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

Schistosomiasis is a major public health problem with an estimated 779 million people at risk of infection [1]. The disease is caused by trematode worms of the genus Schistosoma, where infection with Schistosoma japonicum and S. mansoni causes mostly intestinal schistosomiasis, while S. haematobium is responsible for genitourinary schistosomiasis [2, 3, 4, 5, 6]. Cumulative schistosome infections over years, due to rapid reinfection, result in morbid sequelae, including haematuria, nutritional deficiencies, anaemia, hepatic peri-portal fibrosis and consequent portal hypertension and delayed physical and cognitive development [7, 8, 9]. Moreover, genitourinary schistosomiasis can lead to obstruction and carcinomas of urogenital organs and impairment to female reproductive health [6, 10]. To control schistosomiasis morbidity, health authorities rely on mass administration (preventive chemotherapy) of praziquantel in school-aged children (SAC), the population most affected [11, 12, 13]. In 2010, the World Health Organization (WHO) endorsed the inclusion of preschool-aged children (PSAC) in preventative chemotherapy programmes, since there is increasing evidence that they are also affected by schistosomiasis and could suffer from morbidity [14, 15, 16, 17]. In the absence of an appropriate paediatric formulation, broken or crushed praziquantel tablets are commonly used in PSAC using the standard 40 mg/kg dose [18]. A range of studies showed that this dose was well tolerated and efficacious [15, 19, 20]. However, the heterogeneity of methodology and reporting on praziquantel efficacy and safety assessment make decision-making difficult [21].

In the paediatric population, growth and maturation of organs are dynamic. Changes in body proportion and metabolism occur throughout infancy and childhood that affect how drugs are metabolised [22, 23]. Well-designed paediatric drug trials are therefore warranted in order to guide the proper usage of drug treatments to avoid underdosing, overdosing, ineffectiveness and safety problems.

We recently conducted a randomised, controlled dose-finding study assessing the safety and efficacy of praziquantel in PSAC and SAC infected with S. mansoni. Considerable differences were observed between these two age groups with regard to efficacy. For example, while treatment of SAC with 40 or 60 mg/kg met the WHO standards of clinical efficacy of ≥ 90% egg reduction rate (ERR) based on arithmetic mean (AM), none of the doses administered could reach this threshold in PSAC [24].

This study was designed to support the ongoing efforts to successfully control schistosome infections in PSAC by assessing the efficacy and safety of escalating praziquantel dosages in PSAC compared to SAC infected with S. haematobium. The clinical evidence for praziquantel obtained for both S. haematobium and S. mansoni in PSAC will facilitate the clinical decision-making process, resulting in successful control of schistosome infection and disease.

Over the past decade, preventive chemotherapy programmes for the control of schistosomiasis targeting SAC have scaled up across many countries in tropical and subtropical areas. Great progress has been made in decreasing the burden of this disease [29, 30, 31]. However, recent modelling and health economic studies found that expanded community-wide preventive chemotherapy that includes adolescents, adults and PSAC would better reduce the overall disease burden, rates of transmission and reinfection [32].

It was recommended in 2010 that PSAC should be included in preventive chemotherapy programmes [33] using an adequate dose, though this age group is still lacking a suitable formulation. A paediatric formulation of praziquantel (small, orally dispersible tablets) is under development (https://www.pediatricpraziquantelconsortium.org/node/28), but it will take several more years until the drug is marketed and available to all PSAC. To be able to treat preschoolers safely and effectively, we studied ascending doses of praziquantel in PSAC and SAC infected with S. haematobium. Our results build on an earlier dose-finding study in S. mansoni-infected children [24].

Several findings of our study are worth highlighting. First, the highest overall CRs among PSAC (85.7%) and SAC (68.3%) were obtained with 20 mg/kg and 40 mg/kg praziquantel, respectively and not with the highest dose administered, 60 mg/kg. For both age groups, CRs revealed even a slight inverse dose-rate effect. Similarly, ERRs increased very fast up to 98% and did not increase further regardless of the praziquantel dose administered. Interestingly, 60 mg/kg praziquantel also showed lower CRs in PSAC with moderate/high S. haematobium infection intensities compared to the two lower doses. For example, the CR in PSAC characterised by heavy infection intensities treated with 60 mg/kg praziquantel was as low as 25%. However, only a handful of PSAC suffered from moderate and high infection intensities; hence, no clear picture can be drawn for this age group. In SAC similar CRs were observed in children harbouring heavy infection intensities treated with 40 and 60 mg/kg. In summary, a high dose of praziquantel seems to have no additional benefit in the treatment of S. haematobium infections. This result is in contrast with our recent study, where we reported that in SAC infected with S. mansoni, CRs increased with higher doses of praziquantel [24], while only moderate CRs were observed in PSAC at all doses administered.

Overall higher CRs were observed in PSAC (68–86%) when compared to SAC (56–68%), which mirrors a recent meta-analysis by Zwang et al., where 40 mg/kg praziquantel cured 87.3% of S. haematobium-infected PSAC compared to 71.4% of SAC [34]. Nonetheless, our finding can most likely be explained with the lower infection intensities present in PSAC, as CRs in children characterised by heavy infection intensities were low. Hence, our results confirm the relationship between CRs and infection intensity observed in previous studies [35, 36]. Overall, the results emphasise the need for rigorous treatment programmes in settings with heavy infection of S. haematobium, since reductions in egg output significantly correlated with decreased morbidity [37, 38].

No dose-response relationship was observed for ERRs in both age groups above 20 mg/kg. This finding is in line with an earlier meta-analysis by Zwang et al. [34] which found no significant relationship for dose and ERR for any of the Schistosoma species. However, our dose-finding study in S. mansoni-infected children showed that higher ERRs (based on GMs) were observed in children treated with 40 and 60 mg/kg compared to 20 mg/kg [24]. Recent WHO Standard Operating Procedures have set a threshold of a 90% ERR based on AM for clinical efficacy and recommend that control programmes should investigate drug performance in populations where the ERR is lower [39]. Regardless of age group and whether GM or AM was used to determine ERRs, we found that all praziquantel doses used against S. haematobium, in contrast to preschoolers infected with S. mansoni [24], yielded ERRs above 90%. Despite the excellent efficacy of 20 mg/kg of praziquantel against light S. haematobium infections in this study, the use of two different doses, namely 20 mg/kg for S. haematobium and 40 mg/kg for S. mansoni in settings where Schistosoma species are overlapping, would raise logistical and operational challenges since control programmes are acting at large-scale levels such as district or country levels. Therefore, rigorous cost-effectiveness studies need to be implemented before a change of treatment guidelines could be considered. However, at a point-of-care level, using a test-and-treat approach, 20 mg/kg and 40 mg/kg could be recommended to treat PSAC for S. haematobium and S. mansoni infections, respectively.

In PSAC we observed a high CR in the placebo arm similar to what was observed in our S. mansoni study [24]. The probability of being cured for placebo-treated children was particularly high in children with low egg loads despite using a relatively strong diagnostic approach at baseline and follow-up by collecting per child three consecutive urine samples for each time point (baseline and follow-up). On the other hand, no cured individual was observed in placebo-treated children with heavy infection intensity at baseline. The high CR observed in the placebo treatment arm among PSAC was thus likely reflective of the low sensitivity of the urine filtration method for light infections [40, 41]. Our findings underscore the value of adding a placebo group in Schistosoma drug efficacy trials—the overestimation of CRs due to potential false negatives in light infections is visible. More importantly, our observations emphasise the need for Schistosoma species-related standard operating procedures including reliable diagnostic tools, suitable for drug efficacy assessment for low infection intensities [40, 41, 42].

With regard to safety outcomes, the main adverse events observed in both PSAC and SAC are in line with the adverse events reported in previous studies [16, 24, 34]. We observed an increase of adverse events severity that was proportional to praziquantel dose in SAC, while only one child showed moderate diarrhoea at the 60 mg/kg treatment dose in PSAC. However, as mentioned earlier, the accuracy of the adverse event severity assessment in PSAC is questionable, in particular for the less visible mild adverse events, since the reporting is done by the children’s mothers.

Praziquantel showed a high response rate in PSAC and SAC infected with S. haematobium, with high efficacy observed already at 20 mg/kg, particularly in light infections. No benefit was observed using higher praziquantel doses in the current study. However, to be able to provide ultimate dosing recommendations of praziquantel for PSAC, additional studies might be required to support our conclusions, including pharmacokinetic studies and studies in PSAC suffering from moderate and heavy S. haematobium infections.