Efficacy and safety of ascending doses of praziquantel against Schistosoma haematobium infection in preschool-aged and school-aged children : a single-blind randomised controlled trial

Despite decades of experience with praziquantel treatment in school-aged children (SAC) and adults, we still face considerable knowledge gaps relevant to the successful treatment of preschool-aged children (PSAC). This study aimed to assess the efficacy and safety of escalating praziquantel dosages in PSAC infected with Schistosoma haematobium.; We conducted a randomised, dose-finding trial in PSAC (2-5 years) and as comparator a cohort of SAC (6-15 years) infected with S. haematobium in Côte d'Ivoire. A total of 186 PSAC and 195 SAC were randomly assigned to 20, 40 or 60 mg/kg praziquantel or placebo. The nature of the dose-response relationship in terms of cure rate (CR) was the primary objective. Egg reduction rate (ERR) and tolerability were secondary outcomes. CRs and ERRs were assessed using triplicate urine filtration over 3 consecutive days. Available-case analysis was performed including all participants with primary endpoint data.; A total of 170 PSAC and 174 SAC received treatment. Almost 90% of PSAC and three quarters of SAC were lightly infected with S. haematobium. Follow-up data were available for 157 PSAC and 166 SAC. In PSAC, CRs of praziquantel were 85.7% (30/35), 78.0% (32/41) and 68.3% (28/41) at 20, 40 and 60 mg/kg and 47.5% (19/40) for placebo. In SAC, CRs were 10.8% for placebo (4/37), 55.6% for 20 mg/kg (25/45), 68.3% for 40 mg/kg (28/41) and 60.5% for 60 mg/kg (26/43). ERRs based on geometric means ranged between 96.5% (60 mg/kg) and 98.3% (20 mg/kg) in PSAC and between 97.6% (20 mg/kg and 60 mg/kg) and 98.6% (40 mg/kg) in SAC. Adverse events were mild and transient.; Praziquantel revealed dose-independent efficacy against light infections of S. haematobium. Over the dose range tested, praziquantel displayed a ceiling effect with the highest response for 20 mg/kg in PSAC. In SAC maximum efficacy was obtained with 40 mg/kg praziquantel. Further investigations are required in children with moderate to heavy infections.; This trial is registered with International Standard Randomised Controlled Trial Number ISRCTN15280205

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

Efficacy and safety of ascending dosages of tribendimidine against hookworm infections in children : a randomized controlled trial

The global strategy to control soil-transmitted helminthiasis is mainly focused on preventive chemotherapy with albendazole and mebendazole. We assessed the efficacy and safety of ascending tribendimidine doses against hookworm infections in African school-aged children, key information for the development of tribendimidine.; We performed a single blind, randomized, controlled trial in Côte d'Ivoire between June and August 2017. Eligible participants were randomly assigned to placebo, 100, 200, or 400 mg tribendimidine. Cure rates (CRs, primary outcome) and egg reduction rates (ERRs) were determined 14-21 days after treatment. Clinical symptoms were assessed before treatment and adverse events monitored 3 and 24 hours posttreatment.; CRs calculated for 130 children dose-dependently increased. The observed CRs were 20.6% (7/34), 21.2% (7/33), 38.7% (12/31), and 53.1% (17/32) for placebo, 100, 200, and 400 mg of tribendimidine, respectively. The Emax model predicted a placebo corrected net effect of 34.3 percentage points (95% confidence interval [CI], 13.3-54.4) for the 400-mg tribendimidine dose. The ERRs (geometric mean) were 30.6% (95% CI, -24.7 to 64.1), 65.4% (95% CI, 24.5-85.9), 82.1% (95% CI, 58.4-92.5) and 92.2% (95% CI, 81.0-97.1) for placebo, 100, 200, and 400 mg tribendimidine, respectively. The Emax model predicted an ERR of 95% at 500 mg. Only mild adverse events and no abnormal biochemical parameters were observed.; A 400-mg dose of tribendimidine yielded the highest efficacy and was well tolerated. Because children were mostly lightly infected, further investigations with tribendimidine against moderate/heavy hookworm infection are needed.; The trial is registered at www.isrctn.com number ISRCTN81391471

Flowchart showing study participation.

<p>Flowchart detailing study participation and adherence of preschool-aged children for submitting two stool and two urine samples for the diagnosis of <i>S. mansoni</i>, <i>S. haematobium</i>, and soil-transmitted helminths before and after administration of praziquantel in the two study villages in the Azaguié district, south Côte d'Ivoire, in August and September 2011.</p

Comparison of test requirements of POC-CCA cassette test and Kato-Katz technique.

<p>No detailed requirements of each test are mentioned in this table, but the main requirements of each test are emphasized.</p

Agreement between Kato-Katz technique and POC-CCA cassette test for the diagnosis of <i>S. mansoni</i>.

<p>The study was carried out in Azaguié, south Côte d'Ivoire in August and September 2011.</p>*<p>κ indicating kappa; κ<0, no agreement; κ = 0–0.2, poor agreement; κ = 0.21–0.4, fair agreement; κ = 0.41–0.6, moderate agreement; κ = 0.61–0.8, substantial agreement; κ = 0.81–1.0, almost perfect agreement <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002109#pntd.0002109-Landis1" target="_blank">[35]</a>.</p><p>t−, trace negative; t+, trace positive.</p

Correlation between <i>S. mansoni</i> egg counts and CCA test color reaction scores.

<p>This figure shows the correlation between <i>S. mansoni</i> eggs per gram of stool (EPG) values, as determined by quadruplicate Kato-Katz thick smears, and a single urine CCA cassette test with ‘trace’ considered as negative result (negative (0), 1+, 2+, and 3+.</p

Number of preschool-aged children falling in each POC-CCA test score before and after treatment.

<p><i>n</i> = 86, Day 1: first day of urine collection, Day 2: second day of urine collection.</p>a<p>Combined POC-CCA cassette test (days 1 and 2), as defined in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002109#pntd-0002109-t001" target="_blank">Table 1</a>.</p>b<p>The higher POC-CCA cassette test score from either day 1 or day 2 was considered as final score.</p

Baseline prevalence of helminths according to diagnostic approach (<i>n</i> = 242).

<p>The study was carried out in Azaguié, south Côte d'Ivoire in August and September 2011. Duplicate Kato-Katz thick smears were prepared from each stool sample and a single POC-CCA cassette test was done on urine samples collected over two consecutive days. Infection intensities are based on thresholds put forth by WHO <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002109#pntd.0002109-WHO1" target="_blank">[1]</a>. The POC-CCA test results were categorized as light (1+), moderate (2+), and heavy (3+).</p><p>CI, confidence interval; n.d., not defined; POC-CCA, point-of-care circulating cathodic antigen; t−, trace negative; t+, trace positive.</p

Epidemiology of schistosomiasis in two hgh-risk communities of south Côte d'Ivoire with particular emphasis on pre-school-aged children

Abstract. Schistosomiasis control efforts mainly target school-aged children. We studied the epidemiology of schistosomiasis in two high-risk communities in south Côte d'Ivoire, placing particular emphasis on pre-school-aged children. We used a suite of diagnostic techniques, including Kato-Katz, urine filtration, reagent strips, and urine circulating cathodic antigen cassettes. Risk factors for schistosomiasis were determined by focus group discussions and a structured questionnaire. The prevalence of Schistosoma mansoni in the two study villages among the pre-school-aged children (age > 6 years) was 20.9% and 25.0%, whereas several-fold higher prevalences were found in school-aged children (58.7-68.4%) and adolescents/adults (59.5-61.7%). The prevalence of S. haematobium in the three age groups was 5.9-17.3%, 10.9-18.4%, and 3.8-21.3%, respectively. Most participants had light-intensity infections. Mothers' occupations and older siblings play important roles in the epidemiology of schistosomiasis in pre-schoolers. In the current epidemiologic settings, more attention is warranted on pre-school-aged children and adolescents/adults for successful schistosomiasis control