98

TRANSACTIONSOF THE ROYAL S~CIEIYOFTROPICAL MEDICINEAND HYGIENE (1995) 89,98-102

Treatment of bancroftian filariasis in Recife, Brazil: a two-year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine

Gerusa Dreyer’, Amaury Coutinho’, Demo&to Miianda2, Joaquim Noroes2, Jose Angelo Rizzo2, Eliane Galdino’, Abraham Rochal, Zulma Medeirqs’, Luiz D. Andrade’, Abiel Santosl, Jose Figueredo-Silva3 and Eric A. Ottesen4 bntro de Pesquisas Aggeu MagalhaeslFIOClXJ~, Recife, Brazil; 2Hospital das Clinicas da Universidade Federal de Pemambuco, Recife, Brazil; 3Laboratorio de Imunopatologia Keiso-AsamilUFPE, Recife, Brazil; 4National Institutes of Health, Bethesda, Maryland, USA

Abstract The effectiveness of single oral doses of ivermectin (200 or 400 pg/kg) and diethylcarbamazine (DEC, 6 mgikg), preceded 4 d earlier by either placebo or very small doses of these drugs, was compared, over a 2- year period, in a double-blind trial in 67 microfilaraemic Brazilian men with bancroftian filariasis. Regimens containing ivermectin alone decreased the number of microfilariae significantly faster and more effectively for the first month after treatment than regimens containing DEC alone, but the latter were significantly more effective throughout the second year after treatment (1.7-8.2% of pretreatment levels with DEC vs. 126-30.8% with ivermectin during that period); the higher ivermectin dose showed a tendency towards more effectiveness than the lower dose. Most effective was the combination of ivermectin (20 pg/kg) fol- lowed 4 d later by DEC (6 mg/kg), with reduction of microfilaraemia to 2’4% of pretreatment levels at 2 years. Adverse reactions were well tolerated with all regimens, the reactions being significantly more gener- alized (i.e., fever) following ivermectin and localized (i.e., scrotal inflammatory nodules around dying adult worms) following DEC. Further trials of single-dose combination therapy vs. single high doses of ivermec- tin or DEC should determine the ideal regimen for treatment and control of bancroftian filariasis.

Keywords: fdariasis, Wuchereriu bancrofii, ivermectin, diethylcarbamazine, Brazil

Introduction The first study of the effects of ivermectin in patients

with bancroftian filariasis living in Brazil (COUTINHO et al., 1994) was a dose-finding trial comparing single doses of 20, 50, 100 and 200 Kg/kg. It indicated that Wuchere- ria bancrofti parasites from Brazil are similar to those stu- died elsewhere in their susceptibility to ivermectin (e.g. KUMARASWAMI et al., 1988; Roux et al., 1989; ISMAIL et al., 1991) and that ivermectin is very effective in causing rapid and prolonged microfilarial clearance from the blood, though still commonly inducing systemic adverse reactions. Subsequently, a study in Haiti suggested that ivermectin might be both more effective and well tol- erated in lymphatic filariasis when given in higher dos- ages (200400 yglkg) preceded by a small 20 pg/kg dose of ivermectin, to ‘clear’ microfilariae (mf) relatively slowly from the blood (thereby reducing the severity of adverse reactions), 4 d before the high dose is given (RI- CHARDS et al., 1991; EBERHARD et al., 1992; ADDISS et al., 1993).

The present study was therefore designed with the fol- lowing 4 important goals: (i) to compare the efficacy and tolerability of ivermectin given either in single or in ‘s lit’ doses; (ii) to compare the efficacy and tolerability o F lugh-dose ivermectin (420 pg/kg) with those of lower dose ivermectin (200 pg/kg) and diethylcarbamazine (DEC) administered in these regimens; (iii) to determine and compare the long-term (2 years) efficacy of each of these drugs alone; and (iv) to define the results obtained when a combination of single doses of ivermectin and DEC is used to treat W. bancrofti microfilaraemia.

Materials and Methods Patients

All patients were asymptomatic adult military men from the Brazilian army whose ages ranged from 18 to 44 years (median 22 years), who lived in the endemic area of Greater Recife, Brazil (Recife, Olinda and Jaboatao cities), and who presented microfilaraernias greater than 100 mf/mL. Informed consent was obtained from all par- ticipants.

The study was carried out in ‘double-blind’ fashion, and the patients were allocated randomly into 6 groups receiving the different drugs and dosages outlined in

Address for correspondence: Dr G. Dreyer, C&AM FIOCRUZ, Campus da Universidade Federal de Pernambuco, Av. Moraes Rego s/n, 50730 Recife, Pemambuco, Brazil.

Table 1. ‘Six-arm’ study evaluating ivermectin and DEC in clearing W. bancrofii microlilaraemia; Recife, Brazil

Regimen Microfilaraemia”

Placebo plus Ivermectin 200 pg/kg DEC 6 mgikg

DEC 1 mg/kg+DEC 6 mg/kg Ivermectin 20 pg/kg plus

Ivermectin 200 pg/kg Ivermectin 400 yg/kg DEC 6 mg/kg

Total

554 (106-2528) 366 (105-1828) 550 (103-3279)

775 (148-14135) 674 (127-2900) 890 (114-2753) 616 (103-14135)

No. of patients

11

::

::

fi: “Geometric mean (range in parentheses).

Table 1. The 2 doses of drug or placebo in each regimen were given 4 d apart. On each of the 2 medication days, all patients took the same number of apparently identical capsules containing active drug or placebo, according to the regimen.

Clinical and laboratory evaluations All patients were admitted to hospital for one week at

the Hospital das Clinicas of the Universidade Federal de Pernambuco in Recife. A complete physical examination was performed before treatment; vital signs were checked every 4 h for 2 d, then 3 times daily during the remainder of the period in hospital and at 2 weeks and 1, 3, 6, 12, 18 and 24 months after treatment. Participation was 100% for the first 30 d, 98~5% at 3 and 6 months, 84% at 12 months, 70% at 18 months, and 75% at 24 months. Most absences were related to military duties.

Blood samples (1 mL) were collected between 23:00 and midnight, and examined, on each of 2 d during the week before hospital admission and on days 0, 1, 2, 7 and 14, and months l., 3,6, 12, 18 and 24 after treatment to establish the mlcrofilarial densities by filtration through 13 mm/3 w polycarbonate membranes (Nu- clepore@, Pleasanton, California, USA). To compare the results of each treatment regimen, geometric means of each individual’s mf levels, at each time point, were ‘nor- malized’ by expression as a percentage of the pretreat- ment mf levels.

The laboratory studies included the following: com- plete blood count with absolute eosinophil count, and

determination of levels of serum creatinine, total bi- stool examinations before treatment and on days 30, 90 lirubin, aspartate aminotransferase (SGOT), alanine ami- and 180; and electrocardiogram and chest radiographs notransferase (SGPT), and alkaline phosphatase (AP). before drug administration.

Pulmonary function tests included spirometry, and flow-volume curves were analysed by computer (An- arned’a’ AM 4000). The following items were assessed: forced vital capacity (FVC), forced expiratory volume in fust second (FEV l), and maximal flow at 50% of FVC.

Other evaluations included urinalyses before treatment and at 1, 2, 3,7, 14,21, 30,60 and 90 d after treatment;

Adverse reaction scores Post-treatment vital si

monitored and recorded r s and clinical findings were

y check list every 4 h for 2 d, and then assessed and recorded each morning for 5 d exactly as described previously (COIJTINHO et al., 1994). The clinical findings evaluated were systemic -(fever, weakness? headache, chills, myalgia, dmphoresls), ga- strointestmal (anorexia, nausea, abdominal pain, worm elimination), respiratory (sore throat, cough, dyspnoea, wheezing, rakes), cardiovascular (postural hypotension), cutaneous (palpebral oedema, papules), and localized (nodule formation). Severity of each clinical fmding was scored on a scale of 0 to 3 (none, mild, moderate, severe). By summing the recorded values at every assessment, total reaction scores were generated for each individual.

- DEC6

-c)- DECl+6

60-

40-

0 3 6 9 12 15 16 21 24

cl 6 100

(d .- E 80

2 a

E 60 2

-ff+ her220

-t-- lver20+200

& lver20+400

e e! 20 n

* 0 0 o- 3 6 9 12 15 18 21 24

80

60

-D- DECl+6

& lver20+400

e lver20+DEC6

0 3 6 9 12 15 1e 21 2b

Months Post-Treatment Fig. 1. Post-treatment changes in levels of microfilaraemia in the various treatment groups. Each symbol denotes the geometric mean of the blood micmfilatial numbers of each individual (expressed as a percentage of that individual's pretreatment [Pre-Rx] level) at time points up to 2 years after treatment. Statistically significant differences between groups are noted in the text. A. Comparison of single and split-dose DEC regimens. B. Com- parison of single and split low and high dose ivermectin regimens. C. Comparison of the optimal single-drug regimens (DEC or ivermectin) and the combination regimen. See text for further details (DEC doses are in mg/kg, ivermectin doses in &kg; see Table 1).

99

Statistical analysis Data were analysed by Fisher’s exact test, Student’s t

test and the Wilcoxon signed rank test, as appropriate.

Results &Racy

Pretreatment levels of microfilaraemia in the 6 groups were not sixnificantlv different (Table 1).

With DEC, the single and split dose drug regimens were comparable (Fig. 1, A); the decreases in microfila- raemia were very similar, with good results in both groups one and 2 years after treatment (reductions to 5.2% and 1.7%, and to 8.2% and 5.7%, respectively, of pretreatment levels in the 2 groups). Similarly, with iver- mectin there was no significant difference in efficacy at any time between the single (220 ug/kg) and split dosage (20 ug/kg+ZOO yg/kg) regimens (Fig. 1, B).

When all 3 ivermectin regimens were compared (Fig. 1, B), there was a tendency for the highest ivermectin dosage (420 uglkg) to be more effective than the lower dosages (220 @kg and 20+200 &kg), especially at 2 years after treatment (reductions to 13.7% vs. 26.6% and 30.8% of pretreatment levels, respectively), but the dif- ferences were not statistically significant. It was clear from the comparison that ivermectin was significantly more effective than DEC in reducing microfilaraemia during the first month after treatment (P<O.OOl), though it tended to be less effective thereafter.

Finally, the effects of what appeared to be the best single-drug regimens (the split DEC regimen and the split high dose [420 &kg] ivermectin regimen) were compared (Fig. 1, C) with those of the 2-drug combina- tion (ivermecin 20 ug/kg+DEC 6 mg/kg). Both regimens containing 6 mg/kg of DEC, regardless of whether it was preceded by 1 mg/kg of DEC or 20 yg/kg of ivermectin, gave equivalent, excellent long-term results (reductions to 1.7-5.7% of pretreatment levels) at 12, 18 and 24 months after treatment. Statistically significant dif- ferences, however, between these regimens and that of high-dose ivermectin alone were seen only at 18 months for both DEC-containing regimens (P=O.O35 and P=O.O26, respectively) and at 12 months for the DEC 1+6 regimen (P=O.O27).

Tolerability All but 16% (11167) of patients showed some adverse

reaction to their treatment. In comparing systemic adverse reactions after single or

split dose regimens, though there was a tendency for the reaction scores in the single dose groups (ivermectin 220 ug/kg or DEC 6 mg/kg) to be tive split dose groups, the

eater than in the respec- d&rences were not statisti-

cally significant. Furthermore, whether dru tion was in single or split dose regimens ha t.f

administra- no effect on

the development of local adverse reactions to either drug; and the occurrence of systemic or local adverse reactions

100

was similar whether the ivermectin dose was low or high. Therefore, in Table 2 the data on adverse reactions were grouped for patients taking either DEC or ivermectin re- gardless of whether the doses were single or split, high or low; patients taking the combination of ivermectin and DEC were excluded from this analysis. Following iver- mectin treatment, systemic adverse reactions tended to be more frequent, with the occurrence of fever being sig- nificantly more frequent, than after DEC. Conversely, local (scrotal area) symptoms and/or signs developed sig- nificantly more frequently in the DEC groups.

Table 2. Comparison of adverse reactions following either DEC or ivermectin treatment; Recife, Brazil

Signs or symptoms DEC Ivermectina

No. of. patients “Y;gy:’

Malaise Gastrointestinal Respiratory Neurological

Lo;dn(scrotal area)

Imhunmation Nodules

Renal Haematuria

“Statistically significant differences are indicated thus: *r<o*o2, **r<o-01.

Table 3. Localized urogenital alterations observed after treatment with ivermectin or DEC for bancroftian tilariasis; Recife, Brazil

No. of patients Funiculitis

Alone + Epididymitis + Orchiepididymitis +Hydrocele (acute)

Presence of genital nodule

67

‘Z (28.4%)

t

1; (26.9%)

ug/kg) and most local signs and/or symptoms, in the scrotal area, only after the second drug (DEC, 6 mg/kg); haematuria occurred or intensified after both drugs.

Other adverse reactions seen in the 67 treated patients included headache (generally accompanying fever) in 34 patients on both drugs, myalgia in 6 patients taking iver- mectin and 3 on DEC, dyspnoea in one case after iver- mectin, and palpebral oedema in one patient after DEC. Postural hypotension did not occur in any of our pa- tients.

Lung function tests showed alterations in 10% of pa- tients, some on ivermectin and some on DEC; for only one was the intensity severe (the same individual who presented with dyspnoea).

The serum chemistry tests to monitor liver function in all patients remained normal following treatment. The kinetics of post-treatment blood eosinophilia were similar for all regimens, with significantly increased numbers of eosinophils at 7 and 14 d after treatment. There ap- peared, however, to be no correlation between peak eosin- ophilia and the level of pretreatment microfilaraemia in these individuals (data not shown).

Detailed monitoring of the genital region, where adult worms are likely to be localized (AMARAL et al., 1994; DREYER et al., 1994), indicated that the principal post- treatment alteration was funiculitis (284%), either iso- lated or accompanied by other signs (Table 3). Later, local nodules developed in 26.9% of patients. Biopsies were taken from 8 of the patients with post-treatment no- dules, all belonging to the DEC groups (Table 4). The onset of the urogenital symptoms/signs varied between 1 and 8 d, and the time of biopsy in relation to this onset varied between 23 and 120 d. The density of microfila- raemia before treatment in these 8 individuals ranged from 348 to 3279 mf/mL, and did not differ from that in patients without localized adverse reactions.

All biopsies showed damaged or dead adult worms surrounded by inflammation. The lesions themselves, however, were in different phases of evolution, some worms being almost completely reabsorbed and others showing calcification. Degenerating adult worms were surrounded by granulomatous reactions composed of macrophages, lymphocytes, plasma cells and eosinophils (Fig. 2, Table 4). Free mf could sometimes be observed in the tissues.

Table 4. Histopathological findings in biopsies from 8 patients with bancroftian tilariasis; Recife, Brazil”

Free Plasma Giant Symptomsh Biopsy‘ Drugd Mf mtf Eosinophils Macrophages Lymphocytes cells cells Fibrosis Calcification

7 23 DEC+DEC ++ - +++ ++ ++ ++ + -

7 23 IVZO+DEC +++ +++ +++ +++ ++ ++ - + -

8 31 IVZO+DEC +++ +++ +++ +++ ++ ++ + ++ -

6 ii

IVZO+DEC +++ - +++ +++ ++ ++ + ++ -

1 DEC+DEC ++ - +++ +++ ++ ++ +++ ++ -

4 46 DEC+DEC ++ ++ +++ +++ +++ ++ +++ +++ + 5 46 Pbo+DEC ++ - +++ +++ ++ ++ +++ +++ ++ 6 120 Pbo+DEC ++ - ++ +++ ++ ++ +++ +++ +++

“Graded from -, absent to +++, prominent. bInterval between the first drug dose and appearance of the first symptoms (d). ‘Interval between appearance of the first symptoms and biopsy (d). dTherapeutic schedule (DEC=diethylcarbamazine, IVZO=ivermectin 20 Kg/kg, Pbo=placebo). ‘Microfilariae within the female adult worm. ‘Micofilariae in the tissue.

Haematuria after treatment occurred with almost Discussion equal frequency and intensity after ivermectin or DEC treatment. It generally developed 24 to 48 h after giving

In some of the earlier dose-finding studies of the effi-

the drug, was transient (usually lasting l-7 d), and cacy of ivermectin for decreasing microtilaraemia in pa-

tended to be more prominent and severe after the second tients with bancroftian filariasis, the results suggested

(larger) dose in the split dose regimens. Serum creatinine that higher doses of ivermectin (up to the maximum

values remained unchanged in all patients. tested, 200 ug/kg) might result in more sustained effects

Interestingly, patients in the combination ivermectin (Roux et al., 1989; ISMAIL et al:, 1991; KAR et al., 1993). The current study was designed to extend these

plus DEC group showed most of their systemic adverse earlier findings by (i) testing the hypothesis that adminis- reactions (fever, malaise, respiratory, gastrointestinal and tering a small amount of ivermectin several days before neurological reactions) after the first drug (ivermectin, 20 the larger dose would result in greater efficacy and/or

101

high dose ivermectin (20+400 @kg) with that of DEC or a combination of ivermectin ~1~s DEC (Fig. 1, C). In our study, the effectiveness of ai1 3 groupswas not signi- ficantly different 2 years after treatment, but the regimens containing DEC tended to be more effective. These results, however, are not fully concordant with those reported from Haiti where the same combination of ivermectin and DEC gave results similar to those in the present study, but where DEC alone was significantly less effective (ADDISS et al.. 1993). Aaain, the sizes of the treatment groups in both &dies’we& small so that con- fidence limits are both wide and overlapping.

Fig. 2. Biopsy of scrotal nodule from case no. 6, 46 d after he first re- ceived DEC. A degenerating adult worm is seen surrounded by a vi- gorous granulomatous response. Partial calcification of the parasite is marked by the arrow. Haematoxylin and eosin stain; x 25.

tolerability than giving the same dose at one time, (ii) comparing directly the effects of single or split dose DEC with those of ivermectin, (iii) testing the efficacy of a higher dosage of ivermectin (420 pg/kg) than had pre- viously been used, (iv) evaluating whether a combination of low dose ivermectin followed by DEC was more effec- tive than either ivermectin or DEC alone.

Split dose regimens appeared to have no significant ad- vantage over single dose administration of the same amount of drug (either ivermectin or DEC) with respect to efficacy (Fig. 1, A and B), though the fact that there were only 11 patients in each of these treatment regimens decreases the power of the study to identify all but very obvious differences between single and split dose regimens. Similarly, there was a tendency towards evok- ing fewer and less intense systemic reactions by splitting tD;ermectin dose, but no such tendency was seen with

The second important finding was that the highest dose of ivermectin (total 420 pg/kg) appeared more effec- tive than lower doses of the drug. Similar findings have been made by others (RICHARDS et al., 1991; KAZURA et al., 1993; MOULIA-PELAT et al., 1994), and similar con- clusions have been reached regarding the treatment of other filarial infections with ivermectin, such as Brugiu muluyi (see SHENOY et al., in press), Loa lou (see MAR- TIN-PREVEL et al., 1993). Therefore, the comparison of single dose DEC (6 mg/kg) with single dose ivermectin (220 pg/kg) (Table 1) was not so informative as it would have been if a higher ivermectin dose had been used for the direct comparison with DEC.

More informative was the comparison of the efficacy of

This discrepancy between sets of findings identifies a critical issue that must soon be resolved-namely, whether single dose DEC, single dose ivermectin or sinele dose combination DEUivermectin is the most ef- fe&ve in diminishing microfilaraemia and maintaining it at a low level for periods of 1 to 2 years. It is clear that ivermectin decreases microfilaraemia more rapidly than DEC and that for the first month or so this difference is statistically significant. However, ultimate recommenda- tions for control programmes, when decisions must be made on the basis of long-term effectiveness, tolerability and cost of drug, will require comparative efficacy of these different regimens to be established with certainty. The findings from this study suggest, preliminarily, that a single treatment every 1 or 2 years should be enough to keep microfilaraemia at very low levels and, thereby, perhaps to interrupt transmission in a community. The important question, however, is which treatment regimen should be used, and further study is required of the regimens corn ared in Fig. 1, C, with perhaps even t;r;lFges o P* lvermectm alone or in combmation

The tolerability assessments were particularly interes- ting because clear differences were shown between the kinds of post-treatment reactions seen following ivermec- tin and DEC. Earlier reports (e.g., b

i OTTE~EN et al.,

1990) emnhasized the sunilaritv of t e freouencv and character bf adverse reactions following ivermectin and DEC, but in the present study it was clear that ‘systemic’ adverse reactions, particularly fever, were more promi- nent after ivermectin treatment and that local reactions (scrotal area) were significantly more DEC treatment (Table 2). The reasons or the different F

rominent after

character of these reactions are probably the facts that ivermectin causes more rapid clearance of mf from the blood with a resultant more severe Mazzotti-like reaction than DEC (OTTESEN, 1987) and that DEC has a promi- nent macrofilaricidal activit that induces local inflam- matory responses around ymg parasites. Ivermectin, cy, too, may be macrofilaricidal but, even if it is, its effects do not appear to induce the same degree of acute lo- calized inflammation.

Interestingly, the biopsies of these localized inflamma- tory reactions gave clear evidence of parasite death fol- lowing administration of DEC. These findings and the inferred temporal sequence of changes (Table 4) are very reminiscent of those made earlier by Chinese workers who first presented compelling evidence for the macro- lilaricidal activity of DEC, though they used much higher doses (CH’EN, 1964). Such biopsies are clearly helpful in establishing the macrofilaricidal effect of DEC, but what is still unclear is why some, but not all, worms appear to be killed by DEC. Hopefully, use of the newly introduced ultrasound techniques for localizing and as- sessing activity of adult worms in humans (AMARAL et al., 1994) will permit much more direct and under- standable assessments of the effects of DEC on adult worms. Combined use of ultrasound and bionsv tech- niques should allow us to define with certainty -just what macrofilaricidal effects each of these drues-ivermectin and DEC, alone or in combination-has ‘;n bancroftian filariae .

Another important conclusion from these studies is that drug tolerability is not likely to be the criterion

102

determining the relative usefulness of any of these DEC or ivermectin regimens. The adverse reactions that oc- curred after both drugs, even though affecting more than 80% of the treated individuals, were generally mild or moderate and easily tolerated or managed. Therefore, in future studies the primary focus of assessment should be on maximizing therapeutic efficacy, both in terms of the effects on microftiaemia and on the viability of adult worms. It seems extraordinary that a single dose of DEC appears not only as effective as a single dose of ivermec- tin in reducing microfilaraemia but also as effective as the 12 d regimen of DEC recommended for decades for treatin bancroftian filariasis (WHO, 1992). Even the macro B ilaricidal effect demonstrated by biopsy of scrotal nodules in the present study followed a single dose of 6 mg/kg of DEC (sometimes preceded by low doses of DEC or ivermectin) and not the very high DEC doses ad- ministered in the earlier Chinese study (CH’EN, 1964).

Future chemotheranv trials will need to utilize both these biopsy and othe; iechniques (e.g., ultrasound, cir- culating antigen assays) to determine lust how microfila- ricidal and macrofilaricidal each experimental regimen has been; only then will we be able to understand fully how effective ivermectin and DEC can be in bancroftian filariasis, whether given alone or, as so promisingly seen in the present study, in combination at intervals of every 1,2 or even more years.

Acknowledgements This study was supported in part by a grant from the

UNDPiWorld Bank/WHO Special Programme for Research and Trainin in Tropical Diseases. We appreciate the valuable stimulus an cf help for the study given by Dr C. P. Ramachand- ran., Dr J. Chodakewitz and Mr D. Neu, as well as the editorial asststance of MS Sheryl Rathke and MS Crystal Talley.

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Received 15 March 1994; revised 24 May 1994; accepted for publication 24 May I994