Hepatitis E virus (HEV) is a small RNA virus with a significant impact on global health, responsible for approximately 20 million infections annually, with 3.3 million symptomatic cases and around 44,000 deaths.
The virus is primarily transmitted via the fecal-oral route, with eight known genotypes, among which HEV1, HEV2, HEV3, and HEV4 are most common in humans. HEV infections can manifest in a variety of clinical forms, ranging from acute, self-limiting hepatitis to severe, chronic liver disease, particularly in immunocompromised individuals such as organ transplant recipients or those undergoing chemotherapy.
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Given the diverse clinical presentations and the public health burden, guidelines for the diagnosis and treatment of HEV have been developed over the past decade. This essay systematically evaluates these guidelines, focusing on their quality, primary recommendations, and the reasons behind any differences.
Evaluation methods
The study conducted a comprehensive search for guidelines on the diagnosis and treatment of HEV infection published between 2013 and 2022. The databases searched included PubMed, Web of Science, Ovid, ScienceDirect, Embase, and several Chinese databases like China Knowledge and Wanfang.
Additionally, the International Platform for Practice Guidelines Registry was consulted. The search terms included “hepatitis E,” “viral hepatitis,” “diagnosis,” “therapy,” “guideline,” “statement,” “recommendations,” and “consensus.” Seven guidelines met the inclusion criteria, which required that the guidelines be focused on HEV diagnosis and treatment, available in full text, and published in English or Chinese. Exclusion criteria included outdated guidelines, narrative overviews, and translations.
The quality of the included guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool, which evaluates guidelines across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Four reviewers, trained in the AGREE II methodology, independently scored each guideline, and discrepancies were resolved through discussion. The study also examined the primary recommendations of each guideline, regrading the supporting evidence using the Oxford Centre for Evidence-Based Medicine (OCEBM) grading system.
Seven guidelines
The seven guidelines varied widely in quality, with overall AGREE II scores ranging from 50.68% to 62.29%. The guidelines scored highly in the domains of scope, purpose, and clarity of presentation, with median scores of 95.8% and 95.8%, respectively.
However, the domains of stakeholder involvement, rigor of development, applicability, and editorial independence revealed significant weaknesses. For instance, the rigor of development, which assesses the process of evidence gathering and the methods used to formulate recommendations, had a median score of 46.4%. Similarly, stakeholder involvement, which evaluates the inclusion of patient perspectives and the public in guideline development, had a median score of only 34.7%.
Two guidelines, those developed by the Chinese Society of Hepatology and the British Transplantation Society, were recommended based on their overall quality, with scores exceeding 60%. The other five guidelines were recommended with modifications, indicating the need for improvements in areas such as external expert involvement, the consideration of patient and public perspectives, and a clearer delineation of the evidence supporting the recommendations.
Key issues
The evaluation highlighted several key issues affecting the quality and consistency of the HEV guidelines. One major concern was the variability in the primary recommendations, particularly regarding the management of chronic HEV infection and the use of ribavirin (RBV).
The study found significant differences in the recommended dosage of RBV and the duration of treatment, reflecting the lack of high-quality evidence to support these recommendations. The heterogeneity in the guidelines may be attributed to several factors, including differences in the target populations, the geographical focus of the guidelines, and the methodological approaches used in guideline development.
In terms of diagnostic recommendations, the guidelines universally endorsed the use of a combination of serology and RNA testing to diagnose HEV infection. However, there was a notable lack of consensus on the specific assays to be used and the appropriate diagnostic approach for different HEV genotypes. For instance, while HEV RNA testing is recommended for immunosuppressed patients, the study found that antibody testing is often unreliable in this population, underscoring the need for more robust diagnostic criteria.
The study also revealed that the guidelines scored poorly in the domain of applicability, with a median score of 27.1%. This low score indicates that many guidelines failed to provide sufficient guidance on the practical application of recommendations, including the consideration of resource constraints and the needs of healthcare providers in different settings. Additionally, the editorial independence of the guidelines was questioned, with concerns about potential conflicts of interest and the influence of external sponsors on the recommendations.
Significant variability
The systematic evaluation of HEV infection guidelines revealed significant variability in their quality and recommendations. While some guidelines demonstrated strengths in scope, purpose, and clarity of presentation, others were found lacking in stakeholder involvement, rigor of development, and applicability.
The discrepancies in primary recommendations, particularly regarding the management of chronic HEV infection and the use of ribavirin, highlight the need for more consistent and high-quality evidence to support clinical decision-making.
To enhance the utility and reliability of HEV guidelines, developers must address these deficiencies by incorporating external expert reviews, considering patient and public perspectives, and providing clearer guidance on the application of recommendations. Additionally, future research should focus on generating higher-quality evidence to support the diagnosis and treatment of HEV infection, ultimately improving patient outcomes and public health efforts.
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