Efficacy of five annual single doses of diethylcarbamazine for treatment of lymphatic filariasis in Fiji.

Efficacy of five annual single doses of diethylcarbamazine for treatment of lymphatic filarlasis in Fiji J.U. Mataika,' E. Kimura,2 J. Koroivueta,3 & M. Shimada4 Annual single-dose treatments with diethylcarbamazine citrate (DEC) at a dose of 6mg/kg have been reported effective in reducing microfilariae (mf) rate and density and applicable to large-scale filariasis control campaigns. However, the efficacy of such treatments has not been studied quantitatively in relation to different pretreatment levels of endemicity. This study of 32 villages in Fiji revealed that five treatments repeated annually steadily reduced village mf rate, and that the degree of reduction was not influenced by pretreatment levels of mf density or rate. This indicates that an annual dosage scheme is applicable to high- endemicity areas. The results also suggest that such treatment affected juvenile forms of Wuchereria bancrofti and may prevent them from reproducing. Introduction Diethylcarbamazine citrate (DEC) has been widely used for the treatment of lymphatic filariasis since its filaricidal effect was first reported (1). A series of trials designed to find the most suitable treatment regimen in endemic areas showed that a 12-dose course of treatment (12 x 6mg/kg body weight) was necessary to treat infection with Wuchereria bancrofti (2, 3). This scheme has been employed worldwide with success, but repeating 12 doses can pose considerable operational difficulties. However, a satisfactorily strong effect from a single 6mg/kg dose was reported in French Polynesia (4) and Samoa (5). In Samoa, when assessed 12 months after treatment, the single dose reduced the mf rate by 54% and mf density by 94%. A study in Fiji (6) revealed that five rounds of annual treatment with 6 mg/kg were as effective as a 28-dose course of treat- ment delivered over 2 years (total dose, 140mg/kg) when assessed 5 years after commencement of treat- ment. A single-dose scheme was shown to be effec- tive against Brugia malayi as well (7, 8). A single dose of DEC (6mg/kg) has been re- ported to reduce mf counts by 85-95% in a cohort of mf-positive individuals (5, 9, 10). This implies that I Senior Medical Officer, Wellcome Virus Laboratory, Tamavua Hospital, Suva, Fiji. 2 Professor, Department of Parasitology, Aichi Medical University, Aichi, Japan. 3 Chief Medical Officer, Wellcome Virus Laboratory, Tamavua Hospital, Suva, Fiji. 4 Professor, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. Reprint No. 5898 high-count carriers will remain mf positive after treatment, and therefore that a single treatment will not effectively reduce the mf rate in a commu- nity with many high-count carriers. It has been reported that the recurrence rate of microfilaraemia within a year of DEC treatment was higher where pretreatment mf density had been higher (11). A possible explanation is that juvenile parasites present during treatment were not affected and later began reproduction. It is possible that a high mf density facilitated filarial transmission by vector mosquitos and resulted in the accumulation of juve- nile forms (3rd and 4th larval stages and young adults) in the human population. However, no study has compared the efficacy of annual single-dose treatment in areas with different endemicity. This article reports the influence of pretreatment levels of mf density and rate on reduction in mf rate after annual single-dose treatment. Materials and methods Sample villages, blood examinations, and treatments The study was carried out on Kadavu Island, Fiji, and included 43 villages with a total population of 7600. Of these, 5799 (76.3%) persons were registered in the 1985 pretreatment survey. Eleven villages were excluded from the study because less than 30 persons were examined in each of them as a result of small size and/or poor compliance. All of those reg- istered in 1985 (4686 people in 32 villages) were ex- amined for mf using a 60-il finger-prick (thick smear method). Single-dose mass treatment with DEC Bulletin of the World Health Organization, 1998, 76 (6): 575-579 © World Health Organization 1998 575 J.U. Mataika et al. (6mg/kg) was given in early 1986. Annual blood ex- aminations and subsequent mass treatments were then performed in 1987, 1988, 1989, and 1990, with the final blood survey taking place in 1990-91. Vil- lages were informed about a week before the arrival of the filariasis team. Residents gathered in the vil- lage community hall where names were called by household. Any new arrivals were included for treat- ment. Blood was collected and clinical examinations conducted where necessary. All slides were brought to the Filariasis Office in Suva for processing, micro- scopic examination, and recording. Only the results of those registered in 1985 were enumerated. Details of the villages, mass treatments, and blood examina- tions have been described (6). The village mf rates before and after treatment, and the pretreatment mf density (geometric mean of mf counts per 601.t of blood) are shown in Table 1, together with data on the numbers of people examined and those found positive for mf. Statistical analysis In order to study the influence of pretreatment ende- micity, the villages were grouped into five categories based on pretreatment mf density: catl (mf density < 10, average mf density = 5.6, 10 villages); cat2 (10 S mf density < 15, average mf density = 11.6, 8 villages); cat3 (15 - mf density < 20, average mf density = 17.5, 6 villages); cat4 (20 - mf density < 30, average mf density = 24.2, 3 villages); and catS (mf density ¢ 30, average mf density = 48.4, 5 vil- lages). A total of 192 observations of mf rate were obtained from the 32 villages during the six blood examinations. Under the assumption that treatment would reduce mf rate at a certain rate, all mf rates Table 1: Microfilariae (mf) rate before (1985) and after five annual treatments (1987-91) with diethylcarbamazine citrate mf rate as % (No. mf positive/No. examined) mf densitya Village 1985 1985 1987 1988 1989 1990 1990-91 Muani 1.0 0.4 (1/238) 0.0 (0/174) 0.0 (0/168) 0.0 (0/147) 1.4 (1/72) 0.0 (0/136) Wailevu 3.0 1.0 (1/101) 1.4 (1/71) 0.0 (0/67) 0.0 (0/61) 0.0 (0/60) 0.0 (0/59) Naqalotu 5.6 7.3 (9/123) 1.1 (1/88) 1.1 (1/92) 0.0 (0/84) 0.0 (0/75) 0.0 (0/74) Namara 6.8 2.6 (6/228) 1.7 (3/172) 0.0 (0/142) 0.6 (1/161) 0.0 (0/144) 0.0 (0/143) Tawava 7.1 0.7 (1/145) 0.0 (0/89) 0.0 (0/101) 0.0 (0/106) 0.0 (0/86) 0.0 (0/99) Lomati 7.9 1.3 (2/156) 0.0 (0/112) 0.0 (0/107) 0.0 (0/98) 0.0 (0/107) 0.0 (0/110) Dagai 8.9 0.6 (1/159) 0.0 (0/112) 0.0 (0/98) 1.1 (1/94) 0.0 (0/100) 0.0 (0/101) Cevai 9.3 9.0 (6/67) 2.2 (1/46) 0.0 (0/49) 0.0 (0/46) 0.0 (0/61) 2.0 (1/51) Ravitaki 9.6 5.8 (18/309) 3.3 (7/210) 2.4 (4/170) 1.0 (2/197) 0.0 (0/166) 0.0 (0/193) Qalira 9.8 4.5 (5/112) 0.0 (0/65) 0.0 (0/76) 0.0 (0/79) 0.0 (0/67) 0.0 (0/74) Drue 10.2 1.6 (2/102) 0.0 (0/71) 0.0 (0/66) 0.0 (0/70) 0.0 (0/71) 0.0 (0/57) Namuana 10.2 10.9 (15/137) 7.9 (7/89) 1.4 (1/71) 2.4 (2/83) 2.3 (2/88) 1.6 (1/63) Talaulia 10.7 2.0 (2/102) 0.0 (0/78) 0.0 (0/55) 0.0 (0/71) 0.0 (0/60) 0.0 (0/59) Daviqele 11.2 5.1 (11/217) 2.0 (3/150) 0.0 (0/133) 0.0 (0/145) 0.0 (0/131) 0.0 (0/102) Namalata 11.2 10.1 (28/276) 1.8 (3/163) 5.0 (7/140) 1.3 (2/157) 0.0 (0/154) 0.0 (0/92) Galoa 13.2 8.9 (15/168) 1.7 (2/119) 1.0 (1/103) 1.0 (1/102) 1.1 (1/93) 0.0 (0/89) Kabariki 13.5 3.4 (5/146) 0.0 (0/93) 0.0 (0/103) 0.0 (0/100) 1.0 (1/100) 0.0 (0/92) Solovola 13.8 11.0 (10/91) 3.0 (2/67) 4.3 (2/46) 3.3 (2/60) 1.6 (1/64) 0.0 (0/64) Nabukelevu-i-ra 15.9 0.4 (1/274) 0.0 (0/199) 0.0 (0/164) 0.0 (0/156) 0.0 (0/158) 0.0 (0/153) Mokoisa 17.0 0.7 (1/149) 0.0 (0/110) 0.0 (0/97) 0.0 (0/99) 0.0 (0/99) 0.0 (0/71) Solodamu 17.4 12.1 (11/91) 15.7 (8/51) 2.4 (1/41) 4.8 (3/63) 2.9 (2/68) 1.7 (1/60) Levuka 17.8 7.9 (12/151) 2.4 (3/124) 1.0 (1/98) 0.0 (0/110) 0.0 (0/89) 0.0 (0/75) Tavuki 18.6 12.6 (18/143) 8.0 (7/87) 8.0 (4/50) 1.4 (1/69) 0.0 (0/77) 0.0 (0/58) Nasegai 19.1 3.7 (8/216) 3.0 (5/164) 0.8 (1/131) 0.7 (1/140) 1.6 (2/129) 0.0 (0/102) Nalotu 22.4 17.3 (28/162) 8.5 (11/129) 4.0 (4/100) 2.9 (3/104) 2.0 (2/101) 3.4 (3/87) Baidamudamu 25.7 13.4 (11/82) 19.4 (7/36) 5.4 (2/37) 11.4 (5/44) 3.8 (2/53) 0.0 (0/41) Yakita 26.9 15.8 (12/76) 11.5 (7/61) 3.9 (2/51) 4.2 (2/48) 0.0 (0/51) 0.0 (0/45) Korovou 33.9 9.3 (4/43) 12.1 (4/33) 9.1 (3/33) 16.1 (5/31) 12.9 (4/31) 6.5 (2/31) Matanuku 35.5 8.5 (7/82) 5.9 (4/68) 5.9 (3/51) 4.5 (2/44) 3.1 (2/65) 3.5 (2/57) Muaninuku 38.9 28.0 (30/107) 19.5 (16/82) 15.7 (11/70) 8.3 (6/72) 6.8 (5/74) 7.1 (4/56) Nukunuku 61.7 28.8 (19/66) 23.7 (9/38) 19.4 (6/31) 13.2 (5/38) 12.2 (6/49) 4.7 (2/43) Nasau 67.6 16.8 (24/143) 19.8 (21/106) 12.8 (10/78) 4.5 (4/88) 8.0 (7/87) 2.7 (2/74) Total 6.9 (324/4686) 4.1 (132/3257) 2.3 (64/2819) 1.6 (48/2967) 1.3(38/2830) 0.7(18/2611) a Geometric mean of mf counts per 60tl of blood. WHO Bulletin OMS. Vol 76 1998576 Efficacy of diethylcarbamazine in Fiji were reported as In (100 x (No. positive + 0.5)/No. examined). Rates were grouped by category and year, and the averages are plotted in Fig. 1. The General Linear Models procedure (SAS/STAT, SAS Institute Cary, North Carolina, USA) was used to determine whether there was any difference in the change of mf rate across categories. Type II sum of squares was used as a control hypothesis test. "Year" was treated as a continuous variable. There was a clear positive relationship between pretreatment mf densities and mf rates (r = 0.747, P < 0.001) in the 32 villages. The same analytical pro- cedure was therefore applied to groups based on the pretreatment mf rate: catl (mf rate < 1%, average mf rate = 0.6%, 6 villages), cat2 (1% S mf rate < 5%, average mf rate = 2.8%, 7 villages), cat3 (5% - mf rate < 10%, average mf rate = 7.1%, 8 villages), cat4 (10% - mf rate < 15%, average mf rate = 11.3%, 6 villages), and catS (mf rate - 15%, average mf rate = 20.4%, 5 villages). All statistical tests were considered significant at P < 0.05. Results and discussion The analysis of covariance of log-transformed mf rates across the five groups defined by pretreatment mf density showed statistically significant differences between categories (P < 0.001). When the average mf rates of the five categories were compared using Scheffe's multiple comparison test, cat4 and cat5 each had a significantly higher rate than catl, cat2, and cat3 (P < 0.05). Among the five regression lines obtained, there was no significant interaction be- tween category and year (P > 0.392), which implies that the degree of reduction in mf rate was not differ- ent across all categories. The analysis of covariance of transformed mf rates across the five groups defined by pretreatment mf rate (Fig. 2), showed a statistically significant dif- ference between categories (P < 0.001). However, there was interaction between category and year among the five regression lines (P < 0.002). Further study showed that the regression line of catl was not significant (P > 0.227). After exclusion of catl, the four remaining regression lines were without interac- tion (P > 0.273), indicating that the pretreatment mf rate did not influence the rate of reduction in cat2- catS. The reason why treatment failed to reduce mf rate significantly in catl may reflect sampling prob- lems rather than absence of drug effect. Thus, annual treatments can reduce village mf rate steadily, and pretreatment mf density or rate do not influence the degree of reduction. This would imply that annual single-dose treatment (6mg/kg Fig. 1. Change in microfilariae (mf) rate before (year 0) and after (years 2-6) annual treatment in five endemic- ity categories defined by pretreatment mf density. Cat1 (+): mf density < 10; cat2 (0): 10 S mf density < 15; cat3 (U): 15 < mf density < 20; cat4 (V): 20 S mf density < 30; cat5 (O): mf density > 30. 3- 2- 1- 0 v 0 0 o 0 v U + U 0 + + 0 EVV .-j U ± Fig. 2. Change in microfilariae (mf) rate before (year 0) and after (years 2-6) annual treatment in five endemic- ity categories defined by pretreatment mf rate. Catl (+): mf rate < 1; cat2 (0): 1 S mf rate < 5; cat3 (1): 5 S mf rate < 10; cat4 (V): 10 S mf rate < 15; cat5 (O1): mf rate ¢ 15. 0 0 3- 2 - 1- 0- + V U 0 v V 0 ± 0 0 0 v 0 0 V 0 ++ I a I .I . .- 0 1 2 3 4 5 6 Year 0 1 2 3 4 5 6 YearWHO 98311 WHO Bulletin OMS. Vol 76 1998 4-, -j O. I1_ -I . . . . . . WHO 983 10 577 J.U. Mataika et al. DEC) can be applied in highly endemic areas with- out loss of efficacy. These results imply that the drug may also prevent juvenile forms (3rd and 4th larval stages and young adults) from reproducing. The antilarval effect of DEC has been demonstrated in animal models (12, 13). Although reinfection after treatment would counter the DEC effect, since very few mf positives were found among individuals under 1 year of age, reinfection apparently did not influence mf rate within a year. Annual single-dose treatment with DEC is sim- ple and economical. Since DEC has been proven safe, local people may be more ready to assist in a treatment campaign. In Samoa, a nationwide filariasis control programme covering 160000 people was successfully conducted with the participation of village women's committees (14). By employing the annual single-dose scheme, a filariasis control pro- gramme can economize on the resources required for multidose treatments and put more emphasis on vector control, sanitation programmes and health education. The present results were obtained in an area where diurnally subperiodic bancroftian filariasis is endemic. To judge from the single-dose effects of DEC reported in various other areas of the world (7-10, 15), similar results would be expected with B. malayi and periodic W. bancrofti. Acknowledgements This investigation received financial support from the UNDP/World Bank/WHO Special Programme for Re- search and Training in Tropical Diseases (Grant No. 820006). Resume Efficacite de cinq doses uniques de diethylcarbamazine par annee pour le traitement de la filariose lymphatique a Fidji Le traitement de la filariose lymphatique par I'administration d'une dose annuelle unique de 6 mg de di6thylcarbamazine (DEC) par kg de poids corporel est repute r6duire efficacement l'indice microfilarien (nombre de personnes infest6es/ nombre de personnes examinees) et la densit6 des microfilaires et etre utilisable dans des campagnes de lutte de grande envergure. L'efficacit6 de cette therapeutique n'a toutefois pas fait l'objet d'etudes quantitatives en fonction du niveau d'endemicite existant avant l'intervention. 11 est particulierement interessant de connaitre l'efficacite du traitement monodose dans les zones de forte end6micit6 car il n'est pas exclu qu'il se revele moins efficace dans ces conditions, 6tant donne que la DEC pourrait etre inactive contre les formes juv6niles du parasite pr6sentes au moment du traitement et leur laisser par cons6quent la possibilite de se reproduire ult6rieurement. Dans cet article, les auteurs etudient l'effet de la densit6 des microfilaires et de l'indice microfilarien avant intervention sur les r6sultats du traitement par cinq doses annuelles uniques de DEC. En 1985, on a recherch6 la pr6sence de microfilaires chez les habitants de 32 villages de l'lIe de Kudavu (Fidji) par pr6levement digital de 60il de sang (m6thode de la goutte 6paisse). Debut 1986, on a proc6de a un traitement de masse consistant dans I'administration d'une dose unique de 6 mg/kg de DEC. On a pratiqu6 ensuite des examens h6matologiques annuels et proc6de a d'autres traitements en 1987, 1988, 1989 et 1990, 1'enquete hematologique finale ayant eu lieu en 1990-91. Pour etudier l'influence du degr6 d'endemicite avant traitement, on a r6parti les 32 villages en cinq categories de densite microfilarienne exprimee par la moyenne g6o- m6trique des numerations de microfilaires dans les 6chantillons de 60Ft de sang. Les resultats des mesures de l'idice microfilarien ont 6te exprim6s sous forme logarithmique et r6partis dans chaque categorie selon les deux methodes comme indique plus haut. On a etudie la modification de l'indice microfilarien dans chaque categorie par une ana- lyse de covariance. L'etude fait ressortir une diminution constante de l'indice microfilarien dans les villages sous l'influence du traitement annuel, dans une propor- tion qui ne d6pend pas de sa valeur anterieure ni de celle de la densit6 des microfilaires. Cela signifierait que le traitement annuel est applicable dans les zones de forte endemicite. On peut 6galement en d6duire que les formes juv6niles de Wuchereria bancrofti sont sensibles a la DEC et que le traitement les empeche de se reproduire. References 1. Hewitt RI et al. Experimental chemotherapy of filariasis. III. Effect of 1-diethylcarbamyl-4- methylpiperazine hydrochloride against naturally ac- quired filarial infections in cotton rats and dogs. Joumal of laboratory and clinical medicine, 1947, 32: 1314-1329. 2. Hawking F. A review of progress in the chemotherapy and control of filariasis since 1955. Bulletin of the World Health Organization, 1962, 27: 555-568. 3. WHO Expert Committee on Filariasis. Third Report. 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Comparison of effects of mass annual and biannual single dose therapy with diethylcarbamazine for the control of Malayan filariasis. Southeast Asian journal of tropical medicine and public health, 1991, 22: 402-41 1. 8. Shenoy RK et al. A comparative study of the efficacy and tolerability of single and split doses of ivermectin and diethylcarbamazine in periodic brugian filariasis. Annals of tropical medicine and parasitology, 1993, 87: 459-467. 9. Kazura J et al. Comparison of single-dose diethylcarbamazine and ivermectin for treatment of brancroftian filariasis in Papua New Guinea. American joumal of tropical medicine and hygiene, 1993, 49: 804-811. 10. Andrade LD et al. Comparative efficacy of three dif- ferent diethylcarbamazine regimens in lymphatic filariasis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995, 89: 319-321. 11. Mahoney LE, Kessel JF. Treatment failure in filariasis mass treatment programmes. Bulletin of the World Health Organization, 1971, 45: 35-42. 12. Kimura E et al. The effect of diethylcarbamazine citrate on the 3rd and 4th stage larvae of Brugia pahangi inoculated intratesticularly into inbred GN hamsters. Tropical medicine, 1985, 27: 109- 112. 13. Fujimaki Y et al. Possible direct effect of diethyl- carbamazine on the infective larvae of Brugia pahangi. Journal of helminthology, 1990, 64: 295-301. 14. Kimura E et al. Long-term efficacy of single-dose mass treatment with diethylcarbamazine citrate against diurnally subperiodic Wuchereria bancrofti: eight years' experience in Samoa. Bulletin of the World Health Organization, 1992, 70: 769-776. 15. Addiss DG et al. Comparative efficacy of clearing- dose and single high-dose ivermectin and diethylcarbamazine against Wuchereria bancrofti microfilaremia. American journal of tropical medicine and hygiene, 1993, 48: 178-185. WHO Bulletin OMS. Vol 76 1998 579