Limited efficacy of repeated praziquantel treatment in Schistosoma mansoni infections as revealed by highly accurate diagnostics, PCR and UCP-LF CAA (RePST trial).

BACKGROUND: Most studies assessing praziquantel (PZQ) efficacy have used relatively insensitive diagnostic methods, thereby overestimating cure rate (CR) and intensity reduction rate (IRR). To determine accurately PZQ efficacy, we employed more sensitive DNA and circulating antigen detection methods. METHODOLOGY: A sub-analysis was performed based on a previously published trial conducted in children from Côte d'Ivoire with a confirmed Schistosoma mansoni infection, who were randomly assigned to a standard (single dose of PZQ) or intense treatment group (4 repeated doses of PZQ at 2-week intervals). CR and IRR were estimated based on PCR detecting DNA in a single stool sample and the up-converting particle lateral flow (UCP-LF) test detecting circulating anodic antigen (CAA) in a single urine sample, and compared with traditional Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA). PRINCIPAL FINDINGS: Individuals positive by all diagnostic methods (i.e., KK, POC-CCA, PCR, and UCP-LF CAA) at baseline were included in the statistical analysis (n = 125). PCR showed a CR of 45% (95% confidence interval (CI) 32-59%) in the standard and 78% (95% CI 66-87%) in the intense treatment group, which is lower compared to the KK results (64%, 95% CI 52-75%) and 88%, 95% CI 78-93%). UCP-LF CAA showed a significantly lower CR in both groups, 16% (95% CI 11-24%) and 18% (95% CI 12-26%), even lower than observed by POC-CCA (31%, 95% CI 17-35% and 36%, 95% CI 26-47%). A substantial reduction in DNA and CAA-levels was observed after the first treatment, with no further decrease after additional treatment and no significant difference in IRR between treatment groups. CONCLUSION/SIGNIFICANCE: The efficacy of (repeated) PZQ treatment was overestimated when using egg-based diagnostics (i.e. KK and PCR). Quantitative worm-based diagnostics (i.e. POC-CCA and UCP-LF CAA) revealed that active Schistosoma infections are still present despite multiple treatments. These results stress the need for using accurate diagnostic tools to monitor different PZQ treatment strategies, in particular when moving toward elimination of schistosomiasis. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT02868385.

Efficacy and Safety of Albendazole in Hookworm-infected Preschool-aged Children, School-aged Children, and Adults in Côte d'Ivoire: A Phase 2 Randomized, Controlled Dose-finding Trial.

BACKGROUND: Infections with hookworms affect about half a billion people worldwide. Recommended therapy includes 400 mg of albendazole, which is moderately efficacious. Higher doses have been rarely assessed. METHODS: A randomized, controlled dose-finding trial was conducted in Côte d'Ivoire with the aim of recruiting 120 preschool-aged children (PSAC), 200 school-aged children (SAC), and 200 adults. Eligible PSAC were randomized 1:1:1 to 200 mg, 400 mg, or 600 mg of albendazole; the other age groups were randomized 1:1:1:1:1 to placebo or 200 mg, 400 mg, 600 mg, or 800 mg. The primary outcome was cure rates (CRs) assessed 14-21 days post-treatment by quadruplicate Kato-Katz thick smears. Hyperbolic Emax models were used to determine dose-response. RESULTS: 38 PSAC, 133 SAC, and 196 adults were enrolled. In adults, predicted CRs increased with ascending doses of albendazole, with a CR of 74.9% (95% confidence interval [CI], 55.6%-87.7%) in the 800-mg arm. Observed CRs increased with ascending doses of albendazole reaching a maximum of 94.1% (95% CI, 80.3%-99.3%). In SAC, the predicted dose-response curve increased marginally, with CRs ranging from 64.0% in the 200-mg arm to 76.0% in the 800-mg arm. Sample size in PSAC was considered too small to derive meaningful conclusions. 10.7% and 5.1% of participants reported any adverse event at 3 hours and 24 hours post-treatment, respectively. CONCLUSIONS: A single 800-mg albendazole dose provides higher efficacy against hookworm and is well tolerated in adults and should be considered for community-based strategies targeting adults. For PSAC and SAC, current recommendations suffice. CLINICAL TRIALS REGISTRATION: NCT03527745.

Efficacy and safety of ascending dosages of albendazole against Trichuris trichiura in preschool-aged children, school-aged children and adults: A multi-cohort randomized controlled trial.

BACKGROUND: The efficacy of the widely used albendazole against the soil-transmitted helminth Trichuris trichiura is limited; yet optimal doses, which may provide increased efficacy, have not been thoroughly investigated to date. METHODS: A randomized-controlled trial was conducted in Côte d'Ivoire with preschool-aged children (PSAC), school-aged children (SAC), and adults infected with T. trichiura. Participants were randomly assigned (1:1:1:1) using computer-generated randomization. PSAC were randomized to 200 mg, 400 mg, 600 mg of albendazole or placebo. SAC and adults were randomized to 400 mg, 600 mg, 800 mg of albendazole or placebo. The primary outcome was cure rates (CRs) against trichuriasis. Secondary outcomes were T. trichiura egg reduction rates (ERRs), safety, CRs and ERRs against other soil-transmitted helminths. Outcome assessors and the trial statistician were blinded. Trial registration at ClinicalTrial.gov: NCT03527745. FINDINGS: 111 PSAC, 180 SAC, and 42 adults were randomized and 86, 172, and 35 provided follow-up stool samples, respectively. The highest observed CR among PSAC was 27·8% (95% CI: 9·7%-53·5%) in the 600 mg albendazole treatment arm. The most efficacious arm for SAC was 600 mg of albendazole showing a CR of 25·6% (95% CI: 13·5%-41·2%), and for adults it was 400 mg of albendazole with a CR of 55·6% (95% CI: 21·2%-86·3%). CRs and ERRs did not differ significantly among treatment arms and flat dose-responses were observed. 17·9% and 0·4% of participants reported any adverse event at 3 and 24 h follow-up, respectively. INTERPRETATION: Albendazole shows low efficacy against T. trichiura in all populations and doses studied, though findings for PSAC and adults should be carefully interpreted as recruitment targets were not met. New drugs, treatment regimens, and combinations are needed in the management of T. trichiura infections. FUNDING: Bill and Melinda Gates Foundation.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL TRIALS REGISTRATION: The trial is registered at www.isrctn.com number ISRCTN81391471.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: This trial is registered with International Standard Randomised Controlled Trial Number ISRCTN15280205 .

Efficacy and Safety of Ivermectin Against Trichuris trichiura in Preschool-aged and School-aged Children: A Randomized Controlled Dose-finding Trial.

Background: Although trichuriasis affects millions of children worldwide, recommended drugs lack efficacy and new treatment options are urgently needed. Ivermectin has promising potential to complement the anthelminthic armamentarium. Methods: A randomized placebo-controlled trial was conducted in rural Côte d'Ivoire to provide evidence on the efficacy and safety of ascending oral ivermectin dosages in preschool-aged children (PSAC) and school-aged children (SAC) infected with Trichuris trichiura. The primary outcome was the cure rate (CR) for T. trichiura infection, and the secondary outcomes were safety, egg-reduction rates (ERRs) against T. trichiura infection, and CRs and ERRs against other soil-transmitted helminth species. Results: A total of 126 PSAC and 166 SAC were included in an available case analysis. In PSAC, efficacy against T. trichiura did not differ between 200 µg/kg ivermectin and placebo treatment arm, as expressed in CRs (20.9% [95% confidence interval {CI}, 11.9%-52.8%] vs 19.5% [10.4%-49.9%]) and geometric mean ERRs (78.6% [60.1%-89.5%] vs 68.2% [40.5%-84.8%]). In SAC, the highest administered ivermectin dose of 600 µg/kg had a low CRs (12.2% [95% CI, 4.8%-32.3%]) and moderate ERRs (66.3% [43.8%-80.2%]). Only mild adverse events and no organ toxicity, based on serum biomarkers, was observed. Conclusion: Ivermectin can be administered safely to PSAC with trichuriasis. Given the low efficacy of ivermectin monotherapy against T. trichiura infection, further research should investigate the optimal drug combinations and dosages with ivermectin against soil-transmitted helminthiasis. Clinical Trials Registration: ISRCTN15871729 (www.isrctn.com).

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

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.

Accuracy of urine circulating cathodic antigen test for the diagnosis of Schistosoma mansoni in preschool-aged children before and after treatment.

BACKGROUND: The Kato-Katz technique is widely used for the diagnosis of Schistosoma mansoni, but shows low sensitivity in light-intensity infections. We assessed the accuracy of a commercially available point-of-care circulating cathodic antigen (POC-CCA) cassette test for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. METHODOLOGY: A 3-week longitudinal survey with a treatment intervention was conducted in Azaguié, south Côte d'Ivoire. Overall, 242 preschoolers (age range: 2 months to 5.5 years) submitted two stool and two urine samples before praziquantel administration, and 86 individuals were followed-up posttreatment. Stool samples were examined with duplicate Kato-Katz thick smears for S. mansoni. Urine samples were subjected to POC-CCA cassette test for S. mansoni, and a filtration method for S. haematobium diagnosis. PRINCIPAL FINDINGS: Before treatment, the prevalence of S. mansoni, as determined by quadruplicate Kato-Katz, single CCA considering 'trace' as negative (t-), and single CCA with 'trace' as positive (t+), was 23.1%, 34.3% and 64.5%, respectively. Using the combined results (i.e., four Kato-Katz and duplicate CCA(t-)) as diagnostic 'gold' standard, the sensitivity of a single Kato-Katz, a single CCA(t-) or CCA(t+) was 28.3%, 69.7% and 89.1%, respectively. Three weeks posttreatment, the sensitivity of a single Kato-Katz, single CCA(t-) and CCA(t+) was 4.0%, 80.0% and 84.0%, respectively. The intensity of the POC-CCA test band reaction was correlated with S. mansoni egg burden (odds ratio = 1.2, p = 0.04). CONCLUSIONS/SIGNIFICANCE: A single POC-CCA cassette test appears to be more sensitive than multiple Kato-Katz thick smears for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. The POC-CCA cassette test can be recommended for the rapid identification of S. mansoni infections before treatment. Additional studies are warranted to determine the usefulness of POC-CCA for assessing drug efficacy and monitoring the impact of control interventions.