Impact of seven rounds of mass administration ... - Wiley Online Library

Tropical Medicine and International Health

doi:10.1111/j.1365-3156.2008.02044.x

volume 13 no 5 pp 737–742 may 2008

Impact of seven rounds of mass administration of diethylcarbamazine and ivermectin on prevalence of chronic lymphatic filariasis in south India J. Yuvaraj, S. P. Pani, P. Vanamail, K. D. Ramaiah and P. K. Das Vector Control Research Centre, Pondicherry, India

Summary

objective To evaluate the impact of seven rounds of mass administration of diethylcarbamazine (DEC) and ivermectin on the prevalence of chronic lymphatic filariasis and to compare it with that observed in a placebo arm in a community-level trial. methods Cross-sectional clinical surveys were carried out before and after seven rounds of mass drug administration (MDA). About 54–75% of the target population were treated at each round of MDA. results After seven rounds, the hydrocele prevalence had declined from the pre-intervention level of 20.5–5.1% (P < 0.05) in the DEC arm, from 23.9% to 10.4% (P < 0.05) in the ivermectin arm and from 20.4% to 10.9% (P < 0.05) in the placebo arm, equivalent to reductions of 75.3%, 56.6% and 46.6%, respectively. The lymphoedema ⁄ elephantiasis prevalence declined only marginally and without statistical significance from 3.7% to 3.2%, 4.6% to 3.9% and 2.9% to 2.3% in the DEC, ivermectin and placebo arm. After the seventh MDA, none of the sampled people in the 0–20 age group was found with hydrocele and there was a statistically significant decline in hydrocele prevalence in all other age groups in the communities treated with DEC, the drug known to have macrofilaricidal effect. The impact was relatively less in ivermectin arm. conclusion Repeated DEC administration has the potential to prevent incidence of new hydrocele cases and may resolve the manifestation at least in a proportion of affected people. Apart from reducing the microfilaraemia prevalence and transmission of infection, MDA also results in significant public health benefits by reducing the burden of hydrocele in treated communities. keywords lymphatic filariasis, chronic disease, prevalence, lymphoedema, hydrocele, mass drug administration

Introduction Lymphatic filariasis (LF) is a major vector-borne disease in many tropical countries. Nearly 119 million people are infected and 1.1 billion people are at risk of LF infection. The annual economic loss due to filariasis in India alone is estimated at close to US $1 billion (Ramaiah et al. 2000). A global programme to eliminate LF has been launched in the year 2000. The programme is based on annual single dose mass administration of diethylcarbamazine (DEC) or ivermectin combined with albendazole to interrupt transmission of infection and alleviation of suffering in chronic disease patients through simple and home-based morbidity management programme. Mass drug administration (MDA) programmes are currently being implemented in several countries with the objective of elimination of LF. Although the impact of MDA on microfilaraemia, transmission and antigenaemia has been

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evaluated in many studies (Bockarie et al. 2002; Fraser et al. 2005; Ramzy et al. 2006; Ramaiah et al. 2007), information is scarce on its impact on chronic disease, the major manifestations of which include lymphoedema of lower limbs and hydrocele. Such information is important to understand better the public health benefits and changes in the dynamics of chronic disease prevalence under the influence of MDA. We conducted a study in Villupuram district of Tamil Nadu state, an area endemic for bancroftian filariasis, to understand the impact of MDA on transmission, infection and disease. DEC alone and ivermectin alone were administered to the target communities. The WHO recommends use of DEC or ivermectin combined with albendazole in LF elimination programme. However, DEC and ivermectin are the principal anti-filarial drugs and, hence, their impact on chronic disease may provide valuable information to public health personnel and other 737


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J. Yuvaraj et al. Impact of seven rounds of MDA in South India

stake holders of the LF elimination programme. The results of the study pertaining to impact of MDA on infection and transmission (Ramaiah et al. 2007) and acute disease (Das et al. 2001) have been reported earlier. This paper reports the impact of MDA on the prevalence of the two major chronic disease manifestations, hydrocele and lymphoedema, which are the major causes of disability and economic burden in the affected communities.

Material and methods Study villages and population The study was conducted in 15 villages located in Villupuram district, Tamil Nadu state (Das et al. 2001), whose population ranged from 517 to 3321. All villages are situated within a radius of 50 km and have a similar ecology. Primary Health Centres and private practitioners in the neighbouring towns provide medical care. There was no organized filariasis control activity prior to this study. The study population primarily consists of agricultural labour and weavers. Study design The study villages were matched into three arms of five villages each in such a way that their population size and endemicity levels were comparable. The three arms were randomly allocated to annual mass treatment with single dose (i) DEC (Lederle, India) at the dosage of 6 mg ⁄ kg body weight, (ii) ivermectin (Merck & Co., USA) at 400 lg ⁄ kg and (iii) placebo (Casein, a milk protein extract). The initial two rounds of MDA were doubleblinded. After the second MDA, the drug codes were opened, the study was conducted as an open trial (Das et al. 2001) and the administration of placebo stopped. However, villages in the placebo arm were monitored for changes in infection and transmission. These villages were not offered any additional treatment except the single dose DEC (6 mg ⁄ kg body weight) treatment to the microfilaria (mf) carriers detected during the sample surveys, carried out prior to each round of MDA, to evaluate the impact of MDA on mf prevalence. However, after we observed a significant difference in the decline of microfilaraemia prevalence between the DEC and placebo arms (DEC is the most commonly used drug for the treatment of filariasis in India), villages in the placebo arm were offered annual treatment with anti-filarial drugs. By the time the first treatment was offered, the post-intervention clinical survey in placebo arm described in the present study had been completed. 738

Mass drug administration The impact of MDA on chronic disease was assessed after seven rounds of MDA. The initial two rounds of MDA were carried out at 6-month intervals and subsequent rounds at 12- to 15-month intervals. Lactating mothers, women who reported amenorrhoea and women confirmed for pregnancy were excluded from the MDA; as were children below 15 kg body weight. Teams consisting of health workers visited every household and gave the drug as per the dosage schedule to consenting individuals in every household. Householders were persuaded to take the drugs in the presence of distribution teams. Absent household members were revisited. A physician was stationed in the study villages to supervise the MDA and treat the people affected with side-effects. In addition to the MDA to all the eligible population as mentioned above, single dose DEC (6 mg ⁄ kg body weight) treatment was given to mf carriers detected in the sample surveys carried out to evaluate the effectiveness of MDA on mf prevalence. These surveys were carried out before each round of MDA and the sample included all members of the 7% of the households, which were selected randomly each time (Ramaiah et al. 2007). Prior to the present study (or seventh round of MDA), a total of 349 mf carriers in the DEC arm, 318 in the ivermectin arm and 375 in the placebo arm were detected during the sample mf surveys and given treatment. About 87%, 90% and 87% in DEC, ivermectin and placebo arm, respectively, were detected and treated only once; the others were treated two to four times. Clinical survey The impact of MDA on chronic disease prevalence was assessed by cross-sectional clinical surveys in 1993–94, i.e. prior to the first round of MDA and after the seventh round of MDA in 2001 in the DEC, ivermectin and placebo arms. During both surveys, the sampling unit was a household and the households were randomly selected. All members of the selected households were clinically examined to estimate the disease prevalence. Based on the prevalence of disease in nearby villages, the sample size for estimation of baseline chronic disease prevalence was estimated to be all members of 10% of the households in each village. Based on the disease prevalence observed in the baseline survey, 9% of the households were surveyed to assess the impact of seven rounds of MDA. This was calculated by fixing 80% precision, 20% error margin and 5% risk. As the proposed survey method was cluster sampling, design effect was taken as 1.2 for LF. The samples for the two cross-sectional surveys were independent of each other.



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The survey team consisted of physicians, a nurse and a health worker. The personnel participating in the baseline and post-intervention surveys were trained by a same and senior physician, using a standard protocol, in the diagnosis of clinical manifestations. The team visited all selected households in every village. If any selected household was found locked, the adjacent household was visited. All household members were explained the purpose of the survey and gave oral consent for clinical examination. A uniform clinical criterion for determination of the grade of clinical manifestation (World Health Organization 1992) was followed for both the surveys and the data were recorded in a pre-designed proforma. Chronic disease diagnostic criteria Hydroceles were defined as unilateral or bilateral scrotal swellings, positive with both transillumination test and fluctuation test; they were not graded by size. Lymphoedema was defined as unilateral or bilateral swelling of the limbs, with or without history of adenolymphangitis (ADL) attacks and graded into three categories (recent lymphoedema, persistent lymphoedema and elephantiasis) considering its duration, pitting and reversibility and skin condition (WHO 1992). Data analysis The reduction in prevalence of hydrocele and lymphoedema from pre-MDA to post-MDA period was assessed using the chi-square test. The relative change in the clinical manifestations from pre- to post-MDA period between placebo and DEC and between placebo and ivermectin arms was examined using log odds ratio test. Ethical approval Ethical approval was granted by the Ethical Committee of the Vector Control Research Centre, Indian Council of Medical Research.

Results Treatment coverage The treatment coverage during the seven rounds of MDA ranged from 54% to 73% in DEC arm and 57% to 75% in ivermectin arm. The treatment coverage during different rounds showed no significant difference (P > 0.05) between DEC and ivermectin arms.


Sample size for clinical surveys In the baseline or pre-MDA survey the number of individuals examined in the DEC, ivermectin and placebo arms were 902, 787 and 758 accounting for 9.1%, 9.2% and 9.0%, respectively, of the total population of the study arms. Post-seventh MDA, 1025, 898 and 846 individuals, constituting 10.4%, 10.5% and 10.0% were surveyed. Overall, male and female subjects constituted 41.5% and 58.5 % of the total sample examined prior to MDA and 40.8% and 59.2% post-MDA. Impact of MDA on hydrocele prevalence In the baseline survey the hydrocele prevalence was 20.5%, 23.9% and 20.4% in the DEC, ivermectin and the placebo arms, respectively (Table 1). After seven rounds of MDA, it declined to 5.1%, 10.4% and 10.9%, accounting for 75.3%, 56.6% and 46.6% reduction in the respective arms. The decline was statistically significant in all the three arms (P < 0.05). While the relative decline in hydrocele prevalence between DEC and placebo arms was significant (log odds ratio test: Z = 2.49; P < 0.05), it was not so between ivermectin and placebo arms (P > 0.05). Age-specific hydrocele prevalence fell significantly (P < 0.05) in all age classes after seven rounds of MDA in DEC arm and in all except the younger age group of 0–20 years in ivermectin and placebo arms. The reduction was greater in most of the age classes in DEC arm than that observed in ivermectin arm. All sampled individuals younger than 20 years in the DEC arm were completely free from hydrocele and it was not so in ivermectin and placebo arms (Table 1). Impact of MDA on lymphoedema ⁄ elephantiasis prevalence The prevalence of overall lymphoedema ⁄ elephantiasis or individual grades of lymphoedema declined only marginally from baseline to post-MDA survey and it was not significant (P > 0.05) in any of the three arms. The baseline overall lymphoedema prevalence in the DEC, ivermectin and placebo arms was 3.7%, 4.6% and 2.9%, respectively. The respective figures for post-seventh MDA period were 3.2%, 3.9% and 2.3%. The percentage reduction in prevalence from pre-MDA period to post-seventh MDA period was 13.5, 15.2 and 20.7 in the DEC, ivermectin and placebo arms, respectively (Table 2). Discussion Both DEC and ivermectin are well-known microfilaricidal drugs. Their repeated administration, alone (Ramaiah 739


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Table 1 Number of men sampled and prevalence of hydrocele in different age groups during baseline and post-seventh MDA period No. sampled

Hydrocele rate (%)

Study arm

Age group

Baseline

Post-seventh MDA

Baseline

Post-seventh MDA

% Reduction

P-valueà

DEC arm

0–20 21–40 41–60 >60 Total 0–20 21–40 41–60 >60 Total 0–20 21–40 41–60 >60 Total

202 84 72 32 390 155 67 45 30 297 182 78 46 23 329

166 104 91 53 414 139 94 76 38 347 175 83 73 37 368

5.0 34.5 41.7 34.4 20.5 3.2 44.8 53.3 40.0 23.9 3.8 37.2 39.1 56.5 20.4

0.0 3.8 9.9 15.1 5.1 0.7 13.8 25.0 7.9 10.4 2.3 14.5 21.9 21.6 10.9

100.0 88.9 76.3 56.1 75.3 77.7 69.1 53.1 80.3 56.6 40.6 61.1 44.0 61.7 46.6

0.01 0.00 0.00 0.04 0.00 0.27 0.00 0.00 0.00 0.00 0.39 0.00 0.04 0.01 0.00

Ivermectin arm

Placebo arm

From baseline to post-seventh MDA period. àResult from chi-square test.

Table 2 Number of people sampled and lymphoedema rate in different age groups during baseline and post-seventh MDA period No. sampled

Lymphoedema rate (%)

Study arm

Baseline

Post-seventh MDA

Baseline

Post-seventh MDA

% Reduction

P-valueà

DEC arm Ivermectin arm Placebo arm

903 787 758

1025 898 856

3.7 4.6 2.9

3.2 3.9 2.3

13.5 15.2 20.7

0.60 0.49 0.38

From baseline to post-seventh MDA period. àResult from chi-square test.

et al. 2007) or in combination with albendazole (Mohammed et al. 2006; Ramzy et al. 2006), was shown to reduce microfilaraemia prevalence and transmission very appreciably. Very limited information is available on the impact at community level of mass administration of the anti-filarial drugs on chronic disease, the amelioration of which is an important objective of the LF elimination programmes. This paper highlights the impact of seven rounds of mass administration of DEC or ivermectin on chronic LF prevalence. In the present study, seven rounds of MDA using DEC resulted in 75.3% reduction in hydrocele prevalence, compared with 46.6% reduction (P < 0.05) in placebo arm. No incidence of hydrocele was observed in younger age groups (£20 years), who are generally with less worm burden. This suggests that annual DEC administration has the potential to prevent new cases of hydrocele and this 740

may be more common in people with less worm burden. Significant reduction in prevalence of hydrocele was observed also in all other age groups in DEC and ivermectin arms and this might be due to both lower incidence of new cases and resolution of hydrocele at least in a small proportion of the target population. In contrast to the impact of MDA on hydrocele, we observed only very marginal impact on lymphoedema ⁄ elephantiasis of lower limbs. We observed a reduction of 46% in hydrocele prevalence in placebo arm also. This could partly be due to treatment of mf carriers, on ethical grounds, detected during mf surveys carried out prior to each round of MDA and consequent reduction in mf prevalence and intensity (parasite burden) and transmission (Das et al. 2001). While facilities and expertise for hydrocele surgery are available in nearby towns, the reduction in hydrocele prevalence in any study arm is unlikely due to surgical intervention, as



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very few affected people preferred to undergo surgery (VCRC, unpublished observation). The results of earlier studies on the impact of treatment on chronic LF are mixed. In a study in Tanzania 62–67% of the people affected with hydrocele or elephantiasis of legs showed improvement in their condition, either as a reduction in size of the affected parts or complete disappearance of disease manifestations following 12 low-dose treatments or DEC fortified salt administration over a period of 1 year (Meyerowitsch et al. 1996a). In another study, two single doses given at half-yearly intervals or daily for 12 days resulted in considerable improvements in small hydroceles (Meyerowitsch et al. 1996b). Treatment of 77–86% of the population with four annual rounds of DEC lead to decline of hydrocele from 15% to 5% (P < 0.01) and leg lymphoedema from 5% to 4% (P = 0.04) in a study in Papua New Guinea. Hydrocele and leg lymphoedema disappeared in 87% and 69%, respectively, of those who had these conditions prior to mass treatment (Bockarie et al. 2002). However, no impact of 12-day DEC treatment was seen on the size of hydroceles in treated patients in a placebo-controlled study in Tanzania (Bernhard et al. 2001). Hussein et al. (2004) observed no change in prevalence rates of non-palpable hydroceles and intra-scrotal calcifications, detectable by ultrasound, 2 years after treatment with DEC plus albendazole. The results of this and other studies suggest that the impact of treatment was not uniform and differed from study to study. More information may be required to understand the role of MDA and quantify its impact on chronic disease. However, notably, annually repeated mass administration of DEC that achieved very appreciable reduction in microfilaraemia and transmission and aimed at elimination of LF (Bockarie et al. 2002; Ramaiah et al. 2007), also led to significant reduction in hydrocele prevalence both in Papua New Guinea (Bockarie et al. 2002) and in India. Hydrocele patients suffer sexual disability (Dreyer et al. 1997) and considerable economic loss due to their morbid condition and frequent acute episodes of ADL (Ramaiah et al. 2000). Prevention of new cases and overall reduction in prevalence of hydrocele, which account for about two-third of the total LF chronic disease burden (Michael et al. 1996), in the present study suggest that MDA yields considerable public health benefits. Although there was a significant decline in mf prevalence and intensity and transmission following MDA in ivermectin arm, the reduction in hydrocele was not significantly different from that observed in placebo arm. The role of secondary bacterial infection is unimportant, and, lymphatic filarial worms alone are sufficient to cause


hydrocele and adult worm burden is considered to be an important cofactor in the pathogenesis of hydrocele (Dreyer et al. 2000). Hence mass treatment of the endemic population using the drugs with best macrofilaricidal properties may exert maximum impact on hydrocele incidence and prevalence. It is well-known that DEC kills a considerable proportion of adult worm population (Ottesen 1984) and such action is poor with ivermectin (Dreyer et al. 1996). Higher and significant reduction in hydrocele prevalence in DEC arm, observed in the present study, may be due to the adulticidal action of the drug. However, more information may be required to understand the impact of MDA that uses ivermectin on chronic disease. Incidentally, we also observed, when the data for all 15 study villages was analysed together, a significant correlation between the reduction in hydrocele prevalence and mf intensity (r = 0.86, P < 0.01) and mf prevalence (r = 0.79, P < 0.01) (VCRC, unpublished observation). We conclude that repeated annual mass administration of DEC has the potential to reduce not only microfilaraemia prevalence and intensity and transmission of LF, but also hydrocele prevalence in the target communities and this results in considerable public health benefits. Acknowledgements The study received financial support from UNDP ⁄ World Bank ⁄ WHO Special Programme for Research and Training in Tropical Diseases (Grant No. 920702). The authors acknowledge the assistance of Mrs G. Vijayalaksmi, Junior Nurse, the fieldwork carried out by Drs S. Krishna Kumar, K.R. Jawaharlal, and A. Vijayakumar, and the staff of the Division of Clinical Epidemiology, VCRC. Our thanks are due to the Directorate of Public Health and Preventive Medicine, Chennai, Government of Tamil Nadu, India, for its cooperation in carrying out the study. We thankfully acknowledge the support extended to the study by Drs Hans Remme, V. Kumaraswamy, Eric Ottesen, Gautam Biswas and Boatin Boakye. References Bernhard P, Magnussen P & Lemnge MM (2001) A randomized, double-blind, placebo-controlled study with diethylcarbamazine for the treatment of hydrocele in an area of Tanzania endemic for lymphatic filariasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 95, 534–536. Bockarie MJ, Tisch DJ, Kastens W et al. (2002) Mass treatment to eliminate filariasis in Papua New Guinea. New England Journal of Medicine 23, 1841–1848. Das PK, Ramaiah KD, Vanamail P et al. (2001) Placebo controlled community trial of four cycles of single-dose diethylcarbamazine

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or ivermectin against Wuchereria bancrofti infection and transmission in India. Transactions of the Royal Society of Tropical Medicine and Hygiene 95, 336–341. Dreyer G, Addis D, Noroes J, Amaral F, Rocha A & Coutinho A (1996) Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis. Tropical Medicine and International Health 4, 427–432. Dreyer G, Noroes J & Addis D (1997) The silent burden of sexual disability associated with lymphatic filariasis. Acta Tropica 63, 57–60. Dreyer G, Noroes J, Figueredo-Silva J & Piessens WF (2000) Pathogenesis of lymphatic disease in bancroftian filariasis: a clinical perspective. Parasitology Today 16, 544–548. Fraser M, Taleo G, Taleo F et al. (2005) Evaluation of the program to eliminate lymphatic filariasis in Vanuatu following two years of mass drug administration implementation: results and methodologic approach. American Journal of Tropical Medicine and Hygiene 73, 753–758. Hussein O, Setouhy ME, Ahmed ES et al. (2004) Duplex Doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult filarial worms and adjacent host tissues in bancroftian filariasis. American Journal of Tropical Medicine and Hygiene 71, 471–477. Meyerowitsch DW, Simonsen PE & Makunde WH (1996a) Mass diethylcarbamazine chemotherapy for control of bancroftian filariasis through community participation: comparative efficacy of a low monthly dose and medicated salt. Transactions of the Royal Society of Tropical Medicine and Hygiene 90, 74–79.

Meyerowitsch DW, Simonsen PE & Makunde WH (1996b) Mass diethylcarbamazine chemotherapy for control of bancroftian filariasis: comparative efficacy of standard treatment after two semi-annual single-dose treatments. Transactions of the Royal Society of Tropical Medicine and Hygiene 90, 69–73. Michael E, Bundy DAP & Grenfell BT (1996) Re-assessing the global prevalence and distribution of lymphatic filariasis. Parasitology 112, 409–428. Mohammed KA, Molyneux DH, Albonico M & Rio F (2006) Progress towards eliminating lymphatic filariasis in Zanzibar: a model programme. Trends in Parasitology 22, 340–344. Ottesen EA (1984) The action of diethylcarbamazine on adult worms of the lymphatic-dwelling filariae Wuchereria bancrofti, 1 Brugia malayi and Brugia timori in man. WHO ⁄ FIL ⁄ 84.174. Ramaiah KD, Guyatt H & Ramu K (2000) The economic burden of lymphatic filariasis in India. Parasitology Today 16, 251–253. Ramaiah KD, Das PK, Vanamail P & Pani SP (2007) Impact of 10 years of diethylcarbamazine and ivermectin mass administration on infection and transmission of lymphatic filariasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 101, 555–563. Ramzy RM, El Setouhy M, Helmy H et al. (2006) Effect of yearly mass drug administration with diethylcarbamazine and albendazole on bancroftian filariasis in Egypt: a comprehensive assessment. Lancet 367, 992–999. World Health Organization (1992) Lymphatic filariasis: the disease and its control. Fifth Report of the WHO Expert Committee on Filariasis. WHO Technical Report Series 821, 8–13.

Corresponding Author K.D. Ramaiah, Vector Control Research Centre, Indian Council of Medical Research, Medical Complex, Indira Nagar, Pondicherry 605 006, India. Tel.: +91 413 2272422; Fax: +91 413 2272041; E-mail: [email protected]

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