SOCIO-ECONOMIC AND EPIDEMIOLOGICAL FACTORS THAT PREDICT RESISTANCE TO TRYPANOCIDES

FACTEURS  SOCIO-ECONOMIQUES ET EPIDEMIOLOGIQUES DE LA RESISTANCE AUX TRYPANOCIDES

Hippolyte Affognon¹, Delia Grace², Oumar Diall³, Thomas Randolph⁴, Peter-Henning Clausen² & Hermann Waibel¹

¹Chair of Development and Agricultural Economics, School of Economics and Management, University of Hanover, Hanover Germany
²Free University of Berlin, Institute of Parasitology and International Animal Health, Berlin, Germany
³ILRI Project ICRISAT, Mali
⁴International Livestock Research Institute (ILRI), Livestock & Human Health, Nairobi, Kenya

Résumé

            La chimiorésistance menace l’usage permanent des trypanocides, qui constitue la méthode la plus importante de contrôle de la Trypanosomose Animale Africaine. Au Burkina Faso, la résistance aux trypanocides a été étudiée au cours des études longitudinales où les bovins traités à l’isometamidium sont examinés régulièrement pour la détection des trypanosomes. Les éleveurs des villages à forte résistance ont davantage de petits troupeaux, beaucoup plus de bœufs de labour, font plus de traitements et utilisent plus les services de non professionnels que les éleveurs des villages à faible résistance. Dans les villages à forte résistance, 34,2% des éleveurs avaient connu des échecs de traitement, alors que dans les villages à faible résistance le pourcentage n’était que de 14,5%. Une étude similaire réalisée dans 18 villages au Mali et au Burkina Faso a évalué la résistance au diminazène par l’estimation des échecs de traitement 14 jours après l’administration du diminazène. Dans les villages à forte résistance, il y avait plus de traitements, moins d’usage de trypanocides préventifs et moins de dépenses pour les services vétérinaires comparé aux villages à faible résistance. Au Burkina Faso, on a effectué une régression logistique pour étudier les facteurs relatifs à l’échec de traitement tel que perçu par les éleveurs. Les éleveurs qui ont recours aux services des vétérinaires ou à ceux des  agents zoosanitaires communautaires et qui sont plus éduqués et  comprennent les causes de la maladie, ont moins d’échecs de traitement ; en revanche, ceux qui habitent les villages à forte prévalence et résistance ,  connaissent les symptômes de la maladie et s’adonnent plus aux activités agricoles ont  plus d’échecs de traitement. Au Mali comme au Burkina Faso, les éleveurs dans les villages à forte résistance utilisent plus de diminazène, dépensent moins pour les services vétérinaires, ont moins d’expérience en élevage, disposent davantage d’animaux de plus de 300 kg et possèdent plus de troupeaux de petite taille.

Mots-clés : Trypanosomose Animale Africaine, chimiorésistance, isométamidium, diminazène, Burkina Faso, Guinée, Mali

Summary

            Drug resistance threatens the continued use of trypanocides, the most important method of controlling African Animal Trypanosomosis (AAT). In the cotton belt of West Africa, resistance to trypanocides was determined by longitudinal studies, in which cattle were treated with isometamidium and examined regularly for the presence of trypanosomes. Compared to villages with low drug resistance, livestock keepers in high resistance villages were significantly more likely to treat animals themselves, use less veterinary or Community Animal Health Worker (CAHW) services, and were less likely to know the cause of trypanosomosis. Livestock keepers who have more failures say that AAT is the priority disease, seek advice, and know more signs of AAT. Logistic regression was carried out to investigate the factors related to treatment failure as perceived by livestock keepers. Livestock keepers who obtained drugs mainly from the illegal sector and those with many sick animals were significantly more likely to have experienced treatment failures. There were strong and significant relations between treatment failure, prioritisation of AAT as first disease and propensity to seek advice. Farmers who used veterinarians or community animal health workers had less treatments failures. In Mali as well as in Burkina, conditional logistic regression shows that livestock keepers in villages of high ISMM resistance detected by field trials use more curative trypanocides than those in low resistance villages and have more animals weighing more than 300 kg.

Keywords: African Animal Trypanosomosis, Drug resistance, Isometamidium, Diminazene, Burkina Faso, Guinea, Mali

1          Introduction

            Chemotherapy for African Animal Trypanosomosis (AAT) has been widespread in tropical Africa for many years. The drugs currently recommended for cattle treatment are isometamidium, homidium and diminazene. Because of high costs of developing new trypanocides, and the relatively small market, no new drugs for cattle treatment have been developed during the past 40 years. The use of trypanocidal drugs is common among livestock keepers in Africa (Geerts and Holmes, 1998). Unfortunately, reports show increasing resistance to trypanocides especially in East and West Africa (Clausen et al., 1992; Codjia et al., 1993). Resistance to trypanocides is of particular concern because there is no immediate prospect of enlarging the current trypanocidal pharmacopoeia and because trypanosomosis poses a threat for the most vulnerable people living in sub-Saharan Africa. Resistance to drugs is a growing global problem in crops production, livestock keeping and human therapeutics (Laxminarayan, 2003). Despite this, few socio-economic studies on the phenomenon have been conducted. There is a need to better understand the role of factors that influence the development of trypanocides resistance. In this paper two different approaches are used to assess the existence of drug resistance. One is based on drug treatment failure as perceived by livestock keepers (subjective) and the second is based on field trials of drug treatment failures assessment (objective). The relationships between characteristics of livestock keepers at the household and herd levels and trypanocide resistance in three countries of West Africa, namely Burkina Faso, Guinea and Mali are investigated.

2          Methodology

            Data in this study were collected from three sources: firstly, a survey that on the knowledge, attitude and practice (KAP) of livestock keepers in the three countries; secondly, field assessment for testing the resistance to the two commonly used trypanocides; thirdly a cohort study of livestock production in 12 villages.

2.1       Knowledge, Attitude and Practice Survey

            A KAP survey was carried out in eleven villages in Guinea, eight in Burkina Faso and sixteen in Mali. The questionnaire was kept as short as possible to reduce the burden on respondents and the risk of biased responses. Sensitive questions on purchase and administration of medicines were placed at the end of the questionnaire. The questionnaire was administered in local language. Picture cards and open questions were used in order to minimise affirmation bias. The questionnaire was field-tested in each country to ensure that questions were comprehensible, unambiguous and acceptable. Modifications were made according to the different conditions in each country. Questionnaires were checked soon after completion and any inconsistencies or gaps corrected by a follow-up interview with the farmers.

2.2       Field Assessment of Isometamidium and Diminazene Resistance

            Field assessment of isometamidium and diminazene treatment failures were conducted in six villages in Burkina Faso and 12 in Mali. However, in Burkina, only data for diminazene were collected while for isometamidium results of the previous studies (McDermott et al., 2003) were used. In Mali, 25 villages were selected at random from the 100 villages of the eastern portion of Sikasso region for a cross-sectional survey. The results of the cross-sectional survey were used to determine the prevalence of trypanosomosis. Veterinary epidemiologists consider a prevalence of 10% to be high. Based on this threshold seven villages were identified. Due to research constraints only five villages were selected for further longitudinal studies in order to assess the efficacy of isometamidium. Fifty cattle were selected randomly in each village and were treated with isometamidium at the recommended preventive dose (1mg/kg) and additional 50 cattle were followed as untreated controls. An additional seven villages out of the total number of villages in eastern Sikasso were selected for field assessment of trypanocidal drug resistance. Criteria of selection were based on their proximity to the five villages of the longitudinal study and their accessibility during the rainy season. To assess the efficacy of isometamidium both curatively and prophylactically, treatment failures at 14, 28, 42 and 56 days after the first day of isometamidium treatment were recorded and used in the analysis.

2.3       Cohort Study

            Herds were selected for monitoring from villages in Burkina Faso and Mali, for which data on trypanocide resistance existed (eighteen villages). The criteria to select the herds were as follows: (i) livestock keepers should be willing to provide information and participate in the study and (ii) herds selected should stay in the village for the whole monitoring period (12 months). In all, 208 herds were monitored until the end of the year. Data and animal production inputs and outputs were collected monthly by trained enumerators. Epidemiological data were collected three times (the rainy season, the dry cold season and the dry hot season. Blood were sampled for the estimation of packed red cell volume (PCV) and for the detection of trypanosomes using the phase-contrast, buffy-coat technique (Murray et al., 1977). A random sample of cattle was drawn for each study in each village. The sample size was determined using the method described by Thrusfield (1995). All cattle detected parasitaemic were treated with diminazene aceturate and were examined two weeks later to assess again the presence of trypanosome infection and the efficacy of diminazene aceturate. Apart from blood sampling and month-to-month recording of veterinary inputs, all management decisions were made by the owners of the herd, without external interference.

2.4       Data Analysis

            The KAP survey was a complex, multilevel design, and was analysed using STATA® survey commands, which use Taylor series linearization to account for strata and clustering. Comparisons between high resistance and low resistance village were made using lincom commands. For field assessment of isometamidium and diminazene treatment failures, data were analysed using Cox proportional hazard model which is commonly used for survival analysis in biology. In order to determine factors that can explain the variation in drug resistance, conditional logistic regression for the matched case-control groups was used (Hosmer and Lemeshow, 2000). Data were analysed using STATA® 8.0. The conditional logistic was fitted for the level of isometamidium resistance (0 = low resistance and 1 = high resistance) on the explanatory variables likely to be associated with drug resistance. Twenty five percent (25%) failure rate was used as a threshold for resistance as suggested by WHO for resistance in malaria (OMS, 2003). Four categories of explanatory variables were included in the logistic regressions: characteristics of the household, characteristics of herds, factors related to disease control and drug use and epidemiological information (see Appendix).

3          Results

3.1       Relation between socio-economic factors and resistance.

            Livestock keepers in both high and low resistance villages considered AAT the most important disease. Many livestock keepers treat animals themselves, buy drugs in the informal sector and use traditional medicines. Comparing villages with low and high drug resistance (Table 1), livestock keepers in high resistance villages were significantly more likely to treat animals themselves and significantly less likely to use the services provided by veterinarians or Community Animal Health Workers (CAHW). They were also significantly less likely to know that tsetse transmit AAT.

Table 1: Framers Perception and Attitude in high and low resistance villages

            There was no significant difference in the average age of household head, number of household members, number of bicycles or scooters owned, number of cattle, number of diseases experienced or number of animals sick with AAT. The survey logistic regression (Table 2) showed that livestock keepers who obtained drugs mainly from the illegal sector and those with large number of sick animals were significantly more likely to experience treatment failures. There were strong and significant relations between treatment failure, considering AAT the most important disease and propensity to seek advice. Livestock keepers who used untrained service providers to treat their animals also had higher failures rate. Factors which had no significant relation with reported drug failures included: education of household head (HH), number of children attending school, number of bicycles owned by the household, number of motorised bicycles owned by the household, knowledge of the causes of trypanosomosis, number of strategies used in response to treatment failure, and total number of diseases experienced. Accordingly, these factors were dropped from the model.

Table 2 : Results of the survey logistic regressiom – relation between “No drug failures” as reported by livestock keepers and socio-economic factors.

3.2       Factors associated with isometamidium resistance detected by field assessment

            Using survival analysis with Cox proportional hazard model, two groups of villages were differentiated: high ISMM failure (10 villages, 6 in Mali and 4 in Burkina) and low ISMM failures (8 villages, 6 in Mali and 2 in Burkina). Out of the 208 households included in the survey, 103 fall in the group of low resistance and 105 in the group of high resistance. However, in order to conduct the conditional logistic regression with one-to-one matching, two households in high resistance villages were excluded from the analysis. As far as diminazene treatment failures are concerned no evidence for drug resistance could be established. Table 3 shows the results of the conditional logistic regression.

            The strongest associations were between large herd size and high resistance and between a high proportion of cattle weighing more than 300kg and resistance; both were significant at 5%. Livestock keepers experiencing high resistance have slightly higher expenditure for diminazene than those in low resistance villages and are significantly more likely to buy high quality ISMM drugs. Livestock keepers with higher revenues were slightly less likely to have resistance problems. Perhaps surprisingly, high prevalence (>10%) was associated with low resistance; but this was only significant at 10%. The factors related to experience such as the age of the household head, the number of years of keeping cattle and the number of years of formal education although not significant have the expected signs.

Table 3: Results of the conditional logistic regression

4          Summary and Discussion

            We found that livestock keepers using trained animal health service providers had fewer treatment failures; this is consistent with the hypothesis that untrained service providers are more likely to make errors in treatment leading to failure. Livestock keepers using the illegal sector to buy drugs also tended to have more failures, suggesting the quality of drug or advice may be low. Livestock keepers with more failures have higher numbers of sick animals, greater concern over trypanosomosis, tendency to seek advice and greater awareness of signs of trypanosomosis; these are likely to be consequences rather than causes of drug failure.

            We found strong and significant relations between high numbers of cattle (and hence high numbers of treatments) and resistance; and high proportions of heavy cattle (and hence high proportions of under-dosages) and resistance. According to drug resistance theory (Geerts and Holmes, 1998), quantity of use and under-dosing are the most important factors leading to resistance development. Heavier animals are important for the development of resistance because the single dose package that is common in the study zone is recommended for animal of 250 kg, and as livestock keepers routinely use one dose per animal irrespective of size, heavier animals are systematically under-dosed. No very clear relations emerged between current expenditure on trypanocides, quality premiums and resistance; this may be because of the complex relation between drug use and resistance. High drug use leads to resistance, but high resistance may in turn lead to lowered drug use, increased drug use, brand switching or changes in drugs used.

Acknowledgement

            We gratefully acknowledge the support of the German Development Assistant with funding from BMZ/GTZ under project No. 20017860.8-01.00.

References

Clausen, P. H., I. Sidibe,  Kaboré I. and Bauer, B. (1992). Development of multiple drug resistance of Trypanosoma congolense in Zebu cattle under high natural tsetse fly challenge in the pastoral zone of Samorogouan, Burkina Faso. Acta Tropica, 5, 229- 236.

Codjia, V., Mulatu, W., Majiwa, P. A. O., Leak, S: G: A:, Rowlands, G. J., Authié, E., d’Ieteren, G. D. M. and Peregrine A. S. (1993). Epidemiology of cattle trypanosomosis in the Ghibe Valley, southwest Ethiopia. 3. Occurence of populations of Trypanosoma congolense resistant to diminazene, isometamidium and homidium. Acta tropica 53 (2): 151-163.

Geerts S. and Holmes P. H.,(1998). Drug management and parasite resistance in animal trypanosomiasis in Africa, PAAT Technical and Scientific Series, No. 1, FAO, Rome pp. 31.

Hosmer D. W. Jr. and Lemeshow, S. (2000). Applied Logistic Regression. Second Edition, New Y

Laxminarayan, R. (2002). Battling Resistance to Antibiotics and Pesticides: An Economic Approach. Resources for the Future. Washington DC. 377 pp.

McDermott, J., Woitag, T., Sidibé, I., Bauer, B., Diarra, B., Ouédraogo, D., Kamuanga, M., Peregrine, A. Eisler, M., Zessin, K-H., Mehlitz, D. and P-H. Clausen (2003). Field studies of drug-resistance cattle trypanosomes in Kénédougou Province, Burkina Faso. Acta Tropica 86, 93-103.

Murray, M., Murray, P. K. and McIntyre, W. I. M. (1977). An improved parasitological technique for the diagnosis of African trypanosomiasis. Trans. R. Soc. Trop. Med. Hyg. 71, 325-326.

Thrusfield, M. (1995). Veterinary Epidemiology. Second edition. Blackwell Science Ltd. United Kingdom, University Press Cambridge.

OMS (2003). Evaluation et surveillance de l’efficacité des antipaludiques pour le traitement du paludisme à plasmodium falciparum non compliqué. OMS, Genève, Suisse.68 pp.