Advocacy, policies and practicalities of preventive chemotherapy campaigns for African children with schistosomiasis

Abstract

Preventive chemotherapy campaigns against schistosomiasis have progressively scaled-up during the last decade, administering single standard dose praziquantel (40 mg/kg) treatments to millions of African children. Steps taken in securing international advocacy and national level implementation are traced to highlight an international treatment platform set for further expansion, including surveillance of schistosomiasis, school-level targeting with better on-site drug administration and annual reporting of programmatic indicators (i.e., treatment coverage), potentially in real-time. Several shortcomings in need of resolution are identified and efficacy of praziquantel is assessed by a systematic review. If WHO predictions in reduction of schistosomiasis are to be realized, careful international harmonization and tailoring of national resources are required. Maintaining an effective drug distribution system and regularly checking drug efficacy are paramount.

Keywords::

• cure rate
• egg reduction rate
• intestinal schistosomiasis
• praziquantel
• preventive chemotherapy
• Schistosoma
• urogenital schistosomiasis

Figure 1. Natural history of infection with schistosomiasis begins soon after birth often by exposure to domestic water collected from environmental sources.

(A) As the child gains independence, exploration of these water bodies continues and infections are accrued. Upon reaching school, where treatment is given, worm burdens are reduced by treatment with praziquantel, however, the child will become re-infected upon subsequent water contact. (B) Conceptualization of treatment study measuring the performance of praziquantel. Children within a school are selected and offered treatment. These same children are re-examined typically 24 days later and cure rate is determined as a percentage of those who have stopped shedding parasite eggs. Cure rates typically range from absolute (100%) down to 75%, but in some instances can be much lower.

Figure 2. International advocacy, policy and control programme reporting in action.

Screen shots of the WHO website that highlight recent decisions taken for disease control (A) and data contained within the Preventive Chemotherapy Database for Madagascar illustrating administered treatments (B).

Figure 3. Implementation map of Uganda, as of 2012, highlighting the different agencies involved in control of schistosomiasis, taken from Research Triangle Institute international website.

Figure 4. Generic information, education and communication materials produced by WHO for implementing preventive chemotherapy within schools.

(A) Front cover of teacher training booklet for deworming school children. (B) On-site tools needed for administration of deworming tablets to children: potable water, drinking cups and praziquantel height pole is needed alongside treatment registers for recording treatments and noting any noncompliance or side effects.Figure taken from [14].

Figure 5. Systematic review of literature, review and filtering.

To qualify for inclusion, study design had to be a longitudinal study enrolling individuals (0–22 years of age) infected with Schistosoma haematobium and/or Schistosoma mansoni, as determined microscopically: for S. haematobium, eggs in a standard filtrate of 10 ml of urine, for S. mansoni, eggs in standard Kato–Katz smears (at least a single smear); patients had to be treated with praziquantel, 40 mg/kg single dose; the sample size (number. treated or diagnosed) was reported; the temporal interval between baseline and reassessment had to be reported; the population age ranges were reported and primary outcome (cure rate achieved) had to be reported. Exclusion criteria were: study participants were not human; incomplete information; duplicate publications; full article not accessible; reviews and follow-up period exceeded 90 days or less than 20 days. The following information was independently extracted by two reviewers (AMD Navaratnam and JC Sousa-Figueiredo) and was checked together. The extracted information included: first author’s name and year of publication, country studied, participants age, Schistosoma species, diagnostics methods, follow-up time, raw dichotomous data of efficacy assessment (number. treated/number. positive upon follow-up), cure rate and other outcomes (egg reduction rate). In surveys were the same population was followed-up multiple times, the outcome considered was the one gathered closest to the latest acceptable time period (i.e., 90 days).

Figure 6. Cross study comparison of the performance of praziquantel across Africa in terms of parasitological cure.

Figure 7. Relationship between observed cure rate and local prevalence of schistosomiasis.

(A) Species cure rates for Schistosoma mansoni and Schistosoma haematobium. (B) Cure rates for children in two age ranges (0–6 years and aged 6 plus) differ with cure rates within younger children decreasing quickly with increasing local prevalence highlighting that for preschool-aged children the performance of praziquantel is to be optimized.

Background on epidemiology & treatment

Schistosomiasis is a waterborne parasitic infection which typically gives rise to a chronic inflammatory disease, as typified by immunopathological lesions around schistosome eggs trapped inside host tissues [1,2]. In Africa, there are two forms of schistosomiasis, intestinal and urogenital, which are caused by different species, Schistosoma mansoni and Schistosoma haematobium, respectively [3–5]. Other schistosome species able to infect man include Schistosoma intercalatum and Schistosoma guineensis but these are of minor public health importance [3]. Although widespread, the geographical distribution of schistosomiasis across Africa is often focalized and difficult to predict locally. This is due to interdependence (as part of the schistosome’s lifecycle) with aquatic snails and site-specific conditions of impoverished sanitation and water hygiene. As schistosome larvae (i.e., cercariae) can penetrate skin directly, and infection with schistosomes takes place upon exposure to water containing viable larvae [5]. This can be from contact with either domestic water drawn from environmental bodies or from activities within these water bodies themselves in passive- or active-like water contact mechanisms, respectively, see Figure 1 [6]. Accurate mapping of schistosomiasis is an ongoing challenge but fundamental for effective control by targeting resources [3,7].

Schistosomiasis is not restricted to humans, with several other schistosome species infecting livestock and wildlife, although these have limited medical importance [8–10]. Nonetheless in West Africa, recent detection of novel hybrids between S. haematobium and Schistosoma bovis and Schistosoma curassoni has revealed an unexpected zoonosis thereby challenging conventional wisdom both on epidemiology and control [11,12]. Equally important has been the detection of schistosomiasis in infants and preschool-aged children that highlights other shortcomings in present control tools for example, in diagnostics and of suitable drug formulations [13]. These instances, although important, should not distract attention from the more obvious disease burden and need for control within school-aged children [14]. In resource-limited settings, typically school-aged children are given prioritization which is in-keeping with their higher burden of parasitemia (i.e., infection prevalence and intensity both peak in childhood), their greater vulnerability to disease (but with better reversibility of morbidity if given prompt treatment), as well as their easier accessibility within educational infrastructure (i.e., by attending primary school) as supported by universal primary education (UPE) [4,14].

In endemic areas, interventions are thus targeted towards mass treatment of school children by large-scale administration of single standard dose praziquantel (PZQ) given out at 40 mg/kg bodyweight dosing following international guidelines for preventive chemotherapy (PC) [4]. Although the exact killing mechanism of PZQ against schistosome worms is still unknown (see section below), its efficacy is typically judged by the cessation of parasite egg excretion in stool or urine samples [14,15]. The specimens are processed by routine parasitological methods and parasitological cure (i.e., the percentage of those children who stop shedding eggs) is judged by inspection of a cohort of children before and after PZQ treatment, as shown in Figure 1. Unfortunately, as treatment does not prevent or guard against subsequent infection, if water contact is continued, reinfection can take place relatively quickly [16]. However, the pathology that the eggs induce is somewhat diminished by a reduction in their production (i.e., egg reduction rate) such that future morbidity is averted. To balance against the levels of reinfection, a staggered regime of retreatment is offered (Figure 1 & Table 1) [14]. Upon careful consideration of all alternatives, PC has come to the fore in the fight against neglected tropical diseases (NTDs) [17] with PZQ, the only drug commercially available for control of schistosomiasis, as the backbone medication [14,15]. In the context of this review the advocacy, policies and practicalities of administration and performance of single dose PZQ treatment are reviewed.

Fostering large-scale treatment campaigns

Despite a daily-adjusted life year or quality-adjusted life year statistic that might suggest otherwise [18], control of schistosomiasis ranks highly within the list of appropriate interventions for improving child health in Africa. Over the last decade, there have been significant steps taken in control [19]; at the national level, for example, a tremendous effort has taken place in the scale-up of PC across several countries in sub-Saharan Africa (SSA) administering single standard dose PZQ to millions of children [4]. This scale-up was with the firm intention of abating present morbidity and averting disease associated with schistosomiasis whereas before access to drug was severely limited and induced unnecessary suffering [19]. Brought about by the fruition of international advocacy, this reality was set down upon WHO guidelines of integrated PC, not forgetting a key ingredient of an international donor landscape receptive to offering comprehensive support either in the provision of funds or in medications against NTDs gratis (e.g., orally taken benzimidazoles, mectizan and zithromax) [20,21]. Consolidated by instigation of several national treatment campaigns, these so-called ‘rapid-impact’ packages make convincing sense within public health settings, with an ‘all in’ cost-per-child treated being often cited as US$0.50 [22,23]. However, while the cost per treated child might be appealing, when scaled across several tens of millions of children needing treatment each year, the surrounding budgets become much more substantive [24,25], not omitting the cost for distribution of the drugs themselves that typically accounts for the majority of the assigned budget [26,27].

Securing & strengthening political advocacy

Significant steps taken to shape this donor landscape began by obtaining, in 2001, high-level political support by acceptance of the 54th World Health Assembly (WHA) stipulated resolution 54.19 [28]. This stated that member states were urged to attain “a minimum target of regular administration of chemotherapy to at least 75% and up to 100% of all school-aged children at risk of morbidity by 2010.” Building upon this and recalling previous resolutions WHA3.26, WHA28.53 and WHA29.58 led to the most recent endorsement of WHA65.21 by promoting ‘elimination of schistosomiasis’, in 2012. This reaffirmed the need to reach and treat at least 75% of school-age children at risk of morbidity with PC and also envisaged significant reductions in disease endemicity through future scale-up of PC. Subsequently, further recommendations on 16 other NTDs were made at the 132nd Executive Board of WHO, see Figure 2A, that will then be put forward for due consideration at the 66th WHA in 2013. In so doing, a clear agenda for elimination of several NTDs, embellishing the WHO strategic 2012–2020 roadmap for schistosomiasis in the African (AFRO) and Mediterranean (EMRO) regions, is now ratified [4].

Since WHA 54.19, and thanks to the backing from a number of international organizations, donor foundations, bilateral institutions and nongovernmental development organizations (NGDOs), several African governments have taken up the cause [28]. This was significantly boosted by a US$30 million grant from the Bill & Melinda Gates Foundation to set up the Schistosomiasis Control Initiative (SCI) at Imperial College London (UK) in 2002 [19,29]. Originally with its research partners at Harvard University (MA, USA) and then later Danish Bilharziasis Laboratory, Denmark, SCI provided financial, technical and logistical support to six countries in East (Uganda, Tanzania, Zambia) and West (Niger, Burkina Faso, Mali) SSA [29]. Equally as important was an associated monitoring and evaluation research portfolio, as undertaken as ‘implementation science’ alongside while the programme unfolded [30]. The initial 5-year SCI programme later synergized with subsequent funds from USAID in conjunction with the Research Triangle Institute (RTI) International in the 2006–2011 period. This was part of RTI’s coined ‘NTD Control Program’, originally, earmarked US$15 million of funding in the first year of operations, RTI fostered links with other implementation partners for general control of NTDs in: Burkina Faso, Cameroon, Ghana, Mali, Niger, Sierra Leone, South Sudan, Togo and Uganda [28].

Following G8 commitments to NTDs beginning in the UK in 2005, additional funds were provided to SCI by the Department for International Development in 2010 for implementation of Integrated Control of Schistosomiasis in Africa (ICOSA) for Ivory Coast, Liberia, Malawi, Mozambique, Niger, Tanzania, Uganda and Zambia. With Obama’s Expanded Presidential Global Health Initiative further support of NTD control was fostered, most recently additional support from USAID to RTI international has created a new set of implementation partners (Helen Keller International, IMA World Health and Sightsavers International) brought together within the ‘ENVISION’ programme set to run until 2016 with an earmarked annual budget of some US$89 million. Although a more minor international donor player, the END Fund was created as a financial tool with pooled resources, largely from private philanthropy, for assisting the scale-up of NTD control. The most notable coordinating partner of which was Geneva Global, which provided funds to support schistosomiasis control in Burundi and Rwanda as implemented by SCI [31]. Similarly, the END 7 Fund, created by the Sabin Vaccine Institute, was dedicated to raising the awareness, political will and funding necessary to control and eliminate the seven most common NTDs [20].

A need for global communications

During this time keeping abreast of this growing international commitment was solidified in the creation of new communication tools and groups, with the WHO website having a central coordinating importance with Action Against Worms newsletters that brought new focus upon control activities against worm-related NTDs [201]. Perhaps the most important and formalized new communication was in 2007 the production of an open access journal from the PLoS dedicated to NTDs [32]. With external support from the Bill & Melinda Gates Foundation, PLoS NTDs quickly became the leading journal for academic outputs in NTD-related research. In terms of schistosomiasis, there are well over 200 articles reporting on novel aspects in the use PZQ in PC campaigns and on research on the drug itself. Today it has the highest journal impact factor among its equivalents and has been a tremendous achievement when set against the concurrent performance of other journals, for example, the American Journal of Tropical Medicine and Hygiene that has a longer history and broader membership. There has also been new institutional collaborations too numerous to mention, however, most recently in the UK was the launch of the London Centre for Neglected Tropical Diseases, bringing together Imperial College London, London School of Hygiene and Tropical Medicine and the Natural History Museum. Less formal groups include the formation of ‘Global Network for Neglected Tropical Diseases’ in the USA, the ‘International Society for Neglected Tropical Diseases’ and also ‘Developing World Health’ in the UK. The latter having raised over £130,000 GBP by public donations in its 50 pence donation scheme via its website. It should be noted that there is ongoing debate as to how increased donor funds translate into tangible actions, ensuring their use in pragmatic actions is essential in maintaining continued support [33].

During this time the range and scope of control initiatives and implementation partners against schistosomiasis have evolved to a level never before witnessed [28,31]. This change, although beneficial, has created several unforeseen consequences creating challenging times, such as, co-ordination of ‘basket’ donor funds, global purchase and in-country provision of PZQ, utilization and maintenance of procured in-country resources, as well as, standardization of operational procedures undertaken directly on-the-ground. Percolating from top to bottom and vice versa, these frictions stem at the international level by inducing competition in the selection of countries (and of course those that are not) incurring tensions, then downwards into their unique landscapes of implementation districts [25,34–36]. This administrative landscape is often characterized by decentralized governance, frequently with a confused devolution of responsibilities and budgets as new projects are taken onboard [37]. On the ground further confusion can be augmented by the network of local implementing agencies for example, NGDOs, which often fail to cross-talk regularly and with each sometimes having different health agenda [37]. At the coal-face of control, this inevitably leads to discord in reporting of activities such as drug delivery, parasitological assessment and long-term impact of PC, as witnessed with a specific example of Uganda (see Figure 3). A country with the longest recent history of integrated campaigns offering PC for NTDs, the landscape of interventions is now not simple with several implementation stakeholders; especially so since 2005 when several new districts were created and with it nascent health and educational infrastructures to dialogue with until fully functional [37]. From a geographical perspective, only until recently have there been any serious attempts to service the treatment needs of marginalized populations on the numerous islands within the Ugandan part of Lake Victoria, notwithstanding movements cross-country into Kenya and Tanzania [38–40]. These itinerant communities are typified as hard-to-reach and difficult-to-access populations, yet they are in greatest need of treatment, for here intestinal schistosomiasis is almost universal and particularly aggressive in pathology [41,42].

In parallel with other NTDs there is, as of yet, no standardized reporting mechanism to measure ‘impact’ of control against schistosomiasis [14]. Even at a simple level, this has led to some confusion on what markers could or should be reported, that is, total number of treatments administered versus percentage treatment coverage as estimated by various geographical or demographic strata (see below). At the national level, much of this has been resolved by the creation of the WHO Preventive Chemotherapy Database (PCD) that has up-to-date information reported by country. Summarizing all data collated from 2006 onwards, the website features interactive maps, summary tabulations and graphical outputs that chart ongoing progress in delivery of medications, see Figure 2B [4]. The central importance of this website will become ever more apparent as it becomes the first point of call in measuring progress towards the 2020 WHO targets and monitoring the global demand for PZQ [20,21] as well as an important archive of past actions to see within country scale-up.

A global picture of praziquantel

From 2006, it became increasingly clear that a major limitation in PC campaigns was the availability of PZQ itself, which potentially weakened the drug supply chain for other NTDs when included [20,21]. Globally, PZQ was in such short supply it could not even service the given need in Africa alone, which was much greater than had been previously realized. In order to nurture this global drug supply, encouraging the future expanded production of PZQ in a coordinated and scaled-up fashion, WHO took the important step to better estimate each country’s treatment needs in a formal rationale and make a projection of future needs throughout the forthcoming decade [4]. This was achieved by scaling the treatment schedules by school; see Table 1, by the associated population size of each country and its estimated national prevalence of schistosomiasis. It then became clear that prior control initiatives were only providing just less than 20% of the annual PZQ need in Africa, and some countries were completely overlooked [4]. Indeed, estimating this treatment need for the 2012–2020 period is a fundamental concept in the WHO strategic plan for schistosomiasis. Foremost it is a rally-point for the pharmaceutical sector to act in unison and often in philanthropy [4].

To break through this glass ceiling of PZQ production, the producers of the active ingredient of PZQ and others within the pharmaceutical industry were stimulated into action by the London Declaration on Neglected Tropical Diseases in January 2012. This meeting, chaired by Bill Gates, was a round table of 14 CEOs from key organizations with the director general of the WHO in attendance. It led to important pledges of general pharmaceutical support and goodwill, in particular from Merck-KGaA, to expand their donation of from 25 to 250 million tablets of PZQ each year, for the foreseeable future. This will directly service the need for annual treatment of school-aged children greatly facilitating the WHA54.19 target, but it should not be forgotten that additional supplies are needed for treatment of adults, as well as an appropriate formulation for infants and preschool-aged children as being developed by a public–private partnership of Merck-Serono, TI Pharma, Swiss TPH and Astellas. Spurred on by this incredible level of generosity, the WHO report Schistosomiasis progress report 2001–2011 and strategic plan 2012–2020 [4] was fully endorsed by WHA65.21 in May 2012 by adopting these plans for the elimination of schistosomiasis. There is also an allied portfolio of intensified control and associated set of disease-specific targets to be reached as mapped out with specific implementation milestones (Table 2).

Practicalities of school-based deworming

It is commonly held that many countries in SSA have weak health systems and are largely unable to provide children with sufficient, regular access to PZQ. With the advent of UPE and the recognition that schistosomiasis blights children’s lives, it has been a long-term feature of WHO guidelines and recommendations to co-opt educational infrastructure and staff, that is, teachers to become the first-line distributors of deworming tablets [14]. Moreover, the schools are also centrally important in mapping the distribution of the disease as WHO treatment guidelines typically relate prevalence of disease by surveyed school with local treatment algorithms, Table 1. A variety of low cost, pragmatic methods are used to assess disease prevalence upon routine parasitological sampling (i.e., microscopic examination of Kato-Katz fecal smears or urine filtrates), or by questionnaire methods reporting red urine (i.e., macrohaematuria) [14]. Owing to constraints in finances and logistics, however, not all schools within the putative implementation area are actually surveyed, for to do so would incur prohibitively large expenses [3]. Nonetheless, striking the balance on initial survey information against realistic treatment needs is required, even more when set against short and long-term perspectives, in years and decades, respectively. This is especially important for calculations that attempt to demonstrate cost–effectiveness, in all its guises, that need quality disease-specific information at baseline. Simply put, while presumptive annual treatment of schools at-risk may be favored, if, owing to its unusual focality, schistosomiasis was actually absent within the implementation area, then allocated drugs and resources will have had no served purpose. Furthermore, this would continue to do so through time, until resources were made available downstream for retargeting [3].

To include or exclude areas for control?

Addressing the exact treatment needs across a focalized landscape is not trivial [3]. Where possible, rational decisions that classify areas for inclusion and exclusion should be evidence-based [43,44]. Spatial epidemiological methods of disease prediction have been, and are being, used that utilize remotely sensed environmental information, for example, ground temperature or normalized differential vegetation index, to build an informative disease distribution model [45–48]. Predictive models are able to classify areas with some statistical certainty as to being unfavorable, for example, being too cold, and largely unable to sustain disease transmission within the desired school sampling frame. Thus, large regions can be excluded with minimal surveying costs. However, the performance of such methods in terms of their under and over-treatment is being investigated more formally; as there are instances when they have been more miss-leading than informative, as has been discussed elsewhere [42]. In terms of over-treatment, such mistakes lead to poor cost–effectiveness, however, under-treatment has serious ethical ramifications such that withholding treatment from those that need it is inequitable. Thus, failure to treat those that need it is a serious shortcoming of the modeling approach and can only be rectified by additional ‘ground-truthing’ studies to point out the real-world responsibilities to those that deal only with the theoretical. Additionally, ‘ground-truthing’ will become ever more important as future criteria to satisfy elimination will be more vigorous than that taken for initial treatment targeting [42].

Once an area is selected for deworming, usually a decision taken by the Ministry of Health with outside support, a chain of strategic communications and essential dialogue between the Ministry of Education takes place to put into practice the treatment action plan [14]. This is often conducted over an extended period of preparations and negotiations (typically 3–4 months or longer) allowing sufficient time for bespoke workshops for teacher training, provision of drugs and associated materials to conduct the deworming exercise as safely and as professionally as possible. Over and above, supervision of the whole process for reporting is also needed. Before deworming, formal sensitization of the parents and guardians of the children at the school-site is essential, as if not done correctly, it leads to lack of compliance, and even rejection of treatment, which can be disastrous for the control campaign [49,50]. Forward timetabling and meticulous planning is therefore very important remembering to be culturally sensitive in avoiding unnecessary problems, for example, administration of treatments during Ramadan when fasting practices should be respected [14].

Deworming at the school site

In terms of drug delivery, large-scale administration of PZQ at the school sites is perhaps at the lowest level in geographical stratification and key resources are highlighted at school site (Table 3). It is of course possible to go lower into surrounding villages, and hamlets thereof, but this would be attempted during community-directed treatment initiatives likely using community drug distributors, who may or may not also be local school teachers [14]. An important determinant of the success of deworming at the school-site is naturally the level of school-enrolled versus nonenrolled children from the surrounding area. Ambiguities between these two concepts can further percolate confusion over which denominator is to be used in the calculation of local treatment coverage. For example, treatment coverage at the school site is not the same as treatment coverage of children in the nearby vicinity. If nonenrollment levels are high then reaching the WHA54.19 will be difficult without recourse to community-directed treatment for many children will simply miss out on treatment if entirely school based. It is possible of course to adapt each local treatment strategy balancing either school- and community-based methods into the local area but on-the-ground this is labor intensive and requires accurate household census information. In fishing communities, for example, such census data are difficult to keep up-to-date when people and families are migrating and also in a population where illiteracy is widespread [51].

Another ambiguity in treatment coverage is also assessing treatment coverage through time. At the onset of the SCI was an assertion that children in high endemic areas would be provided with up to three or more annual treatments during their schooling in an effort to diminish morbidity [29]. In Uganda like elsewhere in SSA, school treatment registers are typically started afresh each year, so it is not always possible to capture this information, and as sorting through paper copy lists of names is intensely laborious and error-prone, it can be very difficult to assemble this information of treatments given through time retrospectively. Thus, there is a pressing need to capture these data electronically but unfortunately, there is no field-ready appropriate technology. To some extent an insight into this aspect was provided by the analyses of SCI longitudinal cohort data, however, with an annual drop out typically around 25%, the proportion of children who received three or more treatments quickly erodes [30]. This is widely acknowledged as one of the problems of UPE in SSA, as the majority of children do not complete 7 years of consecutive schooling and also because the formal registration of children at each school can be hampered by illicit practices, for example, where fictitious records are kept such as pupil ghosting to increase UPE budgets allocated to each school [49].

Formalization of recording treatment at the school site, although error-prone, is important for other reasons. Not only does it create a paper chain record for inspection of administered treatments but also acts as a recording mechanism for noncompliance, pharmacovigilance and adverse events [14]. In recent years, this has been given much more importance as capturing the reasons why treatment is rejected when offered freely is very important in the long-term perspective. To reassure the surrounding community, direct-evidence is needed during informed local community-feedback. Once it has been explained and correctly understood that there are side-effects after treatment, owing to intensity of schistosome infections and not due to use of drugs of poor quality, compliance with treatment is usually then raised. By contrast, when these points are not well-explained, it is unsurprising that future demands for treatment quickly drops. At the school site, management of mild side-effects is straight-forward, especially if children have been given food at the time of treatment which mitigates abdominal pain [14]. Later treatment discomfort can be mitigated by simple analgesics, for example, paracetamol, such that symptoms usually resolve 3–4 h after treatment. Where schistosomiasis is particularly rife, there are occasions when children need to be referred to a local health centre for a more detailed assessment. These reactions typically result from an underlying anaphylactic hypersensitivity to worm antigens as released from disturbed and dying worms brought about by PZQ treatment. While the latter can be acutely discomforting, this is most apparent during the first administration of treatment with later administrations in following years being much better tolerated.

On-site tools for treatment

Assuming that there has been satisfactory communication and training, the tools of control used at each school site are relatively simple and robust, see Figure 4. The height pole or treatment stick, is perhaps the most important as PZQ is administered in 40 mg/kg bodyweight [14]. It is of course possible to dose at 60 mg/kg but this would lead to a height pole of differing divisions. Similarly, the dosing by height induces a level of imprecision so in reality the dose is around 40 ± 10 mg/kg. A recent revision to the height pole to extend it downwards from 94 to 60 cm has been proposed, as was a simultaneous upward revision of the 94 cm threshold to 99 cm threshold for single tablet administration that could lead to significant drug savings, but awaits formal endorsement from WHO [52,53].

At each school, a critical component is on-site access to or provision of potable water. Collecting this information during prior mapping surveys is also important but often neglected in that mapping initiatives are often overly focused on gathering parasitological information alone. Yet a broader platform for essential data capture is desirable to ensure future programmatic success. Lack of water on-site is important for two reasons [14]; first drugs should be taken as safely as possible without risk of water-borne infection; second, there should be sufficient water provided to each child to allow swallowing of medications as comfortably as possible. The 600 mg oblong PZQ tablet is towards the largest range of size that can be safely tolerated in the small mouths of children. PZQ is an unusual bitter tasting medication and it is not uncommon for children to reject this medication owing to its non-palatability, especially for tablets without coatings (see below). Typically, PZQ is administered alongside other deworming drugs, such as albendazole or mebendazole which are smaller single tablets, and are often chewable and have an orange flavored formulation [14].

As children report for deworming, class-by-class, registration and recording of treatments administered is usually undertaken by hand. While it is better to register formally all children within the school before deworming and then use this information for a later roll call for issuing treatment, this is often not the case. For example, registration documents are completed as children step forward for treatment without a roll call and then the head count of those treated versus numbers registered in school (typically the annual enrollment) is used as the denominator [14]. Even this simple reporting exercise is not trivial in the context of the time and effort teachers have to set aside to undertake these extra duties. Summary tally sheets within the register are then completed that are reported back, along with any unused drug returned, to the respective implementation agency. Data are thus collected, collated and passed upwardly through the reporting chain for review of programmatic performance. With the advent of mobile phones with digital photographic capture and global positioning system technology, it would be desirable to speed-up collection and collation processes. While such technology is on the developmental horizon, it is likely that several years will pass before units are used routinely in large-scale drug administration settings with future safeguards against being supplanted by other technological upgrades. For the foreseeable future it is likely that achievement PC programmes will continue to report, and their performance be judged upon, a simple total number of children treated. This is a simple fixed yardstick and more favorable perhaps to use of percentage statistics that may alter widely according to which denominators are used, albeit measuring geographical, demographic and (or) temporal coverage.

Monitoring & evaluation with implementation science

One of the unique features of the SCI programme, unlike prior treatment initiatives (and some subsequently), was that a substantial budget was set aside to develop and apply conventional and experimental tools in a new portfolio of monitoring and evaluation [54–56]. A fundamental problem was, however, the need to record and demonstrate changes in morbidity (over and above the dynamics of egg excretion) during the duration of the 5-year project [56,57]. Morbidity research in schistosomiasis has a long history and continues to be perplexing, for at the individual level, reasons why some children progress onto disease rapidly while others do not, is presently not known [57]. Inferring causality for this is complex owing to a multicausal nature of the disease itself, a potpourri of adult worm burden and accumulating numbers of trapped eggs, genetic and phenotypic diversity of the worms themselves alongside host-specific genetic and immunological factors, which is all set within a context of other local diseases, nutritional states and likely maternal effects starting in utero upon the child. Severe morbidity with schistosomiasis is obvious, visually cases of hepatosplenomegaly with ascites are topotypical but its temporal developmental is not [58]. Moreover, it should be noted that morbidity may reverse in a longer time period than that available for programmatic study hence assessing which markers were best to investigate was challenging in the context of the project and available assays in a ready-to-go scenario [56]. Subtle morbidity is difficult to capture but recently fitness tests have attempted to do so with some statistical success [59].

For urogential schistosomiasis the problem is relatively minor as direct measures of morbidity are much more apparent, for example, macro- or micro-levels of hematuria, which in turn reflect the perforation of the bladder wall resultant from the passage of eggs into the lumen. Nonetheless, other aspects of disease recording which require use of advanced imagery, that is, ultrasound, which was often unable to be implemented on the a larger scale, so proxy markers of ultrasound were explored such as levels of excreted urine-albumin or ratios of urine-albumin versus urine-creatine [60,61]. Similarly, the concept of sentinel schools was used where longitudinal child cohorts were followed and became a fundamental tenet within SCI’s monitoring and evaluation programme [56]. While informative in its own right, the shortcoming of this approach included the failure to capture any changes in development of genital schistosomiasis [62–64], either in boys or girls, and address more formally any interplay with other parasitic diseases, for example, malaria, a known shortcoming of vertical disease-specific programmes [55]. As only PZQ and albendazole/mebendazole were being offered, ethically it was judged inappropriate to investigate other diseases without provision of treatment, which would be formally out-of-tune with practices typical of PC. Collection of this cohort data did however, attempt to highlight the importance of soil-transmitted helminthiasis (even though the occurrence of Strongyloides was overlooked due to limitations of fecal sampling methods) [7].

By contrast, the dynamics of morbidity attributable to intestinal schistosomiasis are much more cryptic. Nonetheless, novel attempts were made to record and investigate the occurrence of hepatoplsenomegaly, abdominal distension and liver fibrosis [58]. The latter was detected using portable ultrasonography and in so doing it became clear that in several SCI supported countries the morbidity ascribed to intestinal schistosomiasis developed earlier than previously assumed [13,65]. It was then thought that morbidity was most likely to manifest in early adulthood, however, severe cases of intestinal schistosomiasis could be found in school-aged childhood. These observations were seminal as they pointed toward infection taking place much earlier in life and led to several targeted surveys that began to appreciate the significance of infection in infancy and the need for treatment in pre-school children, as mentioned above [65].

EU-CONTRAST & SCORE

Alongside control operations, international funds were made available for applied research. While there have been several EU-funded projects previously, the most significant in terms of schistosomiasis was EU-CONTRAST (a multi-disciplinary alliance for schistosomiasis control and transmission surveillance), a 4-year project starting in 2006 that brought together 14 research institutes from North–South partnerships. Extensive fieldwork was undertaken, often alongside control teams, and was based in Senegal, Niger, Cameroon, Zambia, Uganda, Tanzania and Kenya. EU-CONTRAST was judged to be very successful with new insights provided into genetic diversity of schistosomes (inclusive of the detection of novel hybrid worms that have a zoonotic cycle) [66,67], innovative mapping and ‘ground-truthing’ studies of disease distributions [68,69], assessment of the performance of PZQ in coinfection settings (i.e., children with both intestinal and urogenital schistosomiasis) [70,71], socio-economic assessments of treatment compliance and participatory hygiene and sanitation transformation method [72] as well as the development of novel DNA assays to detect schistosomes in the aquatic snail stage (essential for transmission detection), with potential in human diagnostics [73].

A later large-scale 5-year research study was initiated in 2008 with a slightly different research agenda, entitled Schistosomiasis Consortium for Operational Research and Evaluation (SCORE), was established from canvassing the schistosomiasis research community [74]. SCORE projects included both field and laboratory-based efforts framed with a concept of ‘gaining and sustaining control’ where different treatment regimes with PZQ were investigated and how these might best synergize with alternatives for example, health education [75]. A flagship project is an ambitious attempt to eliminate urogenital schistosomiasis from Zanzibar where PZQ treatment of school-children is intensified and used alongside molluscicides with the hope of eliminating morbidity and local transmission [76–78]. Nested within these projects are those to evaluate present rapid diagnostic tests, namely the circulating cathodic antigen urine dipstick, which is the only commercially available test for intestinal schistosomiasis, as well as, developing new test formats with other circulating antigens [75]. New diagnostics are essential when considering that present parasitological methods are insensitive and are not always able to judge effectively the performance of PZQ in terms of adult worm death, rather in terms of cessation of egg excretion (Figure 1). Informative reviews by King et al. also pointed to the need for further optimization of repeated PZQ treatments within highly endemic communities which may yield US$153 (S. mansoni) to 211 (S. haematobum) per additional lifetime quality adjusted life year [18,79]. Translating the findings of these schemes into large-scale programmes, of course, enforces a further need for an increase in global stocks of PZQ.

Performance of PZQ

PZQ, [2-(cyclohexylcarbonyl)-1,2,3,5,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-one] is a racemate of dextro and laevo-isomers and was originally marketed as Droncit^®, as cestocide. After its activity against schistosomes was later realized, it was remarketed as Biltricide^® and subsequently eclipsed in importance all other schistosomicidal drugs [16]. In its original drug licensing schedule, oral dosing is at either 40 or 60 mg/kg bodyweight for adults and children (the latter of 4 years of age and older) and is given as a 600-mg oblong tablet, or in divisions thereof in half- or quarter-tablet units subject to tablet scoring [80,81]. Clinical efficacy (i.e., parasitological cure) was to be judged 21–24 days after treatment and calculated upon the cessation of excretion of schistosome eggs, as detected in either stool or urine [16]. Following from off-patent production of the drug by generic manufacturers, the price of each 600 mg tablet fell by over 90% to be less than US$0.10, making treatment en masse an affordable option [29]. Until recently procurement of PZQ was factored into USAID and DfID budgets and then become somewhat supplanted by the London Declaration on Neglected Tropical Diseases when PZQ was pledged to be donated gratis. For example, Merck-KGaA has now committed to supply 250 million tablets each year to the Merck Praziquantel Donation Program. It is presently unclear how commercial generic producers will respond to this mixed market of donation and retail and how aid budgets will be realigned from procurement of PZQ to supporting direct costs of its distribution within PC [15].

Limitations of PZQ

There are several shortcomings of PZQ, which make it a nonideal medication [82]. Foremost the drug is active against adult worms alone and not juvenile stages exhibiting a biphasic mode of action [83]. Being a racemate of dextro and laevo-isomers has disadvantages, for example, it is commonly held that only the laevo-isomer is active against schistosomes while the inactive dextro-isomer confers the unpleasant, bitter taste [83]. The killing mechanism of the drug is not completely known, but thought to interfere with voltage-gated Ca²⁺ ion channels, damaging the adult worm tegument which then interacts with immune-dependant attack to the damaged worm surface [16]. From an operational perspective, traditional tablets are rather cumbersome and can be difficult to swallow, which can lead to rejection or incomplete dosing in noncompliant children. It should also be noted that absorption of drug is enhanced with intake of fatty and (or) carbohydrate foods. Similarly, transitory side-effects after treatment, for example, emesis, are known which can discourage others from the treatment, hence efforts to raise acceptance and reassurance of recipients with appropriate health education is important to ensure there is no future erosion of compliance with large-scale administration [15]. This is a non-trivial manner as there are several instances when rural communities have come to reject the health interventions even if well-meaning and carefully planned.

Judging the efficacy of PZQ treatment can therefore be confounded by a variety of factors, that is, from malabsorption to counterfeit drugs [80]. Low cure rates and observed treatment failures can be explained in part by the presence of immature worms, which then later mature to egg-patent fecundity during the intervening period between treatment and parasitological follow-up. Similarly, in those unable to mount an immunological response that fails to synergize with the effect of treatment will manifest itself in poor cure even though the drug-specific part was satisfactory, for example, this might explain poor drug performance in very young children [13,84]. It is also known that poor cure rates are reported in communities with a heavy intensity of infections [85], thus even if the drug is killing the vast majority of worms, there may still be residual worms that survive initial treatment [15]. Also different isolates of schistosomes have variable levels of tolerance to PZQ [86], likely due to extensive genetic variation within and between worms [66,67]. Hence, regular assessment of the performance of PZQ is recommended by WHO with new standard operating procedures that have been designed as a first-line guard to detect worrisome performance [15]. Throughout the 2010–2012 period there were several workshops, as coordinated by WHO-Geneva, that solicited expert opinions from those involved in worm control, inclusive of representatives from the veterinary sector (where anthelmintic resistance to nematodes is well-known) [55], to develop pragmatic in-field guidelines for programme managers. Novel treatment regimes using double PZQ treatment separated by 2-weeks to improve cure [71,87] were discussed, as was recourse to slightly higher dosing at 60 mg/kg, although recent findings from Cochrane Reviews appear to be equivocal in terms of increased performance [85]. While these research findings are important, it should not be forgotten that large-scale interventions have different programmatic bottlenecks. For example, if 60 mg/kg dosing were to be implemented then the existing 40 mg/kg height pole would be inappropriate and could be confusing to those on the ground [13]. At a wider level, this increase in dosing would inflate present PZQ needs by 150%, which would further strain the global supply chain, and even more by doubling it if two separated PZQ dosing were also envisaged [51].

A systematic review of PZQ performance

To set perhaps a formal yardstick for subsequent review in 2020 perhaps, a more formal assessment of the performance of PZQ was conducted by a computer-aided systematic search of literature of studies on antihelminthic therapies based on single standard dose praziquantel (40 mg/kg) against human schistosomiasis (with no date or language restrictions). Literature databases searched included PubMed (MEDLINE), ISI Web of Science, EMBASE and the Cochrane, up to December 2012. The following search terms were used to identify and initially select the most relevant literature: ‘schistosomiasis + praziquantel + cure rate*’ (167 hits), ‘schistosomiasis + praziquantel + efficacy’ (259 new hits), ‘Schistosoma + praziquantel + treatment’ (1831 hits) and ‘Schistosoma + praziquantel + cure rate’ (78 hits). A customized form was used to record the name of the authors, title, the year of publication, the location of the trial, the parasite species, the human population number, the age range, the study design the outcomes (cure rate and egg reduction rate), the intensity of infection (geometric or arithmetic), the study design, and dosage. Both S. mansoni and S. haematobium were included in this systematic review. The participants included schoolchildren and preschool children surveyed during targeted or community surveys. The main outcome measure was cure rate (the proportion of individuals negative for eggs in their urine/stool at follow-up). The secondary parameter was egg reduction rate and was analyzed using weighted mean difference with standard error.

The numbers of papers initially selected and then included in the formal analysis is shown in Figure 5. Statistical analysis was conducted on PZQ (40 mg/kg) administered as monotherapy (single round). Sub-group analyses were conducted according to parasite species and age-group (preschool children only vs school-based survey). All statistical analysis was performed using R-statistical package. Work conducted over the past few decades on PZQ has unveiled how complex it is to identify the actual efficacy of PZQ, as the observed efficacy of PZQ is dependent on many factors such as, parasite species [88], genotype [89] and developmental stage [90], drug quality [91] host-dependent factors [84,92], transmission seasonality [93,94] and infection intensity [95,96]. Using a systematic review approach, we have identified 52 trials from 38 publications involving single dose (40 mg/kg) of PZQ as chemotherapy for urogenital or intestinal schistosomiasis in African children (see Figure 1 for selection process and Table 4 for details). Cure rates achieved by these trials varied widely from 29.5% in Senegal [97] to 100% in Sudan [98], Zimbabwe [99] and Uganda [100], with an overall average cure rate of 71.3% (number treated: 13,932; 95% CI: 70.5–72.0%) (Figure 6).

Explanatory factors in treatment performance

When looking at the two species separately, of the trials selected 32 trials studied drug performance against urogenital schistosomiasis and 20 against intestinal schistosomiasis. Overall, drug performance against S. haematobium was 69.6% (number. treated 5048; 95% CI: 68.7–70.5%), significantly lower (p < 0.0001) than the average achieved against S. mansoni was 77.5% (number treated: 8884; 95% CI: 75.9–79.0%). For those papers eligible for inclusion, there appeared to be a negligible effect with child age, nine trials included preschool-aged children (≤6 years of age) and 43 trials included children from any age (0–23 years of age); average drug performances achieved among preschool-aged children was 73.6% (number treated: 1026; 95% CI: 70.8–76.3%) and among school-aged children was 71.1% (number treated: 12,906; 95% CI: 70.3–71.9%).

Furthermore, we have found that cure rates achieved by praziquantel are incredibly sensitive to the baseline prevalence of infection, in that the higher the prevalence the lower the cure rate Figure 7. This was true according to species and age class (Figure 7). Interestingly, cure rates among preschool-aged children were far more affected by baseline prevalence than among school-aged children, although perhaps this was influenced by the number of trials available with prevalence data described (six trials that included preschoolers only and 40 trials that included children of any age), it has been previously noted that several factors influence cure in younger children [65].

Expert commentary & five-year view

For control of schistosomiasis, it is unequivocal that performance towards reaching the target of regular single standard dose PZQ treatment to at least 75% of school-aged children, as endorsed by WHA54.19, fell well short of the 2010 mark. Should this be considered a dismal failure? We think not, for can a simple treatment coverage statistic such as this encapsulate the health benefits to those children that had access to treatment against those that had not? Can such a single target ever be relevant to capture the build-up, philanthropic support and general goodwill resultant from the international advocacy that grew from its adoption? Clearly not, as a target it acted foremost as magnet to draw in multisectoral support from those who without it would not have chosen to act. Thus fostering and nurturing this international treatment landscape has been an impressive achievement and a lasting legacy, which is set to endure, perhaps, longer than the life span of PZQ itself. If WHO predictions in reduction of schistosomiasis are to be realized, careful international harmonization and tailoring of national resources are required and maintaining an effective drug distribution system with regular drug efficacy checks is paramount. If the 2010 target is reached by 2020 then it can be safely assumed that the lives of hundreds of million children will have been improved; a laudable target we should all strive for.

Table 1. WHO-recommended treatment strategy for schistosomiasis.

Category	Baseline prevalence among school-aged children	Action to be taken^†
High-risk community	50% by parasitological methods^‡ (intestinal and urogenital schistosomiasis) or 30% by questionnaire for history of hematuria	Treat all school-aged children (enrolled and not enrolled) once a year	Also treat adults considered to be at risk (from special groups^§ to entire communities living in endemic areas)
Moderate-risk community	10% but <50% by parasitological methods (intestinal and urogenital schistosomiasis) or <30% by questionnaire for history of hematuria	Treat all school-aged children (enrolled and not enrolled) once every 2 years	Also treat adults considered to be at risk (special groups^§ only)
Low-risk community	<10% by parasitological methods (intestinal and urogenital schistosomiasis)	Treat all school-aged children (enrolled and not enrolled) twice during their primary schooling age (e.g., once on entry and once on exit)	Praziquantel should be available in dispensaries and clinics for treatment of suspected cases

^†Equivalent to: high-risk community – all school-aged children and adults require preventive chemotherapy annually; moderate-risk community – 50% of school-aged children and 20% of adults require preventive chemotherapy annually; low-risk community – 33% of school-aged children require preventive chemotherapy annually.

^‡For urogenital schistosomiasis, detection of hematuria by chemical reagent strips gives results equivalent to those determined by urine filtration.

^§Special groups: pregnant and lactating women; groups with occupations involving contact with infested water such as fishermen, farmers, irrigation workers or women in their domestic tasks, to entire communities living in endemic areas.

Table 2. WHO vision, goals and objective for control of schistosomiasis.

Vision	A world free from schistosomiasis
Goals	To control morbidity due to schistosomiasis by 2020To eliminate schistosomiasis as a public health problem by 2025To interrupt transmission of schistosomiasis in the region of the Americas, the eastern Mediterranean region, the European region, the south-east Asia region, and the western Pacific region, and in selected countries of the African region by 2025
Objectives	To scale up control and elimination activities in all endemic countriesTo ensure an adequate supply of praziquantel and resources to meet the demand

Data taken from [4].

Table 3. List of key needs and resources for deworming at the school site.

Needs	Formal acceptance of treatment compliance by headteacherPrior community sensitization with appropriate parental dialogueTrained teachers able to administer medicines safelyFormal recording of medications received, rejections and side-effectsA designated timetable for coordination of local resourcesFeedback to communities after treatment with future sensitization
Resources	Culturally appropriate health education materialsTreatment register booklets and PZQ dosing polesAdequate drug stocks, with small surplus for any contingenciesSufficient amounts of potable water, drinking cups and on-site foodProvision of a safe and orderly treatment station, with sick-bay if neededStand-by activation of local health centre(s) for referrals

Table 4. Summary of characteristics of trials selected after systematic review evaluating single dose praziquantel (40 mg/kg) treating urogenital and intestinal schistosomiasis in children.

Study (year, country)	Trial number	Parasite species	Age range	Prevalence (%)	Treated (n)	Formulation	Cure rates (%)	ERR (%)	Follow-up (in days)	Ref.
Adoubryn et al. (2012, Côte d’Ivoire)	1	S.m.	4–15	35.5	137	Tablet	80.9	Not reported	90	[101]
Augusto et al. (2009, Mozambique)	2	S.h.	8–16	54.2	287	Tablet	69.7	33.1	61	[93]
Augusto et al. (2009, Mozambique)	3	S.h.	8–16	51.7	269	Tablet	98.2	68.9	61	[93]
Borrmann et al. (2001, Gabon)	4	S.h.	5–13	42.8	89	Tablet	73.0	Not reported	56	[103]
Coulibaly et al. (2012, Côte d’Ivoire)	5	S.h.	0–6	11.2	18	Tablet	88.9	98.0	21	[104]
Coulibaly et al. (2012, Côte d’Ivoire)	6	S.m.	0–6	21.9	35	Tablet	88.6	96.7	21	[104]
De Clercq et al. (2002, Senegal)	7	S.h.	7–14	90.0	88	Tablet	30.0	80.0	35	[97]
Degu et al. (2002, Ethiopia)	8	S.m.	10–14	50.8	154	Tablet	94.0	97.0	42	[105]
Erko et al. (2012, Ethiopia)	9	S.m.	6–22	74.9	224	Tablet	73.6	68.2	28	[102]
Garba et al. (2012, Niger)	10	S.h.	0–6	Not reported	165	Syrup	85.7	69.4	21	[107]
Garba et al. (2012, Niger)	11	S.m.	0–6	Not reported	96	Syrup	75.0	66.7	21	[106]
Garba et al. (2001, Niger)	12	S.h.	6–16	98.0	311	Tablet	68.0	Not reported	42	[106]
Guyatt et al. (2001, Tanzania)	13	S.h.	8–14	59.0	275	Tablet	94.0	99.0	42	[108]
Inyang-Etoh et al. (2009, Nigeria)	14	S.h.	4–16	38.5	44	Tablet	72.7	79.3	56	[109]
Kahama et al. (1999, Kenya)	15	S.h.	6–17	83.0	147	Tablet	61.5	Not reported	56	[110]
Kahama et al. (1999, Kenya)	16	S.h.	6–17	76.0	149	Tablet	62.1	Not reported	56	[110]
Kahama et al. (1999, Kenya)	17	S.h.	6–15	97.0	117	Tablet	64.9	96.9	61	[111]
Kardaman et al. (1985, Sudan)	18	S.h.	7–11	Not reported	158	Tablet	66.3	Not reported	30	[112]
Kardaman et al. (1985, Sudan)	19	S.h.	7–11	Not reported	158	Tablet	73.2	Not reported	90	[112]
Keiser et al. (2010, Côte d’Ivoire)	20	S.h.	8–16	59.5	26	Tablet	83.0	97	26	[113]
Kihara et al. (2009, Kenya)	21	S.h.	4–18	92.8	158	Tablet	89.9	Not reported	33	[114]
Kihara et al. (2010, Kenya)	22	S.m.	4–18	14.9	79	Tablet	92.6	Not reported	56	[115]
Kihara et al. (2010, Kenya)	23	S.m.	4–18	69.6	361	Tablet	75.8	Not reported	56	[115]
Kihara et al. (2010, Kenya)	24	S.m.	4–18	22.0	85	Tablet	83.8	Not reported	56	[115]
Kihara et al. (2010, Kenya)	25	S.m.	1–18	71.1	342	Tablet	74.7	Not reported	56	[115]
Kihara et al. (2010, Kenya)	26	S.m.	4–18	58.2	223	Tablet	88.1	Not reported	56	[115]
King et al. (2002, Kenya)	27	S.h.	4–23	70.0	125	Tablet	70.0	98.0	42	[117]
Lwambo et al. (1997, Pemba Island)	28	S.h.	5–19	59.9	5616	Tablet	68.0	Not reported	70	[117]
McMahon & Kolstrup (1979, Tanzania)	29	S.h.	7–15	Not reported	33	Tablet	76.0	99.6	84	[118]
Midzi et al. (2008, Zimbabwe)	30	S.h.	2–19	40.4	107	Tablet	90.9	Not reported	42	[119]
Midzi et al. (2008, Zimbabwe)	31	S.h.	5–17	60.0	675	Tablet	88.5	98.2	42	[119]
Mohamed et al. (2009, Sudan)	32	S.m.	8–17	15.9	46	Tablet	100.0	100.0	21	[5]
Mohammed et al., (2006, Sudan)	33	S.h.	7–13	28.0	50	Tablet	58.0	98.0	42	[120]
Mutapi et al. (1998, Zimbabwe)	34	S.h.	6–15	64.9	37	Tablet	100.0	Not reported	42	[99]
Mutapi et al. (2011, Zimbabwe)	35	S.h.	1–5	18.0	18	Tablet	92.0	99.0	42	[121]
Mutapi et al. (2011, Zimbabwe)	36	S.h.	6–10	38.0	135	Tablet	67.0	96.0	42	[121]
Navaratnam et al. (2012, Uganda)	37	S.m.	1–5	27.0	148	Syrup	80.9	86.1	28	[122]
Navaratnam et al. (2012, Uganda)	38	S.m.	1–5	25.9	149	Tablet	81.7	89.0	28	[122]
Obonyo et al. (2010, Kenya)	39	S.m.	6–15	86.0	106	Tablet	65.0	84.1	28	[123]
Olds et al. (1999, Kenya)	40	S.h.	4–18	89.7	98	Tablet	61.5	Not reported	45	[124]
Olds et al. (1999, Kenya)	41	S.m.	6–19	83.7	98	Tablet	56.4	Not reported	45	[124]
Olliaro et al. (2011, Mauritania)	42	S.m.	10–19	18.7	93	Tablet	91.4	89.2	21	[85]
Olliaro et al. (2011, Tanzania)	43	S.m.	10–19	93.0	135	Tablet	86.6	91.9	21	[85]
Pugh & Teesdale (1983, Malawi)	44	S.h.	5–18	23.8	97	Tablet	63.4	99.3	30	[183]
Saathoff et al. (2004, South Africa)	45	S.h.	8–12	68.3	757	Tablet	57.9	95.3	21	[126]
Sacko et al. (2009, Mali)	46	S.h.	7–14	96.0	150	Tablet	37.3	Not reported	84	[127]
Sacko et al. (2009, Mali)	47	S.h.	7–14	89.0	139	Tablet	56.8	Not reported	84	[127]
Scherrer et al. (2009, Côte d’Ivoire)	48	S.m.	4–13	29.0	49	Tablet	97.6	97.7	20	[128]
Sissoko et al. (2009, Mali)	49	S.h.	6–15	26.4	389	Tablet	53.0	95.6	29	[129]
Sousa-Figueiredo et al. (2012, Uganda)	50	S.m.	1–7	37.7	369	Tablet	56.4	96.2	28	[100]
Sousa-Figueiredo et al. (2010, Uganda)	51	S.m.	0–6	16.0	28	Tablet	100.0	100.0	21	[130]
Stete et al. (2012, Côte d’Ivoire)	52	S.h.	7–15	79.0	90	Tablet	95.0	98.5	62	[131]

ERR: Egg reduction rate; S.h.: Schistosoma haematobium; S.m.: Schistosoma mansoni.

Key issues

• • To secure sufficient donor funds to finance the costs of distribution of praziquantel (PZQ).

• • To develop contingency planning to reduce bottlenecks in global PZQ supply.

• • Reaching and sustaining treatment coverage of at least 75% in school-aged children.

• • To develop the wide-scale use of mobile phone technologies for coordinating and reporting drug delivery.

• • To service the treatment needs of preschool-aged children with an appropriate PZQ formulation.

• • To encourage the field-use of direct morbidity markers for both forms of schistosomiasis.

• • To foster application of better diagnostics for disease mapping and elimination.

• • To safe-guard large-scale PZQ performance with regular drug efficacy checks.

• • To advance drug discovery and treatment developments to provide future alternatives to PZQ.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.