Monitoring the efficacy of drugs for neglected tropical diseases controlled by preventive chemotherapy.

In the last decade, pharmaceutical companies, governments and global health organisations under the leadership of the World Health Organization (WHO) have pledged large-scale donations of anthelmintic drugs, including ivermectin (IVM), praziquantel (PZQ), albendazole (ALB) and mebendazole (MEB). This worldwide scale-up in drug donations calls for strong monitoring systems to detect any changes in anthelmintic drug efficacy. This review reports on the outcome of the WHO Global Working Group on Monitoring of Neglected Tropical Diseases Drug Efficacy, which consists of three subgroups: (i) soil-transmitted helminthiases (ALB and MEB); (ii) onchocerciasis and lymphatic filariasis (IVM); and (iii) schistosomiasis (PZQ). Progress of ongoing work, challenges and research needs for each of the four main drugs used in helminthic preventive chemotherapy (PC) are reported, laying the ground for appropriate implementation of drug efficacy monitoring programmes under the co-ordination and guidelines of the WHO. Best practices for monitoring drug efficacy should be made available and capacity built as an integral part of neglected tropical disease (NTD) programme monitoring. Development of a disease-specific model to predict the impact of PC programmes, to detect outliers and to solicit responses is essential. Research studies on genetic polymorphisms in relation to low-efficacy phenotypes should be carried out to identify markers of putative resistance against all NTD drugs and ultimately to develop diagnostic assays. Development of combination and co-administration of NTD drugs as well as of new drug entities to boost the armamentarium of the few drugs available for NTD control and elimination should be pursued in parallel.

Prevalence of strongyloidiasis in Latin America: a systematic review of the literature.

Strongyloides stercoralis is rarely recognized as a major public health issue, probably because its burden is largely underestimated. We reviewed the literature (both PubMed and 'grey' literature) about the prevalence of strongyloidiasis in Latin America, an area of presumable high endemicity. There were finally 88 papers involved in the analysis, covering the period between 1981 and 2011. Studies were heterogeneous in several aspects, such as the populations screened and the diagnostic methods used. Most of the studies relied on direct coproparasitological examination, which has low sensitivity for the detection of S. stercoralis larvae. The following countries presented areas of high prevalence (>20%): Argentina, Ecuador, Venezuela, Peru and Brazil. Globally, for most of the included countries it was not possible to define reliable data because of paucity and/or inadequacy of studies. S. stercoralis requires specific diagnostic methods for its detection; therefore, surveys should be specifically designed in order to avoid underestimation of the infection.

Comparison of the Kato-Katz method and ether-concentration technique for the diagnosis of soil-transmitted helminth infections in the framework of a randomised controlled trial.

Soil-transmitted helminth infections are a major public health problem. An accurate diagnosis is important in order to identify individuals and communities in need of intervention, and for monitoring drug efficacy and potential emergence of resistance. We compared the accuracy of the Kato-Katz method and ether-concentration technique for the diagnosis of soil-transmitted helminth infections within a randomised controlled trial. Quadruplicate Kato-Katz thick smears (duplicate Kato-Katz from two stool samples each) were examined before (baseline) and 3 weeks after treatment (follow-up). Additionally, at baseline and follow-up, the first stool sample was subjected to an ether-concentration method. We determined the prevalence, sensitivity, negative predictive value, diagnostic agreement and cure rates for single and duplicate Kato-Katz thick smears from the first stool sample, quadruplicate Kato-Katz thick smears produced from two stool samples and single ether-concentration as compared to our 'gold' standard (i.e. quadruplicate Kato-Katz plus ether-concentration). Quadruplicate Kato-Katz revealed a higher sensitivity than single ether-concentration for Trichuris trichiura at baseline (94.3 % vs. 88.5 %, p = 0.002) and follow-up (93.8 % vs. 83.5 %, p < 0.001). In contrary, at follow-up, ether-concentration showed a higher sensitivity than quadruplicate Kato-Katz for Ascaris lumbricoides diagnosis (86.7 % vs. 46.7 %, p = 0.012). The ether-concentration method showed similar or slightly higher sensitivity than the Kato-Katz technique based on a single stool sample for all soil-transmitted helminth infections. The estimated cure rates were heavily dependent on the diagnostic technique and sampling effort. In conclusion, data on the prevalence of soil-transmitted helminth infections and the efficacy of anthelminthics are greatly influenced by the diagnostic method and sampling effort. The ether-concentration technique is a valuable alternative to the Kato-Katz method for helminth diagnosis.

Genetic characterization of Giardia duodenalis by sequence analysis in humans and animals in Pemba Island, Tanzania.

Giardia duodenalis represents one of the most widespread human enteric parasites: about 200million people in Asia, Africa and Latin America are infected. Giardia exerts a deep impact on public health because of high prevalence and possible effects on growth and cognitive functions in infected children. The major aim of this study was to detect and genetically characterize G. duodenalis in both human and animal fecal samples collected in Pemba Island, in the archipelago of Zanzibar (Tanzania), in order to deepen the knowledge of genotypes of Giardia in this area. Between October 2009 and October 2010, we collected 45 human fecal samples from children from 2 primary schools and 60 animal fecal samples: 19 from zebus (Bos primigenius indicus) and 41 from goats (Capra hircus). Detection and genetic identification were performed by multilocus analysis of ssu-rDNA and gdh genes. In humans we found a higher prevalence of assemblage B (sub-assemblage BIV), in goats of assemblage E and in zebus of assemblage A. Our study represents an important contribution to the epidemiological knowledge of G. duodenalis in this area of Tanzania.

Comparison of the Kato-Katz thick smear and McMaster egg counting techniques for monitoring drug efficacy against soil-transmitted helminths in schoolchildren on Pemba Island, Tanzania.

The Kato-Katz thick smear technique is widely used to assess prevalence and intensity in soil-transmitted helminth (STH) control programmes, but its usefulness in monitoring anthelminthic drug efficacy needs to be validated and compared with other methods. A promising alternative is the McMaster egg counting technique. In the present study, the efficacy of single-dose albendazole against STH infections in 430 schoolchildren on Pemba Island was assessed using both the Kato-Katz and McMaster techniques. The study revealed comparable drug efficacy results for both methods and confirmed the potency of the McMaster technique as an alternative method for monitoring large-scale deworming programmes.

The impact of baseline faecal egg counts on the efficacy of single-dose albendazole against Trichuris trichiura.

There is considerable variation in the efficacy of single-dose albendazole (400mg) against Trichuris trichiura across human trials. Factors contributing to this variation have not yet been identified. We assessed the impact of mean baseline faecal egg counts (FEC) on the efficacy of single-dose albendazole against T. trichiura in five previously conducted trials. Our results suggest that efficacy measured by reduction in mean FECs decreased significantly (p<0.0001) when mean baseline FECs increased, highlighting that this parameter should be considered as an important confounding factor for drug efficacy.

Praziquantel efficacy and long-term appraisal of schistosomiasis control in Pemba Island.

OBJECTIVE: To determine whether praziquantel (PZQ) has retained its efficacy against Schistosoma haematobium on Pemba Island after 20 years of mass administration--albeit discontinuous--and to analyse retrospectively the performance of schistosomiasis control programmes. METHODS: A sample of Pemba schoolchildren was examined before and after PZQ treatment by urine filtration, macro- and micro-haematuria and viability of excreted eggs. RESULTS: Although 5% of treated children continued to pass some eggs in the urine up to the seventh week after PZQ administration, none of these eggs was viable, indicating an effective schistosomicidal activity followed by a slow release of dead eggs from host tissues. CONCLUSION: No signs of PZQ resistance could be detected in the population under study. An overall retrospective analysis of schistosomiasis control activities in Pemba Island revealed that mass drug administration is clearly effective in reducing infection prevalence, but soon after interruption of drug distribution prevalence returns rapidly to pre-intervention levels.

Progress in the prevention and control of schistosomiasis and soil-transmitted helminthiasis.

In the last two decades important progress has been made in the understanding the epidemiology and the disease burden of schistosomiasis and soil-transmitted nematodes infection. In addition, practical tools for disease control have been developed and a strategy for the prevention and control of morbidy of schistosomaisis and soil-transmitted nematodes infection has been endorsed by the World Health Organization. This paper presents the recent progress in the prevention and control of these infections: the estimates of chronic and subtle morbidity in high risk groups and the evidence that these chronic and severe sequelae of infections can be reversed by appropriate treatment; the use of anthelminthic drugs during pregnancy and lactation; the relevance to control morbidity due to these infections also in pre-school children; the efficacy of anthelminthic drugs and the possible threat of drug resistance; price, quality and accessibility of treatment by delivering drugs through the school system and ways of reaching also non-enrolled school-age children. Finally, the strategy, targets and recommendations of the World Health Organization for the control of schistosomiasis and soil-transmitted nematodes infection are described.

Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar.

OBJECTIVE: To evaluate the efficacy of and resistance to mebendazole (500 mg) and levamisole (40 or 80 mg), alone or in combination, for the treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm infections on Pemba Island - an area exposed to periodic school-based mebendazole treatment since 1994. METHODS: A randomized, placebo-controlled trial was carried out in 914 children enrolled from the first and fifth grades of primary schools. Stool samples collected at baseline and 21 days after treatment were examined by the Kato-Katz technique to assess the prevalence and intensity of helminth infection. FINDINGS: Efficacies of mebendazole and levamisole as single treatments against intestinal nematode infections were comparable with those in previous trials, but mebendazole treatment of hookworm infections gave significantly lower cure (7.6%) and egg reduction (52.1%) rates than reported in a study undertaken before the beginning of periodic chemotherapy (cure rate, 22.4%; egg reduction rate, 82.4%). Combined treatment with mebendazole and levamisole had a significantly higher efficacy against hookworm infections (cure rate, 26.1%; egg reduction rate, 88.7%) than either drug given alone. No difference in mebendazole efficacy was found in children who had been treated repeatedly compared with those who had not been treated previously. CONCLUSION: The overall efficacy of mebendazole against hookworm infections after periodic chemotherapy is reduced. The efficacy of benzimidazoles in chemotherapy-based control programmes should be monitored closely. Combined treatment with mebendazole and levamisole may be useful as a tool to delay the development of benzimidazole resistance.

Methods to sustain drug efficacy in helminth control programmes.

Assessment of the efficacy of anthelminthic treatment in public health is a broad concept, which goes beyond parasitological methods and should be clearly defined according to several indicators of morbidity. Several factors may influence the efficacy of anthelminthic drugs. The quality of drug is an issue of great importance, especially when produced locally as a generic product and used in large-scale chemotherapy-based control programmes. Other factors include the drug-patient interaction, the host-parasite relationship, the diagnostic method used, genetic variations between parasite strains and induced drug resistance. Veterinary scientists have warned that drug resistance can be selected through frequent mass treatment of sheep and goats and have developed a body of knowledge on evaluation of efficacy and detection of resistance in nematodes of veterinary importance. In soil-transmitted nematodes infections of humans, the egg reduction rate (ERR), the egg hatch assay (EHA) and novel molecular biological techniques may be used to monitor drug efficacy in helminth control programmes and to detect early occurrence of resistance. Evidence of reduced drug efficacy of some anthelminthics has been suggested by recent studies and strategies to prevent or delay the emergence of drug resistance in human soil-transmitted nematodes.

Soil-transmitted nematode infections and mebendazole treatment in Mafia Island schoolchildren.

In August 2000, a cross-sectional study was performed to assess the prevalence and intensity of soil-transmitted nematode infections in schoolchildren on Mafia Island. Hookworm infection was widespread (72.5% prevalence) whereas Trichuris trichiura was less prevalent (39.7%) and Ascaris lumbricoides was present at a low prevalence (4.2%), mainly in urban areas. In a subsample of the study population, both Necator americanus and Ancylostoma duodenale were found, although N. americanus was more prevalent. This survey was followed by a parasitological evaluation of mebendazole treatment using a single, 500-mg dose. The data on outcome were used for comparison with those from recent studies of similar treatment regimens in the neighbouring island of Pemba, Zanzibar, where periodic chemotherapy with mebendazole to schoolchildren has been implemented as part of a helminth-control programme since 1994. A higher efficacy of mebendazole against hookworm infection was found in Mafia Island (where a cure 'rate' of 31.3% and an egg-reduction 'rate' of 78.1% were recorded) when compared with that observed in Pemba Island, possibly indicating that hookworms may be developing mebendazole resistance on Pemba Island as a result of intense exposure to the drug there.

Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study.

OBJECTIVE: To measure the effects of iron supplementation and anthelmintic treatment on iron status, anaemia, growth, morbidity, and development of children aged 6-59 months. DESIGN: Double blind, placebo controlled randomised factorial trial of iron supplementation and anthelmintic treatment. SETTING: Community in Pemba Island, Zanzibar. PARTICIPANTS: 614 preschool children aged 6-59 months. MAIN OUTCOME MEASURES: Development of language and motor skills assessed by parental interview before and after treatment in age appropriate subgroups. RESULTS: Before intervention, anaemia was prevalent and severe, and geohelminth infections were prevalent and light-Plasmodium falciparum infection was nearly universal. Iron supplementation significantly improved iron status, but not haemoglobin status. Iron supplementation improved language development by 0.8 (95% confidence interval 0.2 to 1.4) points on the 20 point scale. Iron supplementation also improved motor development, but this effect was modified by baseline haemoglobin concentrations (P=0.015 for interaction term) and was apparent only in children with baseline haemoglobin concentrations <90 g/l. In children with a baseline haemoglobin concentration of 68 g/l (one standard deviation below the mean value), iron treatment increased scores by 1.1 (0.1 to 2.1) points on the 18 point motor scale. Mebendazole significantly reduced the number and severity of infections caused by Ascaris lumbricoides and Trichuris trichiura, but not by hookworms. Mebendazole increased development scores by 0.4 (-0.3 to 1.1) points on the motor scale and 0.3 (-0.3 to 0.9) points on the language scale. CONCLUSIONS: Iron supplementation improved motor and language development of preschool children in rural Africa. The effects of iron on motor development were limited to children with more severe anaemia (baseline haemoglobin concentration <90 g/l). Mebendazole had a positive effect on motor and language development, but this was not statistically significant.

Extending anthelminthic coverage to non-enrolled school-age children using a simple and low-cost method.

School health programmes are the basis of the strategy defined by WHO to reduce morbidity due to soil-transmitted nematodes and schistosomes in school age populations in developing countries. However, low rates of school enrollment can be a major factor limiting their success. In the present study enrolled children were informed by teachers on the date of the next deworming campaign and were invited to pass along this information to parents, siblings and friends of school-age. On the day of the deworming campaign, teachers were instructed to administer anthelminthics to enrolled and not enrolled school-age children present at school. In the month following the treatment day, information about coverage was collected by questionnaire in 257 households in two regions of Unguja Island, Zanzibar. Over 89% of school age children resulted treated (98.9% of those enrolled plus 60% of those not enrolled). The additional cost of treating non-enrolled is limited to the cost of providing additional doses of anthelminthic drug in each school. Non-enrolled school age children can easily, successfully and inexpensively included in school based deworming campaign. Managers of control programmes are invited to test this method adapting it in their particular and cultural environment.

School enrollment in Zanzibar linked to children's age and helminth infections.

UNLABELLED: School health programmes have been identified as a cost-effective strategy to reduce morbidity due to soil-transmitted helminths in the school-age population, but the low rate of school enrollment in developing countries is a major factor limiting their success. OBJECTIVE: The present study was conducted to identify reasons for non-enrollment and to evaluate differences in the occurrence of helminth infection between enrolled and non-enrolled children in Zanzibar, United Republic of Tanzania. METHOD: A questionnaire was submitted to 520 households to obtain information about enrollment and other socio-economic indicators. In addition, one school-age child was randomly selected in each household and investigated for soil-transmitted helminth infection. RESULTS: Overall, 71% of school-age children were enrolled. Enrollment increased with age. Only 41% of children under 9 years of age were enrolled compared to 91% in children older than 12 years. Enrollment is delayed because of an insufficient number of schools. Among non-enrolled school-age children, the proportion of heavy intensity infections was twice that of enrolled school-age children. CONCLUSIONS: Most of the non-enrolled school-age children live together with enrolled siblings in the same household, thereby representing an important opportunity for effective outreach activities. The effectiveness of the school-based helminth control programme in reducing the intensity of infection was confirmed. The significant gains achieved by enrolled school-age children in this study must be viewed as an attainable goal for the important numbers of non-enrolled school-age children in endemic areas. Decision-makers must ensure that outreach activities are included in helminth control programmes targeted to school-age children.

[Epidemiologic surveillance system and control of malaria in the central highlands of Madagascar: results 1999-2000]. / Système de surveillance épidémiologique et d'alerte du paludisme sur les Hautes Terres Centrales de Madagascar: résultats 1999-2000.

The central highlands in Madagascar are characterized by an unstable occurrence of malaria with the risk of sporadic outbreaks. In major parts of the region DDT indoor spraying campaigns have been carried out from 1993 to 1998. This strategy was in 1999 replaced by another anti-vector intervention program targeting residual foci as detected by a surveillance and early warning system. This system is based on monitoring of presumptive malaria cases in the communities by which the number of presumptive cases exceeded a defined warning threshold value per month. The system was in the follow-up period shown to be very sensitive to variation of the coverage of anti-vector interventions: the number of presumptive cases decreased in the villages in which indoor spraying had been carried out and a minor increase was observed in those villages, where indoor spraying has been suspended. An increase of malaria cases was observed in 44 (20.8%) out of 212 study sites in the same period. The increase was in particular predominant in areas at lower attitude at the outer zones of the central highlands.

Hookworms, malaria and vitamin A deficiency contribute to anemia and iron deficiency among pregnant women in the plains of Nepal.

Anemia and iron deficiency during pregnancy are prevalent in developing countries, but their causes are not always known. We assessed the prevalence and severity of anemia and iron deficiency and their association with helminths, malaria and vitamin A deficiency in a community-based sample of 336 pregnant women in the plains of Nepal. Hemoglobin, erythrocyte protoporphyrin (EP) and serum ferritin were assessed in venous blood samples. Overall, 72.6% of women were anemic (hemoglobin < 110 g/L), 19.9% had moderate to severe anemia (hemoglobin < 90 g/L) and 80.6% had iron deficiency (EP > 70 micromol/mol heme or serum ferritin < 10 microg/L). Eighty-eight percent of cases of anemia were associated with iron deficiency. More than half of the women (54.2%) had a low serum retinol concentration (<1.05 micromol/L), 74.2% were infected with hookworms and 19.8% had Plasmodium vivax malaria parasitemia. Hemoglobin, EP and serum ferritin concentrations were significantly worse and the prevalence of anemia, elevated EP and low serum ferritin was increased with increasing intensity of hookworm infection. Hookworm infection intensity was the strongest predictor of iron status, especially of depleted iron stores. Low serum retinol was most strongly associated with mild anemia, whereas P. vivax malaria and hookworm infection intensity were stronger predictors of moderate to severe anemia. These findings reinforce the need for programs to consider reducing the prevalence of hookworm, malaria infection and vitamin A deficiency where indicated, in addition to providing iron supplements to effectively control anemia.

Malaria, hookworms and recent fever are related to anemia and iron status indicators in 0- to 5-y old Zanzibari children and these relationships change with age.

In Zanzibar and other tropical regions, iron deficiency, malaria and multiple helminth infections coexist. We addressed the following questions: 1) What are the predictors of low hemoglobin in Zanzibari preschool children? 2) Are indicators of iron status informative in this population? 3) Does malaria modify the relation of iron indicators to hemoglobin? We used multivariate regression to analyze cross-sectional data from a community-based sample of rural Zanzibari children who were not ill (n = 490; 4-71 mo of age) in whom we assessed hemoglobin, serum ferritin (SF), erythrocyte protoporphyrin (EP), serum transferrin receptor (TfR), recent fever, malaria parasitemia and helminth fecal egg counts. Of hemoglobin values, 80% were <100 g/L and 15.5% were <70 g/L. In children <18 mo of age, 40.2% of hemoglobin values were <70 g/L. Our primary findings were as follows: 1) In children <30 mo old, hemoglobin was associated with malaria but not hookworms, whereas in children >/=30 mo, hemoglobin was related to hookworms but not malaria. In the younger age group, male sex and recent fever also predicted lower hemoglobin. 2) The three iron indicators were informative in this population but did not reflect only iron status. Malaria elevated SF in younger children and TfR and EP in both age groups. Fever elevated SF in older children and EP in both age groups, but not TfR. 3) Malaria modified the relation of all three indicators to hemoglobin. The relation of SF to hemoglobin was weak overall, and absent in malaria-infected children. EP and TfR were strongly related to hemoglobin, but this relation was attenuated by malaria.

Field trial of a haemoglobin colour scale: an effective tool to detect anaemia in preschool children.

The objective of this study was to evaluate the performance of the Haemoglobin Colour Scale, developed by Stott and Lewis, to diagnose anaemia in a primary health care setting where anaemia was prevalent and severe. Three measures of anaemia were compared in 535 preschool children: haemoglobin based on the Haemoglobin Colour Scale, clinical assessment in three sites (conjunctiva, palm and nail bed) and haemoglobin based on a digital haemoglobinometer (HemoCue method) taken as gold standard. A statistically significant correlation (r = 0.80, coefficient = 0.77 and Y intercept = 2.33) was obtained between the results of the Haemoglobin Colour Scale and the HemoCue. In more than 80% of cases, the difference between the colour scale readings and the results of the HemoCue was within 1 g/dl. Of 415 anaemic children (Hb < 11 g/dl by HemoCue), 85.2% were so identified by the Haemoglobin Colour Scale and 19.7% were classified anaemic by clinical pallor. Of 19 severely anaemic children (Hb < 7 g/dl by HemoCue), 73.6% were identified as severely anaemic and 100% were classified as anaemic by the colour scale, 61.1% were classified as anaemic using clinical pallor. We found the Haemoglobin Colour Scale to be a useful tool in identifying anaemic and severely anaemic children. Efficiencies in term of cost, accuracy and time make it an important resource in primary health care settings in developing countries. Further testing with other staff in other settings is recommended to determine the usefulness of large-scale distribution.