Current global estimates, risk factors, and knowledge gaps for Hepatitis E virus (HEV): A scoping review

Figures Abstract Hepatitis E virus (HEV) remains a leading cause of acute viral hepatitis globally, particularly in South Asia and Africa. However, epidemiological prioritization is hampered by fragmented data and discordant disease burden estimates. Following JBI and PRISMA-Sc guidelines, we conducted a scoping review of global HEV evidence. We used the PCC framework: (P) general and high-risk populations (pregnant women, immunocompromised, and displaced groups); (C) quantitative estimates of burden, risk factors, or virological gaps; and (C) global evidence across all WHO regions to include studies. We searched PubMed, Scopus, and Web of Science, supplemented by country-specific searches in Google Scholar and IHME. From 11,583 citations, 395 articles met the inclusion criteria. The temporal distribution shows a marked increase in research volume, with 65.3% of studies published after 2010; however, 54.9% relied on observational descriptive designs while experimental investigations remained infrequent (4.3%). We identified three estimates of the global burden of HEV: the IHME Global Burden of Disease (GBD) published in 2021 (19.4 million cases) and two widely cited systematic reviews published in 2012 (20.1 million infections) and 2020 (939 million infections). A significant virological “blind spot” was observed, as 47.8% of studies did not report genotype information, though Genotype 3 (21.8%) was the most frequently identified among specified reports. Key risk domains identified were environmental (sanitation/water contamination) and cultural/occupational practices. Pregnant women, immunocompromised patients, and patients with pre-existing liver conditions were high at-risk populations. Key knowledge gaps identified were limited confidence in burden of disease estimates: severe molecular blind spots and evidence deserts, limited public health resources for surveillance, diagnostics, and reporting of cases and deaths in highest risk settings; exclusion of outbreaks from estimates of the burden of disease and unreliable convenience sample derived estimates. Hepatitis E virus is often neglected by international communities, global actors and national governments. However, it is difficult for stakeholders to prioritize a pathogen with highly variable and unreliable global burden of disease estimates. Comprehensive country level data based on more access to routine testing could facilitate global initiatives to devise strategies for equitable vaccination and mitigate the morbidity and mortality associated with this vaccine-preventable disease. Author summary Hepatitis E is a major cause of acute hepatitis particularly in South Asia and Africa. Fatality rates are high for pregnant women and patients with pre-existing conditions. However, there is a lack of consensus about the global burden of HEV disease. Global and country-level estimates often vary dramatically. In this scoping review, we aim to summarize the latest evidence and estimates to understand the knowledge gaps related to hepatitis E global burden estimates and risk factors. From the available studies, we extracted genotype, anti-HEV seropositivity, reported outbreaks and the year of most recent outbreak reported in the country specific studies, and HEV incidence for each country. We also tried to identify and confirm specific missing data points for each country. Our scoping review found that there is a severe lack of data on HEV incidence and mortality for many countries across WHO regions. We found a wide range of variations of the global estimates across the countries and populations. Comprehensive country level data based on more access to routine testing could facilitate global initiatives to devise strategies for equitable vaccination and mitigate the morbidity and mortality associated with this vaccine-preventable disease. Citation: Ahmed MK, Maroofi H, Blunt M, Labrique A, Kirkwood C, Vannice K, et al. (2026) Current global estimates, risk factors, and knowledge gaps for Hepatitis E virus (HEV): A scoping review. PLoS Negl Trop Dis 20(3): e0013980. https://doi.org/10.1371/journal.pntd.0013980 Editor: David Safronetz, Public Health Agency of Canada, CANADA Received: September 24, 2025; Accepted: January 28, 2026; Published: March 11, 2026 Copyright: © 2026 Ahmed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. The minimal data set required to replicate all study findings—including the complete evidence synthesis extraction table and country-level burden data—is provided in S1–S3 Tables. Funding: MKA, HM, AL, KRT, JL, BLK were supported by the Gates Foundation (Investment ID INV 016643). KV, CK received a salary from the Gates Foundation. The funder commissioned the study but had no role study design, data collection and analysis, and decision to publish. Competing interests: The authors have declared that no competing interests exist. Introduction Hepatitis E virus (HEV), a member of Hepeviridae family [1], was first called enterically-transmitted non-A, non-B hepatitis. While not isolated until the 1980’s, it has been a recognized cause of large-scale outbreaks in Southeast Asia since the 1950s [2]. Since then, it has emerged as one of the most important causes of acute hepatitis in both developing and developed countries [3,4]. The HEV species that causes human disease has eight genotypes [5]. HEV genotypes 1 and 2, which are largely transmitted through contaminated water, are responsible for most human infections and are of concern for large-scale outbreaks. Genotypes 3 and 4 also cause infections in humans but are zoonotic and are found in several animal species, notably wild and domestic swine [6]. Genotypes 5 and 6 have been found only in wild boar and genotypes 7 and 8 in camels [7]. HEV genotype 1 and 2 are considered endemic in South Asia and Africa [8] while HEV genotype 3 and 4 are mainly observed in the United States, Europe, and East Asia [9]. Hepatitis E (HE) disease presents as acute, viral hepatitis, including jaundice, abdominal pain, fever, fatigue, and anorexia [10]. There is no specific treatment except for supportive care. In the general population, the disease is usually mild and self-limiting with only a 0.1%–4% case fatality rate [11] though chronic infections leading to cirrhosis have increasingly been recognized in immunocompromised individuals such as organ transplant recipients [9]. However, certain populations are prone to severe disease, most notably pregnant women. Pregnant women with HE are more likely to have fulminant hepatic failure and intrapartum hemorrhage, with case fatality rates ranging from 10% to 40% during pregnancy [12–15]. Children are often less likely to experience clinical symptoms of HE, although there have been outbreaks where children are a major impacted group [16]. In sharp contrast to Hepatitis A, children also generally have lower rates of seropositivity [17,18]. HEV causes large scale outbreaks but is also responsible for large proportions of acute viral hepatitis cases presenting to hospitals in endemic areas [19,20]. Most cases in endemic areas are adolescents and young adults. As of now, two vaccine candidates have undergone clinical trials [21,22]. Only one, Hecolin, completed clinical trials and is now licensed in China (since 2011) and Pakistan (since 2015) for use in healthy adults. This recombinant vaccine was found to be 93% effective for preventing clinical disease after four years of follow up [23,24] and 87.3% effective after 10-years of follow up [25]. However, the vaccine has not been submitted for pre-qualification by the WHO and is not widely used. Despite these clinical and preventative advancements, global public health prioritization of HEV is hindered by a critical lack of consensus on its true epidemiological scale. This is evidenced by the staggering discordance between major global burden estimates—ranging from approximately 20 million to nearly 1 billion infections [20,23,25]. Such fragmentation suggests that current literature presents a complex landscape of risk factors and prevalence data that have not been systematically synthesized to identify overarching global trends. Therefore, a scoping review is the most appropriate methodology for this problem; unlike a narrow systematic review, this approach allows for the comprehensive mapping of a heterogeneous evidence base to identify specific geographic “Evidence Deserts” and “Molecular Blind Spots” that currently obstruct evidence-based policy and equitable vaccine deployment. A scoping review is therefore necessary to systematically map this heterogeneous evidence base, clarify the limitations of current burden estimates, and identify the specific areas where data is missing. This mapping is a critical prerequisite for guiding future research priorities and informing global public health policy, particularly regarding vaccine deployment and intervention strategies in high-risk populations. Methods This scoping review followed the framework of Joanna Briggs Institute (JBI) [26] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) [27]. In accordance with JBI guidelines, which define the consultation phase (Step 6) as optional, this review focused on the systematic identification, selection, and synthesis of existing evidence (Steps 1–5) to map the global landscape of HEV epidemiology. The protocol was registered in the Open Science Framework (https://doi.org/10.17605/OSF.IO/A4CV7). A completed PRISMA-ScR checklist is provided in S1 Checklist to ensure reporting transparency. Step 1: Identify the research question The primary objective of this review was to map the global landscape of Hepatitis E Virus (HEV) epidemiology and identify critical gaps in the evidence base. We hypothesized that current burden estimates are characterized by significant geographical and methodological heterogeneity. The specific research questions were: - What are the current global and country-specific estimates of HEV disease burden (incidence and seroprevalence)? - What are the documented risk factors for HEV infection? - Which populations (e.g., pregnant women, immunocompromised, or displaced persons) are at the highest risk for severe clinical disease? - What are the primary knowledge gaps regarding genotype distribution and burden estimates? Step 2: Identify the relevant literature We employed a three-tiered search approach to ensure comprehensiveness across indexed and non-indexed literature: - 1. Systematic Search: We searched PubMed, Scopus, and Web of Science for studies published through December 30, 2023. The search strategy (Table 1) used keywords and MeSH terms organized into three concepts: HEV estimates, risk factors, and vulnerable populations. Full search syntaxes for all databases are available in S1 File. We conducted systematic search at two different times to make sure that the search syntax offers consistent and comprehensive results. We conducted the final systematic search during the week of Jan 5–9, 2024, and exported the bibliographic citations for screening, full text review and data extraction. - 2. Purposive Country-Specific Search: To mitigate indexing bias, we conducted searches in Google Scholar for each country (e.g., “Hepatitis E Bangladesh”) following the World Health Organization regions in Jan 2024. In order to ensure comprehensiveness and report on the most recent published studies, we also conducted final round of purposive country-specific search through Google Scholar in July 2024. These studies informed most recent country specific data for country-specific HEV genotype, anti-HEV seropositivity, reporting of recent outbreaks and year of most recent outbreaks. To ensure reproducibility, we screened the first 50 results for each query. To capture data heterogeneity, when multiple studies reported differing anti-HEV seroprevalence for the same country, we extracted both the highest and lowest reported estimates. - 3. Grey Literature & Global Databases: We searched authoritative sources, including WHO regional reports, strategy documents, guidelines and other grey literature which had relevant data points for our review questions. We searched for a country specific IHME incidence data of acute hepatitis E in December 2024 [28]. While the search was restricted to English-language publications due to resource constraints for high-quality translation, international surveillance reports were utilized to maximize global coverage. Step 3: Select the literature Citations were managed in Rayyan [29]. Following duplicate removal, a two-stage screening process (title/abstract followed by full-text) was conducted by three independent reviewers (MKA, HM, MB). Discrepancies were resolved through consensus or by the Principal Investigator (BLK). We applied the PCC (Population, Concept, and Context) framework to ensure a comprehensive mapping of the HEV research landscape: - Population (P): The review included studies focusing on the general population as well as specific high-risk subgroups, specifically: pregnant women, immunocompromised patients, occupational risk groups, and displaced or humanitarian populations. - Concept (C): The primary concept was the characterization of evidence on disease burden and global knowledge gaps. This was operationalized by evaluating three interrelated domains: - a. Epidemiological Burden: Global and country-specific estimates of incidence and seroprevalence. - b. Risk Determinants: Documented environmental, occupational, and population-specific factors (e.g., severe disease in pregnancy). - c. Virological Gaps: Completeness of genotype distribution reporting and its alignment with disease burden estimates. - Context (C): Global evidence across all six WHO regions. We included original research articles of all study designs, as well as peer-reviewed evidence syntheses (including systematic, meta-analytic, and comprehensive literature reviews) that provided regional or global HEV burden estimates. Modeling studies, such as those from the Institute for Health Metrics and Evaluation (IHME), were also included to provide a benchmark for clinical incidence and mortality data. Exclusion Criteria: We excluded brief editorials, commentaries, and non-systematic opinion pieces and non-authoritative grey literature (e.g., news blogs) that did not provide primary data or formal epidemiological estimates. We also excluded other scoping reviews to avoid duplicative reporting. Step 4: Chart the data The a priori structured matrix using Microsoft Excel spreadsheet was developed to extract data from the included studies. The review matrix inc