Schistosomiasis is still a major public health problem in many tropical countries, particularly in Africa where more than 90% of the global burden of schistosomiasis occurs [
1]. Large-scale administration of the anthelminthic drug praziquantel (PZQ) to at-risk populations has become the cornerstone of schistosomiasis control [
2,
3]. This strategy – known as preventive chemotherapy – has been successful in reducing infection intensities, and hence morbidity [
4,
5]. As morbidity is a result of cumulative exposure to a high number of schistosomes, school-aged children bear the largest burden of disease because they carry the highest intensity infections [
6]. Therefore, mass drug administration (MDA) of preventive chemotherapy targets school-aged children primarily [
6,
7]. These children are intermittently treated with a single oral dose of 40 mg/kg PZQ, the frequency of which depends on the prevalence of the infection in the community [
8]. Target populations are divided into high-, moderate- and low-risk communities in which school-aged children are treated with PZQ once a year, once every 2 years or twice during their primary schooling age, respectively [
9]. PZQ is the drug of choice for the treatment of all forms of schistosomiasis due to its high efficacy and excellent safety profile [
10].
Observed cure rates (CRs) after a single dose of PZQ treatment (40 mg/kg) range between 42 and 79% for
Schistosoma mansoni and between 37 and 93% for
S.haematobium in school-aged children [
11]. A second dose of PZQ at a later time point can increase the CR up to 93% for
S.mansoni [
11‐
13] and up to 99% for
S. haematobium [
11]. However, the estimated efficacy of PZQ is highly dependent on the diagnostic tool used to measure CRs. Most studies have used traditional parasitological methods, such as the Kato-Katz (KK) and urine-filtration (UF) methods based on microscopy and determining the presence/excretion of eggs. These methods lack sensitivity for diagnosing low level infections and as such overestimate CRs [
14,
15]. More sensitive diagnostic tools for schistosomiasis which are currently available and can be implemented in the field, are much more suited to evaluate the efficacy of PZQ and alternative dose regimens. For example, the commercially available point-of-care circulating cathodic antigen (POC-CCA) test, which indicates active worm infection by detection of parasite CCA in urine, has shown a high diagnostic accuracy for
S.mansoni with a sensitivity ranging between 78 and 92% and specificity approaching 100% [
15‐
17]. Over the past 10 years, this test has been widely evaluated in sub-Saharan Africa and is now recommended as the first line diagnostic to map schistosome prevalence and facilitate preventive chemotherapy strategic decision-making [
7,
16,
18]. In addition, there is a pressing need for ultra-sensitive diagnostic tools for areas where prevalence and infection intensity have been reduced to very low levels. Such diagnostic tools are needed to confirm interruption of transmission and possibly elimination of schistosomiasis. The circulating anodic antigen (CAA) detection assay fulfills these requirements. This assay measures parasite antigen both in urine and serum using an ultrasensitive reporter technology (up-converting phosphor particles, UCP) in combination with common immunochromatography, lateral flow (LF). This UCP-LF CAA assay has shown high sensitivity and specificity for all four main schistosome species (
S.haematobium,
S.japonicum,
S.mansoni and
S.mekongi) [
19‐
22]. In addition to the UCP-LF CAA assay, highly specific and sensitive molecular polymerase chain reaction (PCR) techniques that detect parasite-specific DNA in stool and urine have also become available [
16]. The combination of worm-derived antigens and egg-derived nucleic acids, are envisaged to further increase the sensitivity and specificity of the diagnostic toolbox and allow for a comprehensive assessment of PZQ efficacy, with respect to both parasite worm dynamics and fecundity.
Rationale
There is a need for a re-evaluation of previously established PZQ CRs to provide evidence for continuing mass distribution of PZQ in high risk communities. Previously, CRs may have been overestimated due to insensitive diagnostic tools, whereas continuing reinfections and the fact that PZQ has little activity on immature worms, might have led to an underestimation of the therapeutic effect [
23‐
26]. Repeated treatment with PZQ at short intervals (e.g. 2–8 weeks) in areas with ongoing transmission will more effectively target non-susceptible schistosomula as they will have matured into drug susceptible worms during this period [
11,
27], thereby increasing the drug effectiveness. As the short metabolic half-life of PZQ may also limit its effectiveness by suboptimal plasma levels, repeated dosing will increase the chance that all worms are affected [
28]. Whether this will be reflected in a significant decrease in schistosome prevalence and the potential to interrupt transmission, remains to be investigated [
11,
15,
29]. In this study, we will evaluate the effect of multiple doses of PZQ on parasite clearance and tolerance in individuals infected with
S.mansoni.
The primary objective of this study is to determine the efficacy of PZQ treatment for clearing S.mansoni infections in a multiple dose regimen (standard dose, four times, two-week intervals) using the KK technique. Secondary objectives include determining the efficacy of PZQ for clearing S.mansoni infections in a multiple dose regimen using DNA- and antigen-detection techniques, evaluation the safety of PZQ and determining the accuracy of the different diagnostic tests used in this study. Exploratory objectives include modelling the effect of multiple PZQ treatments on the transmission of schistosomiasis as well as modelling the biological effects of multiple PZQ treatments on individual worm burden, egg load and re-infection rates.