Efficacy and safety of praziquantel in preschool-aged and school-aged children infected with Schistosoma mansoni: a randomised controlled, parallel-group, dose-ranging, phase 2 trial

Background Praziquantel has been the drug of choice for schistosomiasis control for more than 40 years, yet surprisingly, the optimal dose for children younger than 4 years is not known. We aimed to assess the efficacy and safety of escalating praziquantel dosages in preschool-aged children (PSAC). Methods We did a randomised controlled, parallel-group, single-blind, dose-ranging, phase 2 trial in PSAC (2–5 years) and school-aged children (SAC; aged 6–15 years) as a comparator group in southern Côte d'Ivoire. Children were randomly assigned (1:1:1:1) to 20 mg/kg, 40 mg/kg, or 60 mg/kg praziquantel or placebo. Participants, investigators, and laboratory technicians were masked to group assignment, while the investigator providing treatment was aware of the treatment group. The primary objective was to estimate the nature of the dose–response relation in terms of cure rate using the Kato Katz technique. Dose–response curves were estimated using Emax models. Available case analysis was done including all participants with primary endpoint data. This trial is registered with International Standard Randomised Controlled Trial, number ISRCTN15280205. Findings Between Nov 11, 2014, and Feb 18, 2015, 660 PSAC and 225 SAC were assessed for eligibility; of whom 161 (24%) PSAC and 180 (80%) SAC had a detectable Schistosoma mansoni infection. 161 PSAC were randomly allocated of whom 154 received treatment: 42 were assigned to 20 mg/kg praziquantel, of whom 40 received treatment; 38 were assigned to 40 mg/kg praziquantel, of whom 38 received treatment; 41 were assigned to 60 mg/kg praziquantel, of whom 39 received treatment; and 40 were assigned to placebo, of whom 37 received placebo. 180 SAC were randomly allocated of whom 177 received treatment: 49 were assigned to 20 mg/kg praziquantel, of whom 47 received treatment; 46 were assigned to 40 mg/kg praziquantel, of whom 46 received treatment; 42 were assigned to 60 mg/kg praziquantel, of whom 42 received treatment; and 43 were assigned to placebo, of whom 43 received treatment. Follow-up (available-case) data were available for 143 PSAC and 174 SAC. In PSAC, the 20 mg/kg dose resulted in cure in 23 children (62%; 95% CI 44·8–77·5), 40 mg/kg in 26 children (72%; 54·8–85·8), 60 mg/kg in 25 children (71%; 53·7–85·4), and placebo in 13 children (37%; 21·5–55·1). In SAC, the 20 mg/kg dose resulted in cure in 14 children (30%; 95% CI 17·7–45·8), 40 mg/kg in 31 children (69%; 53·4–81·8), 60 mg/kg in 34 children (83%; 67·9–92·8), and placebo in five children (12%; 4·0–25·6). For both age groups, the number of adverse events was similar among the three praziquantel treatment groups, with fewer adverse events observed in the placebo groups. The most common adverse events in PSAC were diarrhoea (11 [9%] of 124) and stomach ache (ten [8%]) and in SAC were diarrhoea (50 [28%] of 177), stomach ache (66 [37%]), and vomiting (26 [15%]) 3 h post treatment. No serious adverse events were reported. Interpretation Praziquantel shows a flat dose-response and overall lower efficacy in PSAC compared with in SAC. In the absence of treatment alternatives, a single dose of praziquantel of 40 mg/kg, recommended by the WHO for S mansoni infections in SAC can be endorsed for PSAC in preventive chemotherapy programmes

Efficacy and Safety of Mefloquine, Artesunate, Mefloquine-Artesunate, and Praziquantel against Schistosoma haematobium: Randomized, Exploratory Open-Label Trial

Background. Morbidity control of schistosomiasis relies on a single drug, praziquantel. The antimalarial drug mefloquine possesses interesting antischistosomal properties, yet no clinical studies have been performed. Methods. We conducted a randomized, exploratory open-label trial to assess the efficacy and safety of mefloquine (25 mg/kg), artesunate (3 doses of 4 mg/kg), mefloquine-artesunate (3 doses of 100 mg artesunate plus 250 mg mefloquine), and praziquantel (40 mg/kg) against Schistosoma haematobium. The effects on Schistosoma mansoni, malaria parasitemia, soil-transmitted helminths, and intestinal protozoa were also determined. Results. A total of 83 S. haematobium-infected schoolchildren were included in the study. Cure rates of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against S. haematobium at day 26 after treatment were 21%, 25%, 61%, and 88%, respectively. Both mefloquine-artesunate and praziquantel resulted in egg reduction rates >95%. Significantly lower egg reduction rates were seen in the artesunate (85%) and mefloquine groups (74%). In children coinfected with S. mansoni, praziquantel and mefloquine-artesunate, but not mefloquine and artesunate alone, resulted in high cure rates and egg reduction rates. Mefloquine, artesunate, and mefloquine-artesunate completely cured infections due to Plasmodium falciparum. No effects were found against soil-transmitted helminths and intestinal protozoa. Abdominal pain was the most frequent adverse event, with a higher incidence among children treated with mefloquine (89%), mefloquine-artesunate (83%), and artesunate (60%) than among children treated with praziquantel (46%). Conclusions. The high efficacy of mefloquine-artesunate against S. haematobium warrants further investigation. Individuals coinfected with Plasmodium and Schistosoma who were treated with a mefloquine-artesunate combination against malaria might have a dual benefit: clearance of malaria parasitemia and reduction of schistosomiasisrelated morbidity. Clinical trials registration. Current Controlled Trials identifier: ISRCTN0649876

Epidemiology of malaria in the Taabo health and demographic surveillance system, south-central Côte d'Ivoire

A deep understanding of the local epidemiology of malaria is essential for the design and implementation of setting-specific control and elimination efforts. In Côte d'Ivoire, new initiatives are underway to reduce the burden of malaria, which requires high-quality longitudinal data. The epidemiology of malaria was studied in the Taabo health and demographic surveillance system (HDSS) in south-central Côte d'Ivoire and implications for control are discussed.; Two cross-sectional surveys were carried out in the rainy season of June/July in 2010 and 2011. Inhabitants of approximately 7 % of randomly selected households in the Taabo HDSS were invited to participate. People were clinically examined, ear temperature was measured and spleen size determined. Finger-prick blood samples were collected and subjected to a rapid diagnostic test (RDT). Additionally, thick and thin blood films were prepared on microscope slides and diagnosed under a microscope for Plasmodium infection and parasitaemia. Haemoglobin (Hb) level was determined using a HemoCue device.; A total of 1187 and 1264 people in 2010 and 2011, respectively, had complete data records. The prevalence of Plasmodium infection was 46.0 % in 2010 and 56.6 % in 2011, owing to a statistically significant difference (p < 0.05). Males showed a higher Plasmodium infection prevalence than females (49.6 and 62.8 % versus 42.6 and 51.2 %; respectively, in 2010 and 2011; both p < 0.05). The highest malaria prevalence was observed among infants and young children (aged ≤9 years). The risk of Plasmodium infection was significantly higher in villages compared to small hamlets and urban settings (p < 0.05). Fever, Hb level and splenomegaly were associated with parasitaemia.; Malaria is highly endemic in the Taabo HDSS in south-central Côte d'Ivoire with considerable spatial heterogeneity of Plasmodium infection. There is a pressing need to scale-up control interventions against malaria

Spatial mapping and prediction of Plasmodium falciparum infection risk among school-aged children in Côte d'Ivoire

BACKGROUND: In Côte d'Ivoire, malaria remains a major public health issue, and thus a priority to be tackled. The aim of this study was to identify spatially explicit indicators of Plasmodium falciparum infection among school-aged children and to undertake a model-based spatial prediction of P. falciparum infection risk using environmental predictors. METHODS: A cross-sectional survey was conducted, including parasitological examinations and interviews with more than 5,000 children from 93 schools across Côte d'Ivoire. A finger-prick blood sample was obtained from each child to determine Plasmodium species-specific infection and parasitaemia using Giemsa-stained thick and thin blood films. Household socioeconomic status was assessed through asset ownership and household characteristics. Children were interviewed for preventive measures against malaria. Environmental data were gathered from satellite images and digitized maps. A Bayesian geostatistical stochastic search variable selection procedure was employed to identify factors related to P. falciparum infection risk. Bayesian geostatistical logistic regression models were used to map the spatial distribution of P. falciparum infection and to predict the infection prevalence at non-sampled locations via Bayesian kriging. RESULTS: Complete data sets were available from 5,322 children aged 5-16 years across Côte d'Ivoire. P. falciparum was the predominant species (94.5 %). The Bayesian geostatistical variable selection procedure identified land cover and socioeconomic status as important predictors for infection risk with P. falciparum. Model-based prediction identified high P. falciparum infection risk in the north, central-east, south-east, west and south-west of Côte d'Ivoire. Low-risk areas were found in the south-eastern area close to Abidjan and the south-central and west-central part of the country. CONCLUSIONS: The P. falciparum infection risk and related uncertainty estimates for school-aged children in Côte d'Ivoire represent the most up-to-date malaria risk maps. These tools can be used for spatial targeting of malaria control interventions

Multiple parasite infections and their relationship to self-reported morbidity in a community of rural Côte d'Ivoire

Background Concomitant parasitic infections are common in the developing world, yet most studies focus on a single parasite in a narrow age group. We investigated the extent of polyparasitism and parasite associations, and related these findings to self-reported morbidity. Methods Inhabitants of 75 randomly selected households from a single village in western Côte d'Ivoire provided multiple faecal specimens and a single finger prick blood sample. The Kato-Katz technique and a formol-ether concentration method were employed to screen faecal samples for Schistosoma mansoni, soil-transmitted helminths and intestinal protozoa. Giemsa-stained blood smears were analysed for malaria parasites. A questionnaire was administered for collection of demographic information and self-reported morbidity indicators. Results Complete parasitological data were obtained for 500/561 (89.1%) participants, similarly distributed among sex, with an age range from 5 days to 91 years. The prevalences of Plasmodium falciparum, hookworms, Entamoeba histolytica/E. dispar, and S. mansoni were 76.4%, 45.0%, 42.2%, and 39.8%, respectively. Three-quarters of the population harboured three or more parasites concurrently. Multivariate analysis revealed significant associations between several pairs of parasites. Some parasitic infections and the total number of parasites were significantly associated with self-reported morbidity indicators. Conclusions Our data confirm that polyparasitism is very common in rural Côte d'Ivoire and that people have clear perceptions about the morbidity caused by some of these parasitic infections. Our findings can be used for the design and implementation of sound intervention strategies to mitigate morbidity and co-morbidit

Effect of an integrated intervention package of preventive chemotherapy, community-led total sanitation and health education on the prevalence of helminth and intestinal protozoa infections in Côte d'Ivoire

Preventive chemotherapy with donated anthelminthic drugs is the cornerstone for the control of helminthiases. However, reinfection can occur rapidly in the absence of clean water and sanitation coupled with unhygienic behaviour. The purpose of this study was to assess the effect of an integrated package of interventions, consisting of preventive chemotherapy, community-led total sanitation (CLTS) and health education, on the prevalence of helminth and intestinal protozoa infections and on participants' knowledge, attitude, practice and beliefs (KAPB) towards these diseases including water, sanitation and hygiene (WASH).; A cross-sectional survey was carried out in nine communities of south-central Côte d'Ivoire to assess people's infection with helminths and intestinal protozoa and KAPB. Subsequently, interventions were targeted to five communities, while the remaining communities served as control. The intervention encouraged latrine construction and an evaluation was done 6-7 months later to determine open defecation status of the respective communities. Anthelminthic treatment was provided to all community members. A follow-up cross-sectional survey was conducted approximately one year later, using the same procedures.; Overall, 810 people had complete baseline and follow-up data and were given anthelminthic treatment. The baseline prevalence of hookworm, Schistosoma haematobium, Trichuris trichiura, Schistosoma mansoni and Ascaris lumbricoides was 31.1%, 7.0%, 2.0%, 1.0% and 0.3%, respectively. Four of the five intervention communities were classified open-defecation free. For hookworm infection, we observed higher negative changes in terms of proportion of decrease (-0.10; 95% confidence interval (CI): - 0.16, -0.04) and higher egg reduction rate (64.9 vs 15.2%) when comparing intervention with control communities. For intestinal protozoa, prevalence reduction was higher in intervention compared to control communities (8.2 vs 2.6%) and WASH indicators and intervention outcomes associated with lower odds for infection at follow-up. The intervention significantly impacted on reported latrine use (before: 15.5%, after: 94.6%), open defecation in the community surroundings (before: 75.0%, after: 16.7%) and awareness for environmental contamination through open defecation (before: 20.4%, after: 52.2%).; An integrated package of interventions consisting of preventive chemotherapy, health education and CLTS reduces the prevalence of helminth and intestinal protozoa infection. Additional studies in other social-ecological settings are warranted to confirm our findings

Efficacy of single versus four repeated doses of praziquantel against Schistosoma mansoni infection in school-aged children from Côte d'Ivoire based on Kato-Katz and POC-CCA: An open-label, randomised controlled trial (RePST).

BACKGROUND: Preventive chemotherapy with praziquantel (PZQ) is the cornerstone of schistosomiasis control. However, a single dose of PZQ (40 mg/kg) does not cure all infections. Repeated doses of PZQ at short intervals might increase efficacy in terms of cure rate (CR) and intensity reduction rate (IRR). Here, we determined the efficacy of a single versus four repeated treatments with PZQ on Schistosoma mansoni infection in school-aged children from Côte d'Ivoire, using two different diagnostic tests. METHODS: An open-label, randomized controlled trial was conducted from October 2018 to January 2019. School-aged children with a confirmed S. mansoni infection based on Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) urine cassette test were randomly assigned to receive either a single or four repeated doses of PZQ, administered at two-week intervals. The primary outcome was the difference in CR between the two treatment arms, measured by triplicate KK thick smears 10 weeks after the first treatment. Secondary outcomes included CR estimated by POC-CCA, IRR by KK and POC-CCA, and safety of repeated PZQ administration. PRINCIPAL FINDINGS: During baseline screening, 1,022 children were assessed for eligibility of whom 153 (15%) had a detectable S. mansoni infection, and hence, were randomized to the standard treatment group (N = 70) and the intense treatment group (N = 83). Based on KK, the CR was 42% (95% confidence interval (CI) 31-52%) in the standard treatment group and 86% (95% CI 75-92%) in the intense treatment group. Observed IRR was 72% (95% CI 55-83%) in the standard treatment group and 95% (95% CI 85-98%) in the intense treatment group. The CR estimated by POC-CCA was 18% (95% CI 11-27%) and 36% (95% CI 26-46%) in the standard and intense treatment group, respectively. Repeated PZQ treatment did not result in a higher number of adverse events. CONCLUSION/SIGNIFICANCE: The observed CR using KK was significantly higher after four repeated treatments compared to a single treatment, without an increase in adverse events. Using POC-CCA, the observed CR was significantly lower than measured by KK, indicating that PZQ may be considerably less efficacious as concluded by KK. Our findings highlight the need for reliable and more accurate diagnostic tools, which are essential for monitoring treatment efficacy, identifying changes in transmission, and accurately quantifying the intensity of infection in distinct populations. In addition, the higher CR in the intense treatment group suggests that more focused and intense PZQ treatment can help to advance schistosomiasis control. TRIAL REGISTRATION: www.clinicaltrials.gov NCT02868385

Health & Demographic Surveillance System Profile: The Taabo Health and Demographic Surveillance System, Côte d'Ivoire

The Taabo Health and Demographic Surveillance System (HDSS) is located in south-central Côte d'Ivoire, approximately 150 km north-west of Abidjan. The Taabo HDSS started surveillance activities in early 2009 and the man-made Lake Taabo is a key eco-epidemiological feature. Since inception, there has been a strong interest in research and integrated control of water-associated diseases such as schistosomiasis and malaria. The Taabo HDSS has generated setting-specific evidence on the impact of targeted interventions against malaria, schistosomiasis and other neglected tropical diseases. The Taabo HDSS consists of a small town, 13 villages and over 100 hamlets. At the end of 2013, a total population of 42 480 inhabitants drawn from 6707 households was under surveillance. Verbal autopsies have been conducted to determine causes of death. Repeated cross-sectional epidemiological surveys on approximately 5-7% of the population and specific, layered-on haematological, parasitological and questionnaire surveys have been conducted. The Taabo HDSS provides a database for surveys, facilitates interdisciplinary research, as well as surveillance, and provides a platform for the evaluation of health interventions. Requests to collaborate and to access data are welcome and should be addressed to the secretariat of the Centre Suisse de Recherches Scientifiques en Côte d'Ivoire: [[email protected]

Intestinal parasitic infections in schoolchildren in different settings of Côte d'Ivoire : effect of diagnostic approach and implications for control

BACKGROUND: Social-ecological systems govern parasitic infections in humans. Within the frame of assessing the accuracy of a rapid diagnostic test for Schistosoma mansoni in Cote d'Ivoire, three different endemicity settings had to be identified and schoolchildren's intestinal parasitic infection profiles were characterized. METHODS: In September 2010, a rapid screening was conducted in 11 schools in the Azaguie district, south Cote d'Ivoire. In each school, 25 children were examined for S. mansoni and S. haematobium. Based on predefined schistosome endemicity levels, three settings were selected, where schoolchildren aged 8-12 years were asked to provide three stool and three urine samples for an in-depth appraisal of parasitic infections. Triplicate Kato-Katz thick smears were prepared from each stool sample for S. mansoni and soil-transmitted helminth diagnosis, whereas urine samples were subjected to a filtration method for S. haematobium diagnosis. Additionally, a formol-ether concentration method was employed on one stool sample for the diagnosis of helminths and intestinal protozoa. Multivariable logistic regression models were employed to analyse associations between schoolchildren's parasitic infections, age, sex and study setting. RESULTS: The prevalences of S. mansoni and S. haematobium infections in the initial screening ranged from nil to 88% and from nil to 56%, respectively. The rapid screening in the three selected areas revealed prevalences of S. mansoni of 16%, 33% and 78%. Based on a more rigorous diagnostic approach, the respective prevalences increased to 92%, 53% and 33%. S. haematobium prevalences were 0.8%, 4% and 65%. Prevalence and intensity of Schistosoma spp., soil-transmitted helminths and intestinal protozoan infections showed setting-specific patterns. Infections with two or more species concurrently were most common in the rural setting (84%), followed by the peri-urban (28.3%) and urban setting (18.2%). CONCLUSIONS: More sensitive diagnostic tools or rigorous sampling approaches are needed to select endemicity settings with high fidelity. The observed small-scale heterogeneity of helminths and intestinal protozoan infections has important implications for contro

Spatial risk profiling of Plasmodium falciparum parasitaemia in a high endemicity area in Côte d'Ivoire

Background. The objective of this study was to identify demographic, environmental and socioeconomic risk factors and spatial patterns of Plasmodium falciparum parasitaemia in a high endemicity area of Africa, and to specify how this information can facilitate improved malaria control at the district level. Methods. A questionnaire was administered to about 4,000 schoolchildren in 55 schools in western Ĉte d'Ivoire to determine children's socioeconomic status and their habit of sleeping under bed nets. Environmental data were obtained from satellite images, digitized ground maps and a second questionnaire addressed to school directors. Finger prick blood samples were collected and P. falciparum parasitaemia determined under a microscope using standardized, quality-controlled methods. Bayesian variogram models were utilized for spatial risk modelling and mapping of P. falciparum parasitaemia at non-sampled locations, assuming stationary and non-stationary underlying spatial dependence. Results. Two-thirds of the schoolchildren were infected with P. falciparum and the mean parasitaemia among infected children was 959 parasites/μl of blood. Age, socioeconomic status, not sleeping under a bed net, coverage rate with bed nets and environmental factors (e.g., normalized difference vegetation index, rainfall, land surface temperature and living in close proximity to standing water) were significantly associated with the risk of P. falciparum parasitaemia. After accounting for spatial correlation, age, bed net coverage, rainfall during the main malaria transmission season and distance to rivers remained significant covariates. Conclusion. It is argued that a massive increase in bed net coverage, particularly in villages in close proximity to rivers, in concert with other control measures, is necessary to bring malaria endemicity down to intermediate or low levels