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WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children. This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2–6 years were eligible. In cohort 1, participants aged 4–6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2–3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17–21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140. Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1–6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6–93·5] in cohort 1a vs 81·3% [67·4–91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]). Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis. The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

During a trial of preventive chemotherapy strategies, a hotspot of Schistosoma mansoni infection was found. Significant differences between hotspot and nonhotspot villages were found after 1 year. Villages meeting endpoints at year 5 were predicted from prior data with accuracy. Abstract Background Persistent hotspots have been described after mass drug administration (MDA) for the control of schistosomiasis, but they have not been studied during the course of a multiyear MDA program. Methods In data from a 5-year study of school-based and village-wide preventive chemotherapy strategies for Schistosoma mansoni, spatial scan statistics were used to find infection hotspots in 3 populations: 5- to 8-year-olds, 9- to 12-year-olds, and adults. Negative binomial regression was used to analyze changes from baseline, and receiver operating characteristic analyses were used to predict which villages would reach prevalence and intensity endpoints. Results We identified a persistent hotspot, not associated with study arm, where S. mansoni infection prevalence and intensity did not decrease as much as in villages outside the hotspot. Significant differences from baseline were realized after 1 year of MDA: we did not identify factors that moderated this relationship. Villages meeting specified endpoints at year 5 were predicted from prior year data with moderately high sensitivity and specificity. Conclusions The MDA strategies were less effective at reducing prevalence and intensity in the hotspot compared with other villages. Villages that reached year 5 endpoints could be detected earlier, which may provide the opportunity to amend intervention strategies.

BACKGROUNDPartial protective immunity to schistosomiasis develops over time, following repeated praziquantel (PZQ) treatment. Moreover, animals develop protective immunity after repeated immunization with irradiated cercariae. Here, we evaluated the development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni in healthy, Schistosoma-naive participants using single-sex, controlled human S. mansoni infection.METHODSTwenty-four participants were randomized in a double-blinded (1:1) manner to either the reinfection group, which received 3 exposures (weeks 0, 9, and 18) to 20 male cercariae, or to the infection control group, which received 2 mock exposures with water (weeks 0 and 9) prior to cercariae exposure (week 18). Participants were treated with PZQ (or placebo) at weeks 8, 17, and 30. Attack rates (ARs) after the final exposure (weeks 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events (AEs) were collected for safety.RESULTSTwenty-three participants completed the follow-up. No protective efficacy was observed, given an 82% (9 of 11) AR after the final exposure in the reinfection group and 92% (11 of 12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; P = 0.5). Related AEs were higher after the first infection (45%) compared with the second (27%) and third (28%) infections. Severe acute schistosomiasis was observed after the first infections only (2 of 12 in the reinfection group and 2 of 12 in the infection control group).CONCLUSIONRepeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported following subsequent infections, but did not result in protection against reinfection.TRIAL REGISTRATIONClinicalTrials.gov NCT05085470.FUNDINGEuropean Research Council (ERC) Starting Grant (no. 101075876).

Treatment guidelines for schistosomiasis recommend increasing frequency of preventative chemotherapy (PC) administration of praziquantel to twice per annum in persistent hotspots of transmission, in combination with integrated control strategies. FibroScHot was an individual randomised superiority trial designed to examine twice per annum and four times per annum treatment frequency. It was conducted in two primary schools, Buhirigi and Kaiso, in Hoima District Uganda - a designated Schistosoma mansoni high transmission area in which PC is targeted at children and adults. The baseline parasitology data was assessed against international control programme thresholds of success and the criteria for persistent hotspots. Further, the study also assessed the potential for integrated control strategies within the surrounding communities. The prevalence of infection, heavy infection and the infection intensity were derived for 700 participants from Kato-Katz examination of one stool sample. Neither school met the threshold of morbidity control (<5% with heavy infection). A strong school effect was observed in models of prevalence and prevalence of heavy infection, with these being greater in Kaiso. By prevalence, Kaiso was a high transmission area and Buhirigi a moderate transmission area. Kaiso but not Buhirigi met the definition of a persistent hotspot. Persistent hotspot classification did not change when intensity of infection was used. Intermediate snail hosts were collected at both Kaiso landing site and from the River Hoimo in Buhirigi, though in smaller numbers in the latter. Questionnaire data indicates that reliance on water collection from transmission sites and open defecation occurs more frequently in Kaiso than in Buhirigi. The criteria for persistent hotspots were met in the high transmission but not the moderate transmission community despite neither community meeting the threshold of morbidity control. This disconnect indicates that endemic communities exist in which control has not been achieved but increased frequency of treatment is currently not recommended. FibroScHot will be able to inform on whether widening the current recommendation of increased treatment frequency to these communities will achieve improved control. Evidence provided also indicates scope for the integrated control strategies of vector control and WASH improvements in both the participating communities.

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. 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). 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. 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. www.clinicaltrials.gov, NCT02868385.

Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species. A systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment. Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo). Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa. Efficacy was assessed as cure rate (CR, n=17,017) and egg reduction rate (ERR, n=13,007); safety as adverse events (AE) incidence. The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2-98.0) for S. japonicum, 77.1% (68.4-85.1) for S. haematobium, 76.7% (95%CI 71.9-81.2) for S. mansoni, and 63.5% (95%CI 48.2-77.0) for mixed S. haematobium/S. mansoni infections. Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium. The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni. No significant relationship between dose and ERR was detected. Tolerability was assessed in 40 studies (12,435 subjects). On average, 56.9% (95%CI 47.4-67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE. The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain. The large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses. The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.

Background Schistosomiasis is a neglected tropical disease burdening millions of people. One drug, praziquantel, is currently used for treatment and control. Clinically relevant drug resistance has not yet been described, but there is considerable heterogeneity in treatment outcomes, ranging from cure to only moderate egg reduction rates. The objectives of this study are to investigate potential worm-induced dysbacteriosis of the gut microbiota and to assess whether a specific microbiome profile could influence praziquantel response. Methods Using V3 and V4 regions of 16S rRNA genes, we screened the gut microbiota of 34 Schistosoma mansoni infected and uninfected children from Côte d’Ivoire. From each infected child one pre-treatment, one 24-hour and one 21-day follow-up sample after administering 60 mg/kg praziquantel or placebo, were collected. Results Overall taxonomic profiling and diversity indicators were found to be close to a “healthy” gut structure in all children. Slight overall compositional changes were observed between S. mansoni -infected and non-infected children. Praziquantel treatment was not linked to a major shift in the gut taxonomic profiles, thus reinforcing the good safety profile of the drug by ruling out off-targets effects on the gut microbes. 16S rRNA gene of the Fusobacteriales order was significantly more abundant in cured individuals, both at baseline and 24 hours post-treatment. A real-time qPCR confirmed the over-abundance of Fusobacterium spp. in cured children. Fusobacterium spp. abundance could also be correlated with treatment induced S. mansoni egg-reduction. Conclusions Our study suggests that neither a S. mansoni infection nor praziquantel administration triggers a significant effect on the microbial composition and that a higher abundance of Fusobacterium spp., before treatment, is associated with higher efficacy of praziquantel in the treatment of S. mansoni infections. Trial registration International Standard Randomised Controlled Trial, number ISRCTN15280205 .

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. 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. 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. 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. www.clinicaltrials.gov NCT02868385.

Preschool children suffer from morbidity attributable to Schistosoma mansoni . We compared a single and double dose of praziquantel treatment on the regression of S . mansoni associated morbidity in children less than six years in Uganda. We measured the sizes of spleen and liver as well as liver fibrosis before treatment and 8 months after treatment among children who either received one dose (n = 201) or two doses (n = 184) of praziquantel (standard oral dose of 40 mg/kg body weight). Heamoglobin measurements were also taken. Overall, liver enlargement reduced from 52.2% (95% CI (Confidence interval) 45.1, 59.3) to 17.9% (95% CI 12.9, 23.9) with a single dose and from 48.4 (95% CI 40.9, 55.8) to 17.9% (95% CI 12.7, 24.3) with a double dose and there was no significant difference between the changes in proportion of children with enlarged liver between the two treatment groups. The proportion of children with enlarged spleen was not significantly reduced in the group treated with either one or two doses, 47.8% (95% CI 41.7, 54.9) to 45.3% (95% CI 38.3, 52.4) and 48.4% (95% CI 40.9,55.8) to 40.8% 95% CI 33.6, 48.2), respectively. Liver fibrosis detected among children getting single dose (n = 9) or double doses (n = 13) resolved after treatment with praziquantel. The number of children with low heamoglobin significantly reduced from 51.2% (95% CI 44.1, 58.3) to 0.5% (0.2, 0.8) and 61.4% (95% CI 53.9,68.5) to 1.1% (95% CI 0.1, 3.9) after single and double dose treatment, respectively. These results suggest that there is no evidence of a difference in effect between one dose of praziquantel and two doses in reversing morbidity attributable to S . mansoni among children less than six years of age.

Background Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. Methods This was an open-label, randomised clinical trial involving 426 school-aged children (7–15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. Results Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni -infected children ( n  = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium -infected children ( n  = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. Conclusions A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes. Graphical abstract