Optimal Prevalence Threshold For Guiding The Implementation Of Preventive Chemotherapy In Countries Endemic For Schistosomiasis: Synthesis Of Evidence From Mass Drug Administration Programmes For Developing This Tool
Authors: Danso-Appiah Anthony , Eusebi Paolo , Lo Nathan C. , Orso Massimiliano , Akuffo Kwadwo Owusu , Fleming Fiona M. , Jiangang Guo , Mwinzi Pauline , Colley Daniel G. , Hagan Paul , Murad M. Hassan , Garba Amadou Djirmay 
Published: May 2021

ABSTRACTBackgroundThe WHO-recommended prevalence thresholds for deciding schistosomiasis mass drug administration (MDA) are based on anecdotal evidence and may mislead. This study systematically synthesized evidence to generate a single optimal ‘global’ prevalence threshold that should guide schistosomiasis MDA programmes worldwide.MethodsWe searched several databases from 1978 to 31st October 2021 without language restriction. Two reviewers selected studies, extracted data, and assessed risk of bias using relevant risk of bias tools, and resolved disagreements through discussion. The review followed best practices protocols and guidelines. Data were analysed and presented as prevalence reduction (PR) and relative risk (RR) for dichotomous outcomes or mean difference for continuous outcomes, each presented with their 95% confidence intervals (CI). Meta-regression of observations on prevalence rates and intensity of infection were performed to assess the effect of repeat MDA over time. Sensitivity analysis was performed to test the robustness of the results to the risk of bias components. The overall level of evidence was graded using GRADE.FindingsOf the 1,232 studies retrieved, 38 met our inclusion criteria and 34 were included in the meta-analysis. No direct relation was observed between prevalence and intensity of infection. Praziquantel reduced prevalence of S. mansoni in school age children (SAC) at 12 months (RR 0.56, 95% CI 0.46 to 0.69; 14 studies, n=86,073); 24 months (RR 0.46; 95% CI 0.32 to 0.66; 14 studies; n=83,721); 36 months (RR 0.44, 95% CI 0.33 to 0.58; 7 studies, n=70,933) and 48 months (RR 0.25, 95% CI 0.11 to 0.59; 5 studies; n=27,483). Similarly for S. haematobium, there were reductions in prevalence in school age children (SAC) at 12 months (RR 0.38, 95% CI 0.28 to 0.52; 8 studies, n=37,868); at 24 months (RR 0.30; 95% CI 0.30─0.52; 7 studies; n=37,107); and 36 months (RR 0.39, 95% CI 0.21 to 0.71; 5 studies, n=28,146). There was no significant reduction in prevalence at 48 months (2 studies, n=10,954). Further analyses were performed from a series of prevalence thresholds created from the data at 5%, 10%, 15%, 20%, 30% and ≥40% and the results showed differences in the effect of MDA when each threshold was applied in the regression model. For annual MDA involving SAC, school-based treatment (SBT) appeared to perform better than community-wide treatment (CWT) in terms of prevalence reduction; but this could be subject to the frequency of treatment and retreatment applied in SAC compared to CWT. Using the optimal prevalence threshold of 10%, the model suggested it will take over 10 years to bring the prevalence of schistosomiasis to 1% for S. haematobium and up to 15 years for S. mansoni with repeated annual MDA.InterpretationThis systematic review and meta-analysis provides evidence that 10% prevalence is the optimum that should be used as the ‘standard global threshold’ for implementing MDA in endemic countries.FundingThis work was commissioned and supported by the World Health Organization, Geneva, Switzerland as part of evidence-based schistosomiasis guideline development.Research in contextEvidence before this studyCurrently, the prevalence thresholds used in implementing mass drug administration within the preventive chemotherapy strategy for schistosomiasis control are based on anecdotal evidence and unreliable. We identified relevant studies regardless of language or publication status (published, unpublished, in press, and ongoing). We searched PubMed, CINAHL and LILACS from 1978 to 31st October 2021 without language restriction. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2021), mRCT, Hinari, the WHO Library Database, Africa Journals Online and Google Scholar. Experts in the field of schistosomiasis were contacted, preprint repositories were searched and the reference lists of articles were reviewed for additional or unpublished data. This study was commissioned by the WHO to provide systematically synthesized evidence to inform on a single global prevalence threshold that should be applied by endemic countries when deciding MDA campaigns for the prevention and control of schistosomiasis.Added value of this studyThis is the first systematic review and meta-analysis commissioned by the WHO to determine a single prevalence threshold that should be employed by endemic countries for the implementation of global schistosomiasis mass drug administration. This study pooled data involving thousands of participants across thousands of villages from all endemic settings, making it unique in terms of statistical power and generalizability of the main findings and conclusions. The study used PICOS (P-population, I-intervention, C-comparator, O-outcomes and S-study) to formulate an appropriate review question, clear objectives, stringent inclusion and exclusion criteria as well as rigorous quality assessment and data synthesis, following strictly best practices for preparing and reporting systematic reviews. The search has been very comprehensive including all relevant electronic databases and non-electronic sources, done in close collaboration with experienced information specialist. The review process ensured meticulous attention to details, making the necessary effort to minimize bias, carrying out aspects of the review independently by the reviewers and addressing disagreements through discussions between the reviewers. Given the geographical variations, and differences in the levels of baseline endemicities, diagnostic criteria, age groups treated and follow-up times across studies, this necessitated robust sub-group analyses to detect any sub-group effects. We ran meta-regression analyses to identify any potentially useful trends, and tested the robustness of effect estimates from sensitivity analyses. We have assembled world-class experts from diverse backgrounds and geographical locations, including epidemiologists, evidence synthesis specialists, economists, allied health professionals, statisticians, biomedical scientists, clinicians and non-medical experts to produce this innovative, demand-driven, policy- and context-relevant systematic review and meta-analysis that will help guide policy and practice in the global control of schistosomiasis.Implications of all the available evidenceOur review provides evidence that 10% baseline prevalence is the minimum optimal threshold that should be used to decide the implementation of MDA programmes in schistosomiasis endemic countries. Praziquantel is effective in reducing the prevalence of schistosomiasis at 12 months, but incremental benefit of repeated annual treatment appears to be minimal after 12 months. Effectiveness depends on several factors, which are difficult to disentangle, however, the rate at which prevalence decreases does not appear to be influenced by baseline intensity of infection and treatment approach (whether whole community or school-based). From exploratory analysis, intensity of infection appears to be more stable than prevalence for assessing outcome of MDA. Therefore, further research is needed to determine an optimal intensity threshold and compare it with prevalence threshold. In terms of policy, the difficulty in achieving elimination with mass drug administration alone means that integration of non-pharmacological interventions such access to clean water, improved sanitation, hygiene education (WASH) and snail control to complement MDA if elimination is to be achieved.This systematic review was registered in PROSPERO ̶ CRD422020221548.