O .2 g (= 2 ml) Week 2: O .4 g (= 4 mI) Week 3: 0.6 g (= 6 m1) Week 4: O.8 g (= 8 m1) Week 5: 1.0 g (= 10 ml) Week 6: 1.O g (= 10 ml) The dosage was proportionately reduced for lighter subjects. Depending on the tolerance shovrn by the subjects, the final dose of 1 g sometimes had to be halved or even omitted. In 11 cases treatment was prematurely discontinued because of poor attendance by the patients or serious intolerance. On the basis of this criterion the subjects feLt int.o four groups: I: total course of 4 g: 20 subjects II: total course of 3.5 g: 26 subjects III: total course of 3.O g: 21 subjects IV: treatment discontinued: 11 subjects An injection of 1 g in an individual weighing 60 kg corresponds to a dose of 16.5 mg per kg body weight. 1 3The weekly injections were carried out by nurses of the ophthalmology Group under the supervision of the chief medical officer oi S"ctor No.1 (Dr. M. Hien). The clinical examinations and adjustment of dosages were carried out by an EPI physician (or'A'n')' In order to reduce the risk of collapse at the time of the first injection (Z mf), this injection was performed with extreme caution in three stages: (1) Injection of a few microlitres followed by a one-minute Pause.Atthispointone3O-year-oldwomandisplayed sweating and. dLzziness; she was excluded from the trial. (D Injection of half the total quantity' followed by a further pause of one minute. (3) Injeetion of the remaining quant ity. carried out in 3-5 minutesThe subsequent injections were 4. RNSULTS 4 1 Adverse reactions 4.1.1 litative as ects Immediate reactions: these occur immediately after or within half a day of an more cofitrnon after injection. They are rarely of high int the first injections. They primarily ensity and are consist of nausea, dizziness (hypotension?), abdominal pain and feverish sensations' Reactions duri the firs t three or four weeks: these are not very ific but are very corEnon affecting more than two- thirds of subjects).spec They consisL of headaches, abdominal pain, lumbago and diarrhoea, symptoms often complained of when no treatment is being given' The same applies to mild localized or Seneralized pruritis and a number of benign ocular reactions that are very common in untreaLed onchocerciasis. More specific and more common complaints appear to be pains in the palms of the hands and soles of the feet, with occasional desquamation at these sites. Reac tions occurring between the fifth and seventh weeks: Skin reactions: generalized and sometimes intense pruritis, polymorphic papular eruPtions 1o and pelvic girdle, sometimes on with confluent papules forming a General reactions: sometimes intense asthenia hardly move), polyalgia, persistent headaches, sensation. Transi-tory albuminuria is noted in but never persists and never exceeds #. The these manifestations is given below. ca1ized mainly on the thighs the fore-arms, ofLen extensive genuine skin oedema. (patient can feverish some cases, treatment for 4Reactions occurring from the sixth to fifteenth week: same types of reacEion, cutaneous and general, with high freguency of dermal and hypodermal oedema in the lower 1imbs. A11 the reactions generally disappear withouE treatment. In extreme cases (5) treatment based on low doses of oral corticoids combined with an antibiotic was given for one week. The milder cases were sometimes treated with aspirin and promethazine. Rare reactions: some specific reactions were observed in certain subjects: appearance of hyperchromic patches on the inner surface of the thighs (one case); inflammatory oedema of the left shoulder and right foot, with suppuration in the latter case; t pain in the nodules and/or lymph nodes(three cases) I incipient stomatitis, the development of which was halted by the discontinuation of treatment; subicterus (one case). The treatment \^Ias discontinued in cases where at least two of the following signs were Present: extreme asthenia confluent and extensive rash pink-eye with suspicion of iritis profuse and persistenL diarrhoea oEher intercurrent manifestations(respiratory distress, precordial pain, palpitations, fever, etc.) The final dose was divided into two in cases for some reason it was feared that the treatment might be poorly tolerated. 54.1.2 Quantitative aspects The following table shows the numbers of patients who displayed major reactions after five weeks and after 10-15 weeks respectively, according to the groups as defined above: TABLE I. FREQUENCY OF SIDE-EFFECTS OBSERVED IN EACH GROUP Four subjects whose treatment was discontinued because of non- attendance should be deducted. I Group Fifth week Tenth to fifteenth week I II III IV sfzo (4o%) Lsf26 Q3%) Bfzt G2%) t f tt tloo%) nf zo vf 26 ofzr zfn $s%) (48%) G3%) Q7%) 64 2 Parasitological f indines The skin parasite counts determined three months after the end of treatment were compared with the initial counts. The coefficient of decrease (d) was established on the basis of the following formula: final count initial count x 100 d (%) initial count Example: (subject 498 - 730 130 190) x 1OO 37 .7% 730 The conventions used are to omit the minus sign in the event of a decrease, to indicate the plus sign in the event of an increase, and to round off to the nearest whole number. In the above example the decrease observed is 387". This index is used in Figs. 4 and 5 which show the frequency distribution of the subjects as a function of the decrease observed and the doses administered(Groups I-IV). No significant difference r"Tas observed between males and females in resPect of the decrease in parasite count. The dosage seems to play a Part in that the very marked decreases ( >807.) are more contrnon in groups I and II. It is also interesting Lo note Ehat, even when the total doses are equal to or less than 3 g, appreciable or even large decreases are also very frequent. 4.3 op 7 hthalmological findinss up to now only a few cases of mild iritis and two suspected cases of optic atrophy have been observed. 4.4 Relationships betw""r, iniEial count, filaricidal effecL and adverse reactions The frequency of adverse reactions in the subject was compared in respect of :- (1) initial microfilaria count Adverse effects were observed in 7l% of. subjects with an initial count exceeding 500, compared with 62% of subjects with an initial count below 5OO mf. The result is roughly the same if distinction is made between subjects with counts above and below 200 mf (5S% ana 69% adverse reactions respectively). (2) \decrease observed after Lreatment Adverse effects were observed in 68% of. subjects with a decrease of more than 5O%, compared with 617. of subjects whose initial count dropped by less than 507" If the same analysis is made only for subjects with an initial count of more than 200 mf, the figures obtained are 7l'A ar.d 63% respectively. These differences are not significanL and cannot therefore be used to forecast which subjects are likely to display adverse reactions during treatment or to deduce that good efficacy is associated with frequent adverse reactions. 5 5 OTHER RESULTS 1 Suramin plasma levels Fig.6 (sample of 14 subjects) shows that the suramin plasma level rises gradually during treatment to reach 5 mg% one week after the last injectionl three weeks after the end of treatment the mean plasma level is sti1l around 2.5 mg%. At each point the variaEions between individuals are wide, but no extreme variations were observed which could be attributed Eo greater or lower tolerance of the drug or to greater or lower efficacY. 5.2 Adul t \^7orms The adult worms observed after digestion of the cysts showed no very wide variations in the viability of females after three months. On Ehe other hand, disturbances in embryogenesis were noticed as early as the first check-up (one month after the end of treatment). The next check-ups after eight months and one year should provide confirmation of Ehis trend and indicate whether it is transitory or permanent. 85.3 Ultrastructure Observations of dermal mf under the electromicroscope revealed a change which up to now has been observed only in the case of treatmenE with suramin. This change consists of substantial and regular external layers of the cuticle, clearly visible in the striations on oblique or longitudinal sections. folding of the t rans ve rs e Observations in prfigress should make it possible to determine the nature and significance of these changes. 5.4 Acid phosphatase activity of The StatisEically significant changes in the acid phosphatase actiyity the microfilariae were demonstrated during treatment with suramin. precise significance of this phenomenon is being studied. 6 CONCLUS IONS 6.L Inlhen suramin is injected in 1ow and increasing doses into highly infected onchocerciasis patients, marked microfilaricidal efficacy and an unfavourable effect on the embryogenesis of the adult filariae are observed three months after the end of treatment. Check-ups after eight months and after one year or longer should shed more light on these trends. 6.2 The subjects selected in a hyperendemic conrnunity on the basis of ophthalmological and parasitological criteria tolerated the treatment on the whole; nevertheless, strict medical surveillance was needed for several weeks. It is possible that when more experience has been gained this therapeutic protocol could be mastered by a special nurse. 6.3 Cutaneous and general adverse effects were frequently observed; ocular adverse effects were less cortrnon, but evaluation of their severity will require check-ups after eight months and one year to determine whether the product is harmless for the eyes of the onchocerciasis patient. 6.4 The disturbing adverse effects were dealt with effectively by means of oral corticoids under antibiotic coverage (tetracycline); side effects of lesser importance were apparently relieved by combined Ereatment wiEh aspirin and promethazine (Phenergan). 1 This phenomenon does not occur during treatment wiLh DEC. o o G o o66 @ o @ o@OG o@OGo€ e e @ o e o o@oo o@O€)ocoooo o@oooo o@ o@oooo e ci G o€ o@oeoooe oOEocoooo o G Males Females (32) (46 ) oo 15 25 35 45 55 age Fig.1. Distribution of subjects treated, age and sex by /I I I I :\/@u I I I I I D-r \ Dx tsD \ D>tP \ D|=- @t ! I I Ex -r D{ \* \/ I I I @ r.\ H N F{ jd G) 0.)B r{ F{ il o o o r--{ 0) 0) o\ 3 q.) (.) B @ ji c, qJ B F\ ji o CJB \o JI G,} ra J 0., c) $ fi OJ c)B ca J o G,) o.t Jd o(, B r-l J. c., CJB F-l) - 14z - tr) ca F{ tr) (O sf O) c\l sf N c.J] <r u5 F{ sf Ot sf H cf) tr) c\.l cr) @ H a, H cO sf s U) 6 o 'rl .lJ d 'r{ E$ x OJ .o (u ]J d CJ E +J$ o t{ .lJ tt{ o o) r{ d .lJ CJ E 'F{H C\ b0 lE{ FlH& trr o\ F\ o\ F{ O\r\>o\l-{ .-{d5>,d r-r$5 F)- co@ N F-l tr6oo c! oJd ..t o) +J G)(UB f, Etrdo x.ilG,l .IJ(d hd1r .r.loEc(d 'F{ XEo) 'Fl ri lJ O(,jlr(dPr Fl Q&g rrN r{ 6 o 'rl b0 o "F+Ncoo E r--r .FlFr (d rJ(0 (J$.c .Frtr+J tr 'r{ -C 'r{E o. r-{$o q) x E] .r{ o(dqu! =(,rJp.eO(,).F{'': +r q u)1i<u6q,HoE\- ,Ydod-f '='ilru.'{E .: lt '--{ ll O =tua2. I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I O Males O Females o o rooo mf Fig.3. Frequency distribution of initial parasite counEs aoo c o oeoooo 3 o Goe U U oOGoooc o@ 6 o G o o oe nO5ooaoooooo o o o G €e o (-) o a o o o0 G o c c o6oe o@ 2OO 3OO 4OO sOO 600 7OO BOO gooolo )O 3,59 o ag oo loo 80 60 40 2U 020 I + (+) (-)+ 40 60 80 too% Fig.4. Decreases in parasite counts after 3 months(croups I and II). o oocoooooe€, o tt c a\ o o o o o \J o oocOGOcO-o o-c I o3g o <39 cOr O,O ()rO Ol I 9r ' ^Ood o ooo oo oro Qro 3 oooooooo lOO 80 60 40 20020 t + (+) (-) + 40 60 80 loo% Fig.5. Decreases in parasite counts after 2 months(Groups III and IV) 9 ao o) v +J G 0, E 'lJd G) tr rJ o0 a 'F{ ro o o o G,l{ U) F-l (.) CJ F{ (U E o(u F{ o. 'rl E(d t{) U) dd o) d o0 .rl trr a (o U) ln a $ a (f) a t c0 N o E o o t,)$oN o