Introduction The carcinogenic liver fluke Opisthorchis viverrini is a major public health problem in the Mekong basin region. The liver flukes can induce cholangiocarcinoma, a bile duct cancer that causes a significant burden of mortality and economic loss. Various public health interventions have been conducted to reduce opisthorchiasis but the prevalence of O. viverrini remains high in endemic regions. The aim is to quantify the effectiveness of public health interventions in reducing the prevalence of O. viverrini infection.
Methods and analysis Seven databases (including PubMed, SCOPUS, Web of Science, EMBASE, ScienceDirect, Thai thesis database and TCI (Thai journals online)) will be searched from initiation through to 2022 to identify studies of interventions to reduce the prevalence of O. viverrini infection. The prevalence, incidence or number of O. viverrini-infected people will be used as the source of O. viverrini prevalence data. A conventional meta-analysis and a Bayesian network meta-analysis will be conducted to undertake direct and indirect comparisons of different interventions. Meta-regression will be used to determine the effect of each intervention. The risk of bias will be assessed using the Cochrane Collaboration’s risk of bias tool. Heterogeneity between studies will be determined by forest plots and I2 and publication bias investigated with funnel plots and the Egger’s test.
Ethics and dissemination Ethical approval will not be required because this study will only use published data. The final report of this review will be disseminated through publication in a peer-reviewed scientific journal and will also be presented at relevant conferences.
PROSPERO registration number CRD42022323066.
- Protocols & guidelines
- STATISTICS & RESEARCH METHODS
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Strengths and limitations of this study
We will conduct the first systematic review and network meta-analysis to investigate the effectiveness of public health interventions in reducing the prevalence of Opisthorchis viverrini.
The systematic review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
The study screening, data extraction and assessment of the risk of bias will be performed independently by two authors and disagreements will be resolved by a third author.
The quality of the studies included in the systematic review will be evaluated and the quality of the evidence will be assessed using the Cochrane risk of bias tool.
The liver fluke Opisthorchis viverrini is a foodborne trematode that can cause cholangiocarcinoma (CCA). The parasite is distributed throughout the Mekong basin in Southeast Asia, where more than 10 million people are infected.1 The life cycle of O. viverrini is complex, involving aquatic snails of the genus Bithynia spp as a first intermediate host and cyprinid fish as a second intermediate host. Humans are the definitive host of the parasite and become infected after eating undercooked fish products.2
The prevalence of O. viverrini throughout the Mekong basin regions has not been established via national surveys except in Thailand, and in schoolchildren in Laos and Cambodia.1 The prevalence in Laos ranged from 17% to 88.7%,3–5 whereas in Vietnam, the prevalence ranged from 15.2% to 36.9%.1 In Cambodia, data have been collected in a few provinces with prevalence ranging from 0% to 47.5%.6 In Myanmar, data have been reported from a small area in which overall prevalence was found to be 9.3%.7 Only Thailand has implemented an intensive national liver fluke control campaign, which has been driven by the Thai Ministry of Public Health for decades. The nationwide prevalence of liver fluke infection decreased from over 15% in 1996 to 2.2% in 2019.8 The national programme aimed to eliminate liver fluke infection in Thailand by 2025.1
Interventions for O. viverrini infection are multifaceted, being targeted at different stages of the parasite life cycle. Anthelmintic drugs are used to control infection by killing adult worms in the human host and animal reservoirs. However, the reinfection rate of O. viverrini had been high, and efforts have been made to design new, sustainable interventions.9 10 Sustainable control involves multiple options such as health education, improved sanitation and ultrasound screening, in addition to mass drug administration. However, the most effective intervention or combination of interventions remains unknown.
This systematic review will systematically search the literature for evidence regarding the effectiveness of O. viverrini interventions and seek to measure the effectiveness of interventions in reducing infections in humans using network meta-analysis methods. The outcomes of this study will be important for policymakers to design sustainable prevention and control programmes for O. viverrini in endemic countries such as Thailand, Laos, Cambodia and central and southern Vietnam.
We have developed this systematic review and network meta-analysis protocol according to the Preferred Reporting Items for Systematic Reviews and Network Meta-Analyses Protocols 2015 guidelines (see online supplemental table S1)11 (figure 1) . The study will commence in August 2022 and we plan to end it in November. This information is now provided.
Seven medical databases, including PubMed, SCOPUS, Web of Science, EMBASE, ScienceDirect, Thai thesis database and TCI (Thai journals online), will be searched for studies focusing on interventions for O. viverrini. Electronic searches will be conducted from the inception of each database up to 13 August 2022. The searches will not be limited to any language, and in the case of languages other than English, native speakers will be consulted for full-text translations. The details of the search strategies for each database are provided in online supplemental table S2. Medical Subject Heading terms and keywords containing the name of the parasite (ie, O. viverrini, liver fluke), the names of the diseases caused by the parasite (eg, opisthorchiasis, CCA) and public health interventions (eg, health education, sanitation, food safety controls and mass drug administration) will be used for the search. The keywords will be combined during the search using appropriate Boolean operators. Reference lists of the included papers will be reviewed for additional studies. We will also run a backward and forward search of the included papers to check for additional studies. Corresponding authors will be contacted by email when additional information is required.
Articles that meet the population, intervention, comparison, outcome and study design criteria will be eligible for inclusion in this systematic review (table 1).
All articles identified in the databases will be imported to an EndNote library. After the removal of the duplicates, the articles will be exported to Rayyan for screening. The titles and abstracts of the studies will be screened independently by two investigators (MA and PS). The full-text articles will be then reviewed by the same two investigators using the predefined eligibility criteria. At this stage, the title and abstract will be reviewed, and a decision will be made as to whether an article should be included or excluded. The reasons for excluding studies include study design, publication type, outcome measure, or population that do not meet the study requirements, as well as no control or comparison group, and no usable data. Disagreement between the two reviewers will be resolved through discussion with a third reviewer (KAA).
Data will be extracted from eligible studies using piloted data extraction tools by the same two investigators (PS and MA) independently. The following data will be extracted: (1) first author; (2) country of the study; (3) year(s) when the study was conducted and data were collected; (4) study design; (5) population characteristics of the study (age, gender, inclusion/exclusion criteria of the participants); (6) intervention (type, duration, number of people receiving the intervention and number in the control group); and (7) number of cases, prevalence or incidence of O. viverrini at baseline and after implementation of the intervention. When multiple studies used data from the same database, the most updated and complete reports will be used to extract the data for our systematic review (online supplemental table S3).
The risk of bias will be assessed by two authors independently using the Cochrane Collaboration’s risk of bias tool.12 Risks will be categorised into domains and assessed as low, high or unclear risk for each domain (online supplemental table S4).
Random-effects models will be used for conventional pairwise meta-analysis. Direct comparisons of the interventions will be evaluated by pooled relative risks (RRs) with 95% CIs and p values will be calculated using the statistical software Stata (StataCorp, College Station, Texas). Forest plots will be used to visually evaluate heterogeneity between studies. Heterogeneity will be measured quantitatively using the heterogeneity squared (I2) index with 95% CI. The I2 value can be interpreted as evidence of substantial levels of heterogeneity when the value is greater than 75%. Egger’s regression test and funnel plot symmetry will be used to further assess the risk of publication bias.
The outcome measure will be the RR of O. viverrini infection in the intervention relative to the control groups with 95% CIs. The primary outcome will be a change in the incidence or prevalence of O. viverrini. A conventional meta-analysis will be first conducted for the studies to directly compare different interventions. Then, a Bayesian network meta-analysis will be conducted to undertake direct and indirect comparisons of different interventions.
Direct and indirect evidence will be summarised by a random-effects network meta-analysis model. Transitivity (ie, similarity in methodological characteristics across studies) will be explored using subgroup analyses. Consistency will be explored by examining whether indirect evidence (ie, those that are not directly compared within studies) is similar or different from direct evidence (ie, those that are directly compared within studies). We will run pairwise meta-analyses in R V.3.6.3 for direct comparisons of each outcome. The automated generalised pairwise modelling framework will be used to compare the effectiveness of different interventions (eg, education campaigns, sanitation, food safety controls and mass drug administration). Markov chain Monte Carlo methods, implemented with the WinBUGS software, will be used to calculate the pooled estimates. Further analyses will be conducted using STATA.
Meta-regression will be used to explore the source(s) of heterogeneity in intervention effects.
Patient and public involvement
This systematic review and network meta-analysis does not require patient or public involvement beyond their prior involvement in the published studies included in the review.
Various interventions have been implemented by governmental and non-governmental organisations to reduce the burden of O. viverrini infection in endemic countries. Integrated public health interventions have been applied in some settings to mitigate the economic burden and public health impacts of the diseases.13–16 To our knowledge, this will be the first systematic review and network meta-analysis study to synthesise evidence on the effectiveness of public health interventions in reducing the prevalence of O. viverrini infection. While public health interventions have paramount importance in reducing the burden of opisthorchiasis, their comparative effectiveness in terms of reducing the prevalence or incidence of infection is yet to be investigated. Our systematic review and network meta-analysis will help identify the most effective public health intervention or combination of interventions. These findings would be crucial for both policymakers and health professionals to select the most effective interventions and scale up to regional or national levels for maximum impact.
A protocol of this systematic review is comprehensive, prospectively submitted in PROSPERO and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.17 In using a network meta-analysis approach, the study will be able to compare the effectiveness of different interventions without the significant costs required for comparison of multiple interventions by prospective design. The systematic review and network meta-analysis will be limited by the number and quality of available studies on the topic and the range of interventions tested by published studies. However, we will evaluate and assess the quality of evidence by using the Cochrane risk of bias tool and include all eligible studies.
Ethics and dissemination
Since we will use published data, formal ethical approval is unnecessary. The results of this review will be submitted to a peer-reviewed journal. Amendments of the basic protocol will be documented in the comprehensive review.
Patient consent for publication
Contributors PS, KAA, BS and ACAC developed the initial conceptualisation of this study. PS designed the search strategy. PS, KAA, ACAC, BS, ST and MA contributed to the development of the selection criteria and designing the study. KAA and ACAC assisted in statistical analysis. PS, KAA and ACAC contributed to drafting the protocol. All authors approved the final work prior to submission.
Funding This research was supported by the Royal Golden Jubilee PhD Program (grant PHD/0004/2559 to PS), the Thailand Research Fund (TRF) and the Khon Kaen University Research Program (grant number: RP64018). KAA is funded by an Australian National Health and Medical Research Council Investigator Grant (APP1196549).
Disclaimer The funder had no role in the design and conduct of the study; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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