Efficacy of co-administration of albendazole and diethylcarbamazine against geohelminthiases: a study from south india

Tropical Medicine and International Health Efficacy of co-administration of albendazoleand diethylcarbamazine against geohelminthiases:a study from South India T. R. Mani1, R. Rajendran1, A. Munirathinam1, I. P. Sunish1, S. Md. Abdullah2, D. J. Augustin2and K. Satyanarayana1 1 Centre for Research in Medical Entomology (Indian Council of Medical Research), Madurai, India2 Department of Public Health & Preventive Medicine, Government of Tamil Nadu, Chennai, India The efficacy of single-dose combination drug therapy with diethylcarbamazine (DEC) plus albendazole(ALB), and single-drug therapy with DEC alone against geohelminths was compared as part of a mass drugadministration (MDA) for elimination of filariasis. This study was conducted in two blocks of VillupuramDistrict of Tamil Nadu State, India, covering a population of 321 000 including about 100 000 children1–15 years of age. Prevalence and intensity of geohelminth infection were determined by the Kato–Katztechnique immediately before and 3 weeks after the MDA. A pre-treatment cross-sectional survey wasundertaken in 18 statistically selected villages out of 204 villages, including 646 school children. About60% were infected with one or more geohelminths. The overall prevalence rates were 53.9%, 12.4% and5.7% for Ascaris lumbricoides, hookworms and Trichuris trichiura, respectively. Combination therapy(DEC + ALB) produced a cure rate of 74.3% and an egg reduction rate of 97.3% for geohelminths, whichwere higher than the corresponding rates (30.4% and 79.0%) observed in the single drug therapy arm withDEC alone. The odds of cure with combination therapy were significantly higher for roundworm(5.3 times) and hookworms (3.5 times), then odds of cure with DEC alone. Both therapies were equallyeffective against trichuriasis, recording cure rates >77% and egg reduction rates >83%. In combinationtherapy, 53.5% of the children noticed expulsion of worms after MDA, while in single drug therapy only20.9% did. Our study indicated that MDA of combination therapy was operationally feasible at thecommunity level, and it may secure higher community compliance because of its perceived benefits andenhanced efficacy against geohelminths than single-drug therapy.
keywords geohelminths, albendazole, diethylcarbamazine, ascariasis, trichuriasis, hookworms correspondence Dr K. Satyanarayana, Centre for Research in Medical Entomology, 4, Sarojini Street,Chinna Chokkikulam, Madurai 625 002, India. E-mail: [email protected] diethylcarbamazine (DEC) and this is being attempted in India as a new initiative in a pilot programme (Ramaiah Large-scale chemotherapy plays a vital role in the control et al. 2000). Several antihelmintic drugs, especially when of many parasitic infections such as lymphatic filariasis given in combination, have a significant antifilarial effect (LF), onchocerciasis, schistosomiasis and intestinal ne- providing a number of good tools to control filariasis matode infections (Savioli et al. 1997). The greatest (Turner & Michael 1997). Two new drugs, ivermectin successes were through the development of single-dose (IVR) and albendazole (ALB), when combined with DEC, therapy and mass treatment control programmes for a have been shown to be highly effective in the management number of diseases (Stephenson & Wiselka 2000).
of microfilariasis because of lymphatic filarial worms Currently, the most practical and feasible method for (Ottesen et al. 1999). Hence, the revised elimination the control of LF is the rapid reduction of microfilarial strategy for LF is designed to break the chain of load in the community by mass annual single dose of transmission in populations exposed to the risk of Tropical Medicine and International Health T. R. Mani et al. Albendazole + DEC against geohelminthiases infection by administering a single dose of two drugs, 2000, as a part of a large-scale MDA programme for annually for 5–6 years (Karam & Ottesen 2000).
filariasis control/elimination in 12 districts, covering a Consequent upon the formation of the Global Alliance population of about 27 million. During the fourth round to Eliminate Lymphatic Filariasis, free supply of alben- (March 2001), the Tamil Nadu Government decided to co- dazole tablets was announced by WHO and SmithKline administer ALB along with DEC in six districts, covering a Beecham for mass chemotherapy along with DEC towards population of about 14 million. However, the Villupuram filariasis elimination [World Health Organization (WHO) District along with five other districts received DEC alone.
1999]. About 40 million persons worldwide were expected Thus, the fourth round MDA by the Government of Tamil to be covered by two-drug yearly mass drug administration Nadu during the month of March 2001 was the first round (MDA) in the year 2001 by national programmes with two for our new study. Two blocks, Tirukoilur and Mugaiyur or three options for drug choices, including DEC + ALB from Villupuram District with 204 villages and a popula- (WHO 2001). The national programmes were expected to tion of 321 000 (including about 100 thousand children cover 80–90% population for five to six MDAs in this between 1 and 15 years of age), were selected for this endeavour, which may ultimately lead to elimination of LF, project. The health system distributed the drugs. All and the current status was reviewed (Das et al. 2001; community members aged 1 year and above were targeted for drug consumption, after a well-orchestrated health Intestinal helminth infections are widespread, causing education campaign in all the 12 districts. Tirukoilur Block nutritional deficiencies and impaired childhood cognitive was assigned for co-administration of two drugs and development (Stephenson & Wiselka 2000). In India, most Mugaiyur block was assigned for the administration of a pre-school children are underweight and stunted, with single drug (DEC) alone. In order to have baseline data for intestinal helminth infestation being one of the contribu- the two blocks, 24 villages from Tirukoilur and 27 villages ting factors (Awasthi & Pande 1997). The availability of from Mugaiyur (total of 51 villages) were screened and drugs such as DEC and ALB, which have antihelmintic and nine index villages were selected from each block, using antifilarial properties, opens the possibility of integrating a statistical considerations based on population size of the geohelminth control programme with a filariasis control villages. Representation was given to small, medium sized programme, where these nematodes occur concurrently and big villages in this selection. The baseline survey on (Beach et al. 1999; Ananthakrishnan & Das 2001). Single geohelminths was conducted in these 18 index villages by doses of albendazole (600 mg) in combination with DEC including all 18 primary schools in the area, whose (6 mg/kg) proved to have both long-term effectiveness in students had never been treated against helminths by any decreasing microfilaraemia and adult filarial worm antigen community-based programme. Within a given school, levels in Wuchereria bancrofti infections (Ismail et al.
children aged 9–10 years were selected by a simple random 1998). Combination drug therapy with DEC + ALB has sampling technique, to draw the necessary numbers been suggested as a comprehensive measure to control both (20–50) from children of that age group.
intestinal helminths and LF because of the ‘ancillary A total of 321 school children (177 boys and 144 girls) benefits’ of ALB and the resultant enhanced compliance of were enlisted from Tirukoilur Block for baseline prevalence the population at risk (Ottesen et al. 1999). However, the assessment prior to DEC + ALB intervention. Similarly, a current technical data does not clearly reveal the efficacy of total of 325 school children (180 boys and 145 girls) were the combination of DEC + ALB over DEC alone, although examined to assess the prevalence rate for geohelminthiasis control of intestinal worms and filariasis together, partic- from Mugaiyur Block prior to intervention with DEC ularly in children, could have a higher cost benefit (Das & alone. After explaining the purpose of the study and Pani 2000). Therefore, a two-arm community-based obtaining informed consent from headmasters and parents, research study was undertaken to examine the impact of numbered sterile vials along with spatula were given to co-administration of DEC + ALB on the prevalence and enrolled school children, who were asked to bring a stool intensity of intestinal helminthic infections and filarial sample on the following day. During the distribution of the transmission and infection in one arm, and DEC alone in vials, the amount of stool sample needed and the collection the other arm. The data pertaining to intestinal helminths method by using the spatula were explained to them. Stool are presented in this communication.
samples were collected in the morning of the next day andtransported to the laboratory and examined by the Kato–Katz technique, following World Health Organization (WHO) recommendations (WHO 1993), to assess the The Villupuram District of Tamil Nadu state was covered prevalence of geohelminthiasis, species profile and by three MDAs by single-dose DEC alone from 1998 to Tropical Medicine and International Health T. R. Mani et al. Albendazole + DEC against geohelminthiases Microscopy of nematode eggs was used to diagnose a therapy and single-drug therapy were evaluated for cure helminthic infection, while the concentration of those eggs rate for the three nematodes studied. Egg counts (epg + 1) was used to estimate the intestinal worm burden in the were transformed to common log for statistical application host. The prevalence rate was expressed as the percentage and are reported as the GM. The egg reduction rate was of subjects found positive for any of the three geohelm- expressed as the percentage GM epg reduction, i.e.
inths, viz. roundworm (Ascaris lumbricoides), hookworms percentage fall in geometric mean epg counts. Pre- and (Ancylostoma duodenale and Necator americanus) and post-treatment prevalences for each geohelminths within whipworm (Trichuris trichiura). The intensity of geo- the two arms were compared using the chi-square test.
helminth infections was defined as eggs per gram (epg) of Cure rates were tested by calculating log odds ratio faeces and the mean epg was calculated as the geometric between the two treatment arms, and Student’s t-tests mean (GM) intensity by using the following formula: were conducted on transformed values of intensities of GM epg values to measure the significance of the egg output reduction within each treatment group.
log(epg + 1) is the sum of the logarithms of each individual epg, one egg was added to each count to permit calculation of the logarithm in case of epg ¼ 0, and ‘n’ the number of subjects investigated. The GM controls for thedrift in epg among untreated subjects and takes into Among the 646 stool samples examined from the two account the over-dispersed nature of the egg counts. In this treatment groups of school children, the overall prevalence procedure all children were included for calculations, of geohelminths at enrolment was 53.9% for Ascaris, including those without any eggs in their stool sample, 12.4% for hookworms, and 5.7% for Trichuris; 59.6% of similar to the procedure adapted by earlier workers all school children examined had one or more geohelmin- (Kightlinger et al. 1995). The threshold proposed for use thic infections. All infections were of light intensity by a WHO Expert Committee in 1987 for the classes for according to the WHO classification. Of the 385 infected intensity for each helminth in stools were followed to individuals, 79.2% had a single infection and 20.8% had determine the classes of intensity of infections (Montresor mixed infections. Among 77 children who had mixed et al. 1998). According to this, light intensity infection was infection, dual infection constituted 95% and 5% triple defined as having < 5000 epg for roundworm, < 2000 epg infection. Ascaris lumbricoides with hookworms was the for hookworms and < 1000 for whipworm.
predominant dual infection (67.5%) followed by Ascaris Three weeks after MDA (post-treatment), 541 (83.7%) plus Trichuris (28.4%). Hookworms plus Trichuris of the 646 children surveyed before the MDA were tested again to assess the impact of MDA on intestinal worm In the combination therapy group (DEC + ALB), the burden. In order to compensate for the loss of sample prevalence of geohelminths was 60.4%, while it was because of examination schedules, sickness and absentee- 58.8% in single drug therapy group (Table 1). The two ism, 131 children were selected as a replacement (age- and treatment groups did not differ significantly, except the sex-matched bench-mates of missing children, from among prevalences of hookworms (16.5% vs. 8.3%; P < 0.005; those who had participated in the MDA but who were not Table 1). Whipworm infection was comparatively rare in covered for stool examination in the baseline studies both treatment groups with 5.0% and 6.8% prevalence, earlier) bringing the total to 672 for post-MDA evaluation.
All children in the class were requested to report sightingof expelled worms after MDA, at the first survey itself, in Reported participation and side reactions the school. While collecting the post-MDA stool samples,a questionnaire was used to enquire whether they noticed All the children covered in this study reported that they expulsion of worms in stools after the MDA. The consumed drugs assigned to their families and the local proportion of children who had perceived the benefit of health workers covered a small number who missed MDA by way of seeing expulsion of worms in stools after MDA, during mop-up operations in the schools. A receiving MDA, were computed for each arm and were separate questionnaire survey on about 850 households compared. The difference in the prevalence rates for each indicated that about 80% of the families participated in geohelminth between pre- and post-treatment values was this 5-day MDA (17–21 March 2001) programme, by expressed as percentage of pre-treatment value and was reporting consumption of tablets distributed by the referred to as cure rate. Thus, the efficacy of combination health system, in both arms. There were no major Tropical Medicine and International Health T. R. Mani et al. Albendazole + DEC against geohelminthiases Table 1 Baseline prevalence and intensity of geohelminths *Significantly different.
 Eggs per gram of stool.
adverse side reactions, although mild side-effects such as very effective against Trichuris, each inducing cure rates fever, giddiness and vomiting were reported in about 9% >77% and egg reduction rates > 83%.
of participants which could be managed by the local The odds of cure for Ascaris in DEC + ALB therapy was health authorities. These details are being reported 5.3 times the odds of cure in DEC alone arm and the odds ratio was significant (P < 0.001; not shown in table).
Similarly, the odds of cure in the combination therapy armfor any of three helminths (5.7 times; P < 0.01) and hookworms (3.5 times; P < 0.001) was higher than the The prevalence and GM epg counts before and after odds of cure in the single-drug arm.
treatment and the cure and egg reduction rates are given inTable 2. Within each arm the prevalences of individual parasites came down significantly after the MDA, exceptfor DEC alone arm for hookworms. This is despite A greater proportion (53.5%) of school children perceived significantly greater prevalence for hookworms in the pre- the benefits of expulsion of worms after the co-adminis- treatment period in the combination therapy arm. The cure tration of DEC + ALB and noticed expulsion of worms rates were significantly higher in the combined therapy arm after MDA, while only one-fifth (20.9%) gave such a for Ascaris, hookworms and any of three worms, but not history in DEC alone treatment group.
so for Trichuris, for which both arms were equallyeffective. The GM epg values in both arms were signifi- cantly reduced after therapy, except for the DEC alone armfor hookworms. This pattern on intensity of worm burden Control of filariasis in India had taken a new turn with the was similar to the observations on the reduction of introduction of single-dose, two-drug (DEC + ALB) mass prevalences and both parameters behaved in a similar administration by the Government of India on a pilot scale, fashion. Though there were significant reductions in the with donation of ALB by SmithKline Beecham through GM epg in both arms, except for hookworms in the DEC WHO (WHO 1999). We had an opportunity to study and alone arm, there were substantial differences in the report the role of DEC + ALB on filariasis and intestinal magnitude of egg count reduction (egg reduction rate) for geohelminths control, against the DEC alone arm, prob- various parasites. The figures for any of three worms and ably reporting for the first time from this region.
for Ascaris were similar with 18–20% difference in favour Our data reveal that the study population of this area of combined therapy (Table 2). Extreme patterns were seen was infested at a moderate level, the prevalence of soil- for hookworms on the one hand and whipworm on the transmitted helminthiasis being about 60%. The intensity other, the latter did not show any difference between the of helminth infections was comparatively low and all arms, where as in the case of hookworms a 58% difference children had light infections according to WHO criteria. In was observed between the two arms, registering very general, there was higher prevalence of ascariasis and strong benefits for combined therapy. On the whole, low prevalence of hookworms infection and trichuriasis.
combined therapy registered higher egg reduction rates Intensity as measured by GM epg was very low and except for Trichuris, and the same pattern was noted for different from other developing countries. Hall & Holland cure rates derived from prevalences. Both treatments were (2000) have reported that school children from Mexico, Tropical Medicine and International Health T. R. Mani et al. Albendazole + DEC against geohelminthiases Madagascar, Myanmar, Nigeria, and Kenya bear a heavy burden of infection and considerable morbidity because ofthe soil-transmitted helminthiases. The heaviest worm burden of Ascaris in the world was reported fromMadagascar (Kightlinger et al. 1995). The GM epg value was 675 for Ascaris in 1–10-year-old children, with an increase with age and 10-year-old children in Madagaskar had a GM epg value of 7161, against the very low value (< 25 GM epg) in our study. Srinivasan et al. (1987) observed very high prevalence (92%) but with moderate intensity of hookworms infection (> 2000 epg) in 4% of infected patients in South India, compared with highintensity in Nigeria (Udonsi 1984). In Nigeria, 58% of children studied had hookworm infection and 60% hadepg counts of 10 000 or more. In the present communi- cation, data on boys and girls and on the predisposition of some children with higher egg output after therapy were not taken up and these will be communicated separately.
There are limited studies comparing the efficacy of DEC + ALB with other drugs for geohelminths control.
Ismail & Jayakody (1999) studied this combination in the treatment of trichuriasis in Sri Lanka and Njenga et al.
(1999) in Kenya. Our current report contributes informa- tion along with the filariasis control programme in Tamil Nadu, India, which involves a large number of children.
The co-administration of DEC and ALB was clearly more effective than DEC alone against Ascaris and hookworm infections, both in terms of cure rate (74.3% vs. 30.8%; 89.5% vs. 26.0%) and egg reduction rate (96.6% vs.
76.6%; 94.2% vs. 36.1%). The pattern of results in 541 children who were examined at both the points (541 vs.
541) were similar to the results mentioned above for the larger sample (646 vs. 672) given in Table 2. The cure rates for Ascaris (71.4 vs. 34.0 for 541 children as against 74.3 vs. 30.8 in the larger sample) and any of three worms (73.4 vs. 39.6 against 74.3 vs. 30.4) were similar for both samples. Likewise, the egg reduction rates for Ascaris (91.3 vs. 76.4 as against 96.6 vs. 76.6) and for any of three worms (94.1 vs. 78.5 as against 97.3 vs. 79.0) were similar, hence the results for the followed-up sample (541 vs. 541) and those for the replacement sample (646 vs. 672) were similar. Some drop-out children returned for the post- treatment survey, bringing the total to 672. High cure rates and egg reduction rates of Ascaris and hookworm infection with a single dose of ALB have been reported in many studies (Albonico et al. 1994; Norhayati et al. 1997).
As far as trichuriasis is concerned, both treatment regimens, viz. DEC + ALB and DEC alone produced very similar cure rates (81.6% vs. 77.3%) and almost the same egg reduction rates (84.0% vs. 85.6%). This shows that addition of ALB to DEC produced no appreciable impact on T. trichuris infection, unlike higher efficacies observed Tropical Medicine and International Health T. R. Mani et al. Albendazole + DEC against geohelminthiases for the other two geohelminths. Similar findings on the treatment for intestinal nematodes ‘good value’ even if effect of ALB on trichuriasis have also been recorded in 25% of the children (community) are infected. The instant Bangladesh (Hall & Nahar 1994), in Guatemala (Watkins deworming effect of DEC + ALB may help secure higher & Pollitt 1996) and in Thailand (Sukontason et al. 2000).
community compliance in the forthcoming MDAs, from In a study in Sri Lanka, a significantly higher cure rate 56.5% in the second MDA in 1998 (Ramaiah et al. 2000) (79.3%) and egg reduction rate (93.8%) was recorded and 80% reported consumption of drugs in this study for against trichuriasis, when ALB and IVR were co-adminis- the fourth MDA in 2001. Community co-operation has tered, compared with ALB alone or ALB + DEC (Ismail & been found to be very encouraging when the LF elimin- Jayakody 1999). In some studies, ALB alone produced a ation programme was integrated with control of intestinal low cure rate but higher egg reduction rate for trichuriasis helminth infections (WHO 2000a) and benefits regarding (Bartoloni et al. 1993; Albonico et al. 1994; Norhayati improvement of community acceptance and co-operation et al. 1997). High cure (67.4%) and egg reduction rates in filariasis control programmes were forecast by Mey- (87.0%) were also reported against trichuriasis with ALB rowitsch & Simonsen (2001) when studying DEC treat- in Thailand (Jongsuksuntigul et al. 1993) and a very high ment and worm expulsion in children. The instant cure rate (90.5%) was reported by Jagota (1986) in India.
deworming of children after ALB treatment created In a small-scale field-based clinical trial in Kenya with immense confidence in the community (WHO 2000a). This 21–22 children in each group, 67.4%, 71.1%, 78.8% cure was also reflected in our study among school children, who rates for intestinal helminths were obtained among persons reported worm expulsions with enthusiasm. We have a treated with DEC, ALB and a combination of the two built-in control group with DEC alone to nullify errors, if drugs, respectively, 6 months after treatment (Njenga et al.
any, in this kind of self-reporting by school children.
1999). In this study, the identity of helminths was not Ottesen has stated in a meeting (WHO 2000b) that specified and therefore we cannot directly compare data.
children stand to benefit most from the LF elimination However, our combined therapy arm recorded similar cure efforts. This is also the case with geohelminth control, as the heaviest infections with worms typically occur among Treatment with DEC alone has significant therapeutic children aged between 5 and 14 years (Savioli et al. 1992; effects on some enteric parasites including Ascaris (Turner Ananthakrishnan & Das 2001) and this age group is & Michael 1997). Our current study has also brought out therefore most likely to benefit from treatment (Hall et al.
additional information on the efficacy of DEC against 1997).Childhood is the period when most filariasis infec- geohelminths in a public health scale intervention. In tion is acquired, often as much as one-third children single-dose DEC treatment, although the cure rate was low becoming infected before age 5 (Witt & Ottesen 2001).
in Ascaris infection (30.8%), the egg reduction was more Sunish et al. (2002) also emphasized this aspect and evident (76.6%). Similar results were recently reported in proposed measurement of new infections in children 26 Tanzanian children using single-dose DEC, with 60.2% reflected by childhood antigenaemia prevalence (CAP) as an reduction of egg output, 7.7% cure rate for Ascaris important indicator of a successful filariasis control pro- infection and 10 children (38.5%) noticing expulsion of gramme. These reviews indicate that the combined strategy worms within 2 days after therapy (Meyrowitsch & (DEC + ALB) for multiple disease (filariasis and geohelm- Simonsen 2001). In our study, expulsion of worms was inths) control can benefit children immensely and could be noticed by 20.9% of children in DEC alone arm.
implemented in a cost-effective manner at the community Single-dose DEC therapy could produce equivalent cure level, as suggested by Beach et al. (1999), Cline et al. (2000) (> 77%) and egg reduction rates (> 84%), as combination and Stephenson & Wiselka (2000). Our results indicate that therapy for T. trichuris. However, DEC alone gave a poor future compliance for the overall filariasis control pro- cure (26%) and egg reduction rate (36%) for hookworm gramme could be improved and/or sustained because of the infection and was definitely inferior to combination drug higher perceived benefits felt by the beneficiary community, therapy. Co-administration of ALB with DEC enhanced and will help in reducing the time period required for the most of the properties of DEC alone (> 74%) and its control/elimination of filariasis, apart from substantial benefits were perceived by more people (32.6%).
benefits for control of geohelminthiases.
Integrated programmes for simultaneous treatment of In our study, the odds of cure with combination therapy multiple diseases appear to be an efficient and cost-effective were significantly higher than odds of cure with DEC alone approach for addressing geohelminthiasis (Beach et al.
for roundworm (5.3 times) and hookworms (3.5 times).
1999). Periodic mass treatment is warranted when the This was also true for odds of cure (5.7 times) for any of prevalence of intestinal nematodes in school children three geohelminths, between arms, giving a distinct exceeds 50%, although Guyatt (1999) considers mass advantage to combination therapy. The combination Tropical Medicine and International Health T. R. Mani et al. Albendazole + DEC against geohelminthiases resulted in enhanced efficacy of the broad-spectrum Cline BL, Savioli L & Neira M (2000) Introduction: opportunities activity against geohelminths, especially against Ascaris to work together: intestinal helminth control and programmes and hookworms, and a greater proportion of school to eliminate lymphatic filariasis. Parasitology 121, S3–S4.
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