Search strategy

A search strategy was developed for economic evaluations of schistosomiasis interventions. Four databases were searched: MEDLINE, EMBASE, Web of Science (WoS) and EconLit between 1998 and July 2020 (S6–S9 Tables). The year 1998 was chosen as a starting year, to reflect the development of the WHO-CHOICE project [6]. WHO-CHOICE has created recommendations for CEAs to help strengthen the standardisation of studies and establish minimally acceptable quality specifications [6]. A scoping search did not reveal any highly cited schistosomiasis full economic evaluations before this date. After selecting the final articles, a hand search of their reference lists was conducted to identify any additional eligible studies.

Literature screening criteria

The PICO acronym (population, interventions, comparators, outcomes) was used to inform the search strategy and inclusion criteria. Studies that contained any intervention related to the prevention, treatment, control, elimination, interruption of disease transmission for schistosomiasis or a combination of any of the above were included. There were no restrictions for comparators in this review. The outcomes included were any that were health related. The study type was defined as a full economic evaluation (S1 Glossary).

The search and initial screening of articles was undertaken by SU. Search results from all databases were exported to an EndNote X9 folder, and the duplicates were removed. The remaining studies were categorised by SU independently and then checked by LJ independently by adapting an established three-stage system [14]. When additional advice was required, SB provided input.

Two stages were used in sorting. In Stage I, the studies were categorised into five groups A-E (Table 1). Group D and E studies were discarded. For Stage II, the studies in groups A, B and C were read in full and further classified into sub-groups (Table 1). The studies grouped as A(1,2) and B(1,2) were included in the quality assessment and narrative synthesis. All papers classified under sub-group 6 were discarded. The remaining studies [A(3–5) and B(3–5), all of category C] were used for additional background information.

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Table 1. Categorisation of Studies.

https://doi.org/10.1371/journal.pntd.0010822.t001

Data extraction and synthesis

Data extraction took place using predefined data extraction tables [13]. Data relating to study characteristics, methodology, results, conclusions, and key assumptions were extracted. The data were tabulated and synthesised narratively. This is an appropriate method of synthesis for studies with methodological heterogeneity [12].

Assessment of methodological quality

The methodological quality was assessed using the Consensus on Health Economic Criteria (CHEC) list for trial-based economic evaluations and the Philips checklist for modelling studies [15,16] as recommended by the Cochrane Handbook for Systematic Reviews [17]. All studies were further assessed with the international decision support initiative (iDSI) reference case (RC) for economic evaluations to ensure that the LMIC context was considered. The iDSI RC was initiated by the BMGF and is also known as the Gates reference case. The transition from the Gates RC to iDSI RC intended to create political neutrality and distance the RC from any private organisations [18]. The use of the iDSI reference case promotes standardisation to increase the transferability of economic evaluations in LMICs. Transferability greatly maximises the value and justifies the costs invested in the economic assessments conducted [18]. The results of the quality assessments were used to inform the analysis rather than to exclude studies.

Study characteristics

Overall, 18 papers were identified which were concerned with the economic evaluation of interventions to prevent, control or eliminate schistosomiasis (Table 2). There were 11 studies which focussed on preventative chemotherapy (PC) as an intervention [19–29], six on integrated interventions involving a combination of chemotherapy [26,30–35], molluscicide and health education, and one hypothetical vaccination model. Praziquantel was the chemotherapy drug used in all the papers analysed. Four species of schistosoma were considered in the studies: S. japonicum, S. haematobium, S. mansoni and S. mekongi. Study settings were in 10 countries from Africa and Asia, with the highest number of studies concerned with China [29,30,34,35].

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Table 2. Summarised Study Characteristics.

https://doi.org/10.1371/journal.pntd.0010822.t002

Methodological considerations

Study perspective.

The perspective of the studies was mainly quasi-governmental and governmental organisational viewpoints, which were often not fully described (Table 3). Approximately 30% of papers did not clearly state their study perspective [20,24,25,30,34,35]. A societal perspective was not widely used, with only two papers adopting this approach [22, 31]. Kirigia [31] employed a societal perspective and Croce et al. [22] took productivity gains into consideration by adopting both a governmental and a societal perspective.

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Table 3. Methodology.

https://doi.org/10.1371/journal.pntd.0010822.t003

Only three studies justified their chosen perspective [19,28,33]. Brooker et al. [19] explained that they had adopted a government perspective as their school-based MDA programme would only involve minimal costs to society. Ndeffo-Mbah et al. [28,33] cited health-payers (defined as national governments and donors), as the chosen perspective due to them being the primary providers of medical care related to human immunodeficiency virus (HIV) and schistosomiasis in sub-Saharan Africa (SSA).

Outcome measures

A range of outcome measures were used in the studies. Five studies utilised DALYs [23,26–28,32], and only one study utilised quality-adjusted life years (QALYs) [31]. The five studies utilising DALYs used published data from other papers, that were based on the 2010 Global Burden of Disease schistosomiasis DALY weightings. The other studies utilised a range of effectiveness measures, and five opted for the use of more than one effectiveness measure [20,22,29,34,35]. None of the trial-based economic evaluations used DALYs or QALYs as outcomes. Four papers utilising DALYs highlighted the shortcomings of the disability weights used in schistosomiasis as a limitation to their economic evaluation [23,26,27,32].

Model type

For the nine model-based studies, dynamic models were the main type of model used (Table 3). De Neve et al. [23] and Kirigia [31] utilised static models, with only De Neve et al. acknowledging the limitations of their model type for schistosomiasis economic evaluations [23].

All the model-based papers discussed their assumptions (S1 Table), though some papers were more explicit and exhaustive than others when listing these. Four of the papers developed their mathematical transmission model de novo for the study [23, 28, 31, 33], with three providing information on the methodology used in the creation of their dynamic models. The other studies adapted pre-existing models from one or more published studies.

Sensitivity analysis

The majority of papers specified the type of sensitivity analysis employed, which was largely univariate (Table 3). Sensitivity analysis was not discussed in four papers [24,30,34,35]. Only four studies utilised probabilistic sensitivity analysis (PSA) methods [23,26,28,33]. The most common input parameter analysed was the cost related to the interventions.

Most papers included univariate analysis of medication or vaccination costs alone, as part of their sensitivity analysis. This is important to note as certain countries are entitled to receive free chemotherapy [2], which can significantly alter the cost-effectiveness of their schistosomiasis prevention and treatment programmes.

Cost-effectiveness findings

The studies found that schistosomiasis interventions were always cost-effective compared to a “do-nothing” approach (Table 4). The studies found that a range of interventions are likely to be cost-effective for preventing, controlling, and treating schistosomiasis, compared to a comparator. For example, Yu et al [29] stated that mass chemotherapy was more cost-effective than selectively only treating confirmed positive cases (screen chemotherapy). Community based, school-based and school-aged mass drug administration (MDA) were all cost-effective dependant on the setting and local prevalence of schistosomiasis [20,23,26,28,33]. Guyatt et al. [24] and Brooker et al. [19] found that school-based MDA was cost-effective in averting childhood anaemia, which can have long-lasting effects on childhood development and learning abilities. The use of snail control was also explored by Lo et al. [32] and was found to be highly cost-effective when combined with MDA.

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Table 4. Results and Conclusions.

https://doi.org/10.1371/journal.pntd.0010822.t004

There existed some conflicting results. Yu et al. [29] found that MDA was more cost-effective than selective chemotherapy, whereas Guo et al. [30] and Kirigia [31] reported the converse. Lo et al. [26] further identified community-wide PC treatment (CWT) of schistosomiasis and soil-transmitted helminths (STH) was highly cost-effective, whilst Lo et al. [27] found only SAC selective chemotherapy to be robust through sensitivity analysis. Lo et al. [27] additionally stated that the cost-effectiveness of interventions was dependent on the prevalence of the condition (Table 4).

Only six studies reported their incremental cost-effectiveness ratios (ICERs) [22,23,26,27,31,32] (Table 4). Three of these studies reported ICERs that were inclusive of cost-effectiveness measures for other NTDs [23,26,27]. With different effectiveness measures being used, the ICER ranged from US$ 7.02 per person treated in a Cambodian national MDA programme against S. mekongi to as high as US$ 1,531 per DALY averted through an integrated snail-and-chemotherapy intervention against S. haematobium in low-burden areas in Kenya [22,32]. One study considered a schistosomiasis vaccination which had a hypothetical basis, therefore, no concrete decision was able to be made about its cost-effectiveness [36]. Ndeffo-Mbah et al. [33] found that having a schistosomiasis PC programme with the addition of water, sanitation and hygiene (WASH) interventions or snail control (mollusciciding) was potentially cost-effective in HIV prevention, with additional public health benefits (Table 4).

Only two papers touched on the affordability of the interventions [22,23]. Both studies concluded that although their findings showed that MDA was cost-effective in their respective settings, the programmes were still unaffordable for the context.

Most of the analysed papers did not state that any cost-effectiveness threshold (CET) was used to present their findings. Amongst the seven papers that applied a threshold, different thresholds were utilised. Yu et al. [29] used a weighting system to rank the outcomes in ascending order of importance. Collyer et al. [36] used a benchmarking technique to calculate a critical vaccination cost. They deemed the cost-effective threshold as being a vaccination cost that was equal to or less than that of MDA. Lo et al. [26,27,32] and Ndeffo-Mbah et al. [33] used their respective countries’ and region’s GDP per-capita amounts, as their cost-effective thresholds.

Three papers conducted a CBA alongside a CEA [22,23,35] and estimated a range of benefit cost ratios (BCRs). De Neve et al. [23] explored a CBA in addition to their CEA and converted the benefits of NTD control (such as DALYs and educational gains) into monetary units and divided this value by the total cost of the NTD control programme investment. The BCR of the entire control programme was estimated to be 13 (5–31), with an alternative scenario yielding a BCR of 7 (1–19) (Table 4). Zhou et al. [35] also conducted a CBA and the net BCR of their national schistosomiasis control programme was 6.20 (Table 4). The authors noted that limited literature on CBA of schistosomiasis control programmes existed at the time of their economic evaluation [35]. Croce et al. [22] explored both a societal and Ministry of Health (MoH) perspective. From a societal productivity perspective, the programme was noted to be economically beneficial, yielding US$ 3.84 per US$ 1 spent (Table 4), whereas the narrower MoH perspective yielded a cost-benefit value (CBV) of 0.24 [22].

Principal findings

Very few studies were identified which considered the costs and outcomes for interventions to prevent, control and eliminate schistosomiasis. The evidence, which does exist, suggests that a range of interventions are likely to be cost-effective compared to a ‘do nothing’ approach. However, the review identified some methodological limitations in the existing literature and highlighted a need for greater standardisation of economic evaluations in this area.

A societal perspective was not widely adopted, which may lead to the benefits of the interventions being underestimated. NTDs often have a significant effect on the long-term productivity of the affected individuals, by causing chronic disease that impairs not only an individual’s ability to work physically but also their mental wellbeing [2]. This decreased productivity can translate to a loss of income which would affect the worker and their families. For NTDs, where possible, it is important to adopt a societal perspective in an economic evaluation to ensure that the impacts on employment and families are factored into decision making. Furthermore, the effects on productivity may be pivotal in decision-making processes, such as whether to fund a school-based versus a community-based control programme.

The variation in the time-horizon used in the studies was vast, hampering comparison of studies. There was no lifetime-horizon employed, which would be of value in a disease of possible lifetime duration. The reasons behind the time-horizons adopted were not fully explained in many studies.

Policy makers and programme funders need to scrutinise the epidemiology and prevalence rates used in economic evaluations and assess if they align with their region-specific prevalence rates, as this will affect the extent of the EEs generalisability. De Neve et al. [23] and Brooker at al. [19] highlighted that regional variation existed in their respective countries within a single schistosomiasis intervention programme. The targeting of predominately SAC children for MDA is appropriate, as children are known to be at an increased risk of infection due to underdeveloped immunity, and tend to harbour heavy infection [2,26,28] and the disease can produce long term adverse effect on development in childhood [2]. Furthermore, the prevalence of schistomiasis in SAC in a region determines how frequent MDA will be administered in the respective region [2].

The disability weights allocated to DALYs in schistosomiasis have been heavily criticised for underestimating the effect of the disease [38–40]. Whilst significant improvement has been made in the weighting of schistosomiasis DALYS since the 1990 Global Burden of Disease report, many authors still believe that currently DALYs do not fully capture the effects of schistosomiasis [38–40].

The reasons for this have been attributed to exclusion of serious disease complications and inadequate incorporation of new disease-related information into weightings, and limited understanding of the disease complexity [11,38–40]. Schistosomiasis is a complex disease, and the effect on morbidity of infection diagnosis in childhood and adulthood in endemic areas differs. There are certain complications that when diagnosed later in adulthood cannot be rectified by treating the disease and are independent of the levels of intensity of disease at the time of diagnosis [40]. There is evidence to suggest that reducing the intensity of infection can create a reduction in schistosomiasis related morbidity [41]. Heavy and light infection with schistosomiasis have been assigned different disability weightings; however King et al. [42] argues that factors such as inflammation mediated by the immune system in schistosomiasis is found to not be attributable to intensity of infection. This creates uncertainty around weightings given to light infections, as their effects on morbidity have been found to be underestimated. Diagnosis of this may be missed leading to underestimation of their impact [40].

Turner et al [40] recommend that urgent attention should be given to improve the estimates of DALYs. They propose that a framework is needed that takes into consideration: differentiation of the reversible and non-reversible complications of disease and which can distinguish between levels of infection in different age groups and Schistosoma species [11]. It is therefore important that future economic evaluations are transparent about how DALYs have been calculated and highlight associated limitations. Funders and health policy makers need to be aware of these issues, and their effects on future DALY calculations, and transmission models for schistosomiasis.

Four studies [26–28,32] found their interventions to be cost-effective when utilising the WHO GDP based CETs (Table 3). The WHO has in recent years encouraged LMICs to adopt local CETs, that can take their available financial resources into consideration [43,44]. Bertram et al. [43] acknowledged that whilst the WHO GDP based CET may be helpful in guiding assessments, they are not to be used in isolation by policy makers for deciding on health intervention funding. Kazibwe et al. [45] conducted a review of CEAs using a cost-per-DALY metric in LMICs between 2015–2020 and found that over 80% of papers reviewed used WHO GDP values as a CET, with some studies forfeiting local thresholds to use a GDP based CET. The WHO has acknowledged that the GDP based thresholds neglect the affordability and practicality of implementation of CETs. The use of generic CETs may lead to funders and health decision makers funding programmes that are unsustainable in their context, leading to inefficient allocation of resources [43]. This highlights the importance of including criteria to assess affordability within economic evaluation checklists, to ensure optimal allocation of healthcare resources.

The iDSI reference case highlighted important considerations for economic evaluations in this context: affordability and equity. Unfortunately, the affordability of the intervention for the context-specific health budget was only mentioned in two papers [22, 27] and only three studies considered equity issues [21,23,25]. The importance of highlighting affordability and equity considerations in NTDs cannot be overemphasised. NTDs tend to affect the most vulnerable populations globally, and without considering equity and affordability, studies are unlikely to address key concerns for decision makers.

Comparison to the existing literature

Very few systematic reviews relating to economic evaluations of interventions for schistosomiasis or NTDs more generally have been undertaken. Turner et al. [11] conducted a systematic review of the economic evidence relating to human schistosomiasis and identified a higher number of studies than the current review, as they included studies that were not formal economic evaluations [11]. The authors highlighted issues relating to the types of models and outcome measures used. The study focussed more on the results of the included studies than on the methods used and did not employ a quality assessment tool.

Garcia et al. [10] conducted a systematic review of peer-reviewed papers on economic evaluations of interventions against STH and schistosomiasis between 1990 and 2012 and used the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist to appraise quality. They found that the papers performed well and would be beneficial in policymaking. The differences in the results between this current review and those of Garcia et al. [10] may be attributable to the different quality appraisal methods used with the CHEERS checklist more focussed on reporting rather than methodological quality.

Strengths and weaknesses of the study

The strengths of the review included that a broad and comprehensive search was conducted using general and inclusive terms, and that a systematic categorisation strategy was employed. This review analysed the methodological quality of economic evaluations using the CHEC-list, the Philips checklist and the iDSI checklist. The use of the iDSI checklist is novel in this context and allows consideration of factors particularly crucial in an LMIC context.

The studies were limited to papers published in the English language—which means there exists the risk of accidental exclusion of valuable untranslated papers. There was considerable variation in the methods and outcome measures used in the papers which made comparison of studies difficult.

The starting year for inclusion of papers was 1998 based on the WHO-CHOICE initiation. In reality, however, studies (particularly trial-based) would have taken some time to adapt to the new recommendations. The iDSI (previously known as the Gates reference case) was only established in the year 2014 [46], however even the more recent studies did not fully adhere to all criteria.

Meaning of study: Possible implications and mechanisms for policymakers

Schistosomiasis interventions were collectively found to be cost-effective, but the quantity and quality of studies was generally limited, with a need for greater standardisation. Economic evidence is particularly important for NTDs, which by definition have tended to be neglected in resource allocation decision-making. The identified studies used a range of outcome measures, which hinders the comparison of cost-effectiveness. Furthermore, the outcomes considered are generally not broad enough to cover all the effects of schistosomiasis interventions, with many focussing on clinical outcomes alone. Based on the chronicity and long-standing effects of untreated or missed disease, a lifetime-horizon is likely to be appropriate for interventions in this area. However, if this is not possible, consensus regarding the time-horizons appropriate for different types of intervention is needed. Consideration of equity and affordability is likely to be needed for decision-making in this context.

The use of CBA has some strengths as the use of monetary benefits allows comparison across a range of different sectors and disease areas. However, some limitations of this approach in relation to NTDs have been highlighted. Zhou et al. [35] noted that the use of CBA creates the complicated situation of putting a monetary value on the welfare and wellbeing of people in certain regions. Furthermore, schistosomiasis and other NTDs mostly affect communities who are already unfairly disadvantaged, and hence there is a risk that focusing on monetary benefits will contribute to the continued neglect of control programmes, and perpetuate health inequities. Hence, caution and further research is needed.

Only two economic evaluations included WASH interventions [28,34]. Access to water and sanitation is considered a human right, and is enshrined in the sixth SDG [4,47]. The availability of WASH in communities has been proven to improve child and maternal health, as well as reduce and control infectious diseases including diarrhoeal diseases and NTDs. Diarrhoeal diseases are a significant source of mortality in children under five, particularly in LMICs [47]. WASH is known to be a critical component of schistosomiasis control and helps provide a more sustainable effect on reduction of schistosomiasis transmission [48]. The cost and increased amount of commitment potentially required for implementing WASH interventions may have created a barrier to WASH inclusion [49]. The cost-effectiveness of WASH interventions thus requires further investigation and analysis.

The combination of schistosomiasis and STH programmes has been shown to be cost-effective in the studies looking at combined programmes. The common co-existence of STH in endemic schistosomiasis areas and the regular combination of STH and schistosomiasis statistics [2,50] makes this a feasible option that needs more exploration in future economic evaluations. Policy makers will however have to reassess the cost-effectiveness of these thresholds within their respective local context, and health resource availability. Future EEs should move away from reliance on WHO GDP-based CETs.

The effects of migration, improvement in WASH, and climate change will all contribute to the changing epidemiology of schistosomiasis in the regions [51]. This will mean that policy makers and programme funders will need to ensure that up to date region specific prevalence estimates are incorporated into calculations. Surveillance systems need to be strengthened and maintained in endemic areas. With WHO advocating for disease control and an eventual break in transmission and then elimination, there needs to be a shift from analysing the cost-effectiveness of schistosomiasis control interventions to a future focus on the cost-effectiveness of interventions to eliminate schistosomiasis.