Open research questions in Hepatitis Viruses Studies and Epidemiology

What the literature leaves open

• While the extent and duration of protection conferred by anti- HEV IgG positivity against HEV infection remains unclear, it is noteworthy that all identified HEV in- fections occurred in patients who were previously negative for anti- HEV IgG.

  Acute HEV Infection Is a Relevant Cause of Decompensation and ACLF in Patients With Liver Cirrhosis · 2026 · DOI

• Consequently, anti-HEV potential such as seropositivity and clinical conditions immunodeficiency/immunosuppression or chronic liver disease could not be evaluated using inferential statistical methods.

  Investigation of Hepatitis E Virus Seroprevalence at Bursa Uludağ University Faculty of Medicine Hospital · 2026 · DOI

• The identity, abundance, and function of infiltrating immune cells in the necrotic foci were not explored in this study but may shed light on the mechanisms of OROV-induced tissue damage, clearance, and hepatic repair.

  Oropouche virus causes acute hepatitis in mice controlled by type I interferons · 2026 · DOI

• Based on the findings of this study, future research is recommended to integrate more comprehensive hepatitis B laboratory examination data into the system to improve the accuracy of early detection. In addition, the system should be further enhanced by developing more interactive, user-friendly, and comprehensive menus and features to improve its usability and user experience. Future studies are also encouraged to involve larger and more diverse populations to comprehensively evaluate the feasibility, effectiveness, and generalizability of the Hepatitis B Early Detection System (SIDIHEP-B). Furthermore, collaboration with healthcare providers and public health institutions is recommended to support the implementation and wider adoption of the system as a complementary tool for the early detection of hepatitis B among pregnant women. REFERENCES Aprianto, A. K., Permadi, I., & Wijayanto, B. (2023). Expert system for diagnosing cat diseases using forward chaining method on Telegram bot. Jurnal Teknik Informatika (JUTIF), 4(4), 857–866. https://doi.org/10.52436/1.jutif.2023.4.4.1207 Febriyanti, N. M. D., Sudana, A. A. K. O., & Piarsa, I. N. (2021). Implementasi black box testing pada sistem informasi manajemen dosen. JITTER: Jurnal Ilmiah Teknologi dan Komputer, 2(3), 535. https://doi.org/10.24843/JTRTI.2021.v02.i03.p12 Hasanah, F. N. (2020). Buku ajar https://doi.org/10.21070/2020/978-623-6833-89-6 rekayasa perangkat lunak. Umsida Press. Hendra, H., & Riti, Y. F. (2023). Perancangan dan implementasi website dengan konsep UI/UX untuk mengoptimalkan marketing perusahaan. Jurnal Informatika dan Teknik Elektro Terapan, 11(3s1). https://doi.org/10.23960/jitet.v11i3s1.3430 Herlambang, B. A., Prathama, A. G., & Waliyansyah, R. R. (2021). Aplikasi pendeteksi dini penyakit hepatitis menggunakan mesin inferensi forward chaining berbasis Android.

  The Use of Forward Chaining for Early Detection of Hepatitis B Risk Among Pregnant Women at Beber Community Health Center, Cirebon Regency · 2026 · DOI

• (2026): The Use of Forward Chaining for Early Detection of Hepatitis B Risk Among Pregnant Women at Beber Community Health Center, Cirebon Regency RECOMMENDATION Based on the findings of this study, future research is recommended to integrate more comprehensive hepatitis B laboratory examination data into the system to improve the accuracy of early detection.

  The Use of Forward Chaining for Early Detection of Hepatitis B Risk Among Pregnant Women at Beber Community Health Center, Cirebon Regency · 2026 · DOI

• [8] reported promising performance of a single ICT kit compared with a microparticle enzyme immunoassay; however, their evaluation was limited to a single rapid assay.

  Analytical performance evaluation of commercially available hepatitis A virus IgM immunoassays: ELISA, ICTs, and chemiluminescence immunoassay · 2026 · DOI

• analog (NA) therapies are being used as posttransplant prophylaxis to decrease the rate of transmission depending on the donor and recipient serological profile (Table 2). Currenltly tenofovir alafenamide, and tenofovir disoproxil entecavir are currently preferred over lamivudine due to their higher genetic barrier to resistance and to their superior antiviral potency [34]. [33]. Moreover, fumarate, Liver transplantation from HBV core antibody (antiHBc Ab) donor carries a high risk (on average around 50%) of transmitting hepatitis B to the recipient. A serological profile indicative of previous contact with HBV in the recipient. However, in HBsAg/HBsAb negative patients is possible, but prophylactic treatment and constant post-transplant monitoring is recommended. Similar short- and long-term graft and patient survival rates have been observed when compared with HBcAb negative grafts [5, 35]. transplantation is preferable liver Non hepatic transplantation of HBV core positive organs does not pose any additional risk to patients with a serological profile indicative of previous contact with HBV. Non liver transplantation from antiHBc Ab positive donors in HBsAg/HBsAb negative

  Donor-derived viral infections: the usual suspects and the new kids on the block · 2026 · DOI

• Viral hepatitis represents a heterogeneous disease spectrum caused by a diverse array of DNA and RNA viruses, with genome sizes spanning nearly two orders of magnitude from 1.7 kb to 235 kb. Despite marked differences in viral architecture, replication strategies, and host tropism, these pathogens converge on common pathogenic pathways—direct cytotoxicity and/or immune-medi- ated injury—to produce a remarkably broad clinical spectrum ranging from subclinical infection to fulminant hepatic failure, and from acute self-limited hepatitis to chronic progressive disease. This biological and clinical diversity underscores the substantial global burden of viral hepatitis and the complexity of its clinical management. Beyond the classical hepatotropic viruses (HBV, HCV, HAV, HEV, and HDV), emerging and opportunistic path- ogens including CMV, EBV, HSV, and YFV increasingly contribute to severe hepatic injury, particularly in immunocompromised hosts and endemic settings. The overlapping clinical phenotypes among these agents necessitate a paradigm of precise differential diagnosis anchored in multiplex serological profiling and nucleic acid amplification technologies (Zhao et al., 2016; Seto et al., 2020). Looking forward, several priorities warrant focused attention. First, the integration of next-generation sequencing, artificial intelligence- assisted imaging, and multiplex molecular diagnostics promises to revolutionize early detection and real-time surveillance of both established and emerging hepatotropic viruses. Second, therapeutic innovation must extend beyond the current direct-acting antiviral and nucleos(t)ide analogue regimens to address persistent virolog- ical reservoirs—most notably HBV cccDNA and HCV reinfection cascades—through combinatorial strategies involving gene editing, therapeutic vaccines, and host-targeting agents. Third, universal vaccination coverage, harm-reduction programs, and strengthened blood safety remain indispensable pillars for primary prevention, particularly in resource-limited regions where the disease burden remains highest. Finally, achieving the WHO 2030 elimination targets for viral hepatitis will require coordinated global efforts to bridge diagnostic and treatment gaps, eliminate stigma, and ensure equitable access to care across diverse healthcare systems (Koff, 1974). Through sustained multidisciplinary collaboration spanning virology, immunology, hepatology, and public health, the transition from disease control to elimination of viral hepatitis as a public health threat represents an attainable, albeit demanding, objective for the coming decade.

  Therapeutic, preventive, and pathogenetic advances in viral hepatitis · 2026 · DOI

• Future research should examine factors associated with the risk of HEV on farms, conduct further epidemiologic investigations in humans in the same geographic area, and understand seasonal and geographic patterns of HEV distribution to prevent the introduction and spread of the virus on farms.

  Seroprevalence survey of Hepatitis E Virus in Domestic Pigs in Guangdong, China · 2024 · DOI

• However, it is possible that these results may not be representative because the sample size in 2024 was relatively small, and sampling was conducted on only one farm in a single region where seropositivity was also very high in 2023.

  Seroprevalence survey of Hepatitis E Virus in Domestic Pigs in Guangdong, China · 2024 · DOI

• Of note, experi- mental evidence has revealed that cDNA-derived progenies of HEV-5 successfully in- fected non-human primates (cynomolgus monkeys) [26], underscoring its potential for human infection; however, the zoonotic capacity of HEV-6 remains unclear.

  The Full-Genome Analysis and Generation of an Infectious cDNA Clone of a Genotype 6 Hepatitis E Virus Variant Obtained from a Japanese Wild Boar: In Vitro Cultivation in Human Cell Lines · 2024 · DOI

• Consequently, the biological relevance of ORF1 function during active viral replication in vivo remains poorly defined.

  Impact of hepatitis E virus ORF1 mutations on virus replication and disease severity · 2026 · DOI

• The current evidence base is insufficient to guide effective elimination strategies, highlighting the urgent need for the research priorities and policy recommendations outlined in this review.

  Hepatitis Prevalence Among Key Populations in Nigeria: A Scoping Review · 2026 · DOI

• The current evidence base is insufficient to guide effective elimination strategies, highlighting the urgent need for the research priorities and policy recommendations outlined in this review.

  Hepatitis Prevalence Among Key Populations in Nigeria: A Scoping Review · 2026 · DOI

• Future research should explore the lived experiences and perceptions of risk among Sardinian waste collection workers to better understand vulnerabilities and guide more effective and context-sensitive public health interventions.

  High Hepatitis A Virus Seroprevalence and Low Self-Reported Vaccination Coverage Among Waste Collection Workers in Sardinia, Italy: A Retrospective Cross-Sectional Study · 2026 · DOI

• through However, the current clinical landscape is significantly limited by a lack of standardized consensus screening and management protocols for old and emerging risk viruses.

  Donor-derived viral infections: the usual suspects and the new kids on the block · 2026 · DOI

• Future research should examine additional cytokines and differentiate between natural and vaccine-induced im- munity to better understand the effects of these infections on inflammatory and thyroid hormone levels.

  Analysis of Inflammatory and Thyroid Hormone Levels Based on Hepatitis A and B Virus Immunity Status: Age and Sex Stratification · 2024 · DOI

• Awareness and understanding of viral hepatitis among patients of the study are insufficient, particularly regarding prevention strategies.

  Patient awareness of viral hepatitis infection in Al-Madinah, Saudi Arabia: a cross-sectional study · 2026 · DOI

• Vaccine Development against Zoonotic Hepatitis E Virus: Open Questions and Remaining Challenges.

  Integrated Bioinformatics Analysis Reveals the Impact of SHEV ORF3-Related LncRNA Network on Bile Secretion Pathway (ko 04976) in HepG2 Cells · 2026 · DOI

• BACKGROUND: Hepatitis E virus (HEV) is a major cause of acute hepatitis worldwide, yet its impact in Latin America remains underexplored.

  Hepatitis E Virus Infection in Patients With Chronic Liver Diseases: A Latin American Multicenter Study · 2026 · DOI

• However, they also raise important questions, particularly regarding generalizability, immunity, and the persistent lack of standardization in prolonged or retreatment strategies (Figure 1).

  Two decades of hepatitis E in solid organ transplantation: From endemic insight to unresolved therapeutic questions · 2026 · DOI

• Vaccine Development against Zoonotic Hepatitis E Virus: Open Questions and Remaining Challenges.

  Identification of Riboflavin Metabolism Pathway in HepG2 Cells Expressing Genotype IV Swine Hepatitis E Virus ORF3 Protein · 2025 · DOI

• Limited studies in hepatitis C populations showed impaired responses, partially improved with higher or booster doses.

  Vaccination Strategies Against Hepatic Diseases: A Scoping Review · 2025 · DOI

• These findings highlighted the need for further research on HEV transmission risks through dairy products and emphasize the importance of monitoring zoonotic HEV strains in food safety assessments.

  Detection and Characterization of Paslahepevirus balayani (Hepatitis E Virus) in Dairy Products from Hebei Province, China · 2025 · DOI

• In this paper, the research progress on HEV in vitro culture systems is reviewed to provide a convenient reference for further research on HEV, aiding comprehensive efforts toward the widespread prevention and control of related diseases.

  Research Progress on Hepatitis E Virus Culture · 2025 · DOI

Most-cited papers in Hepatitis Viruses Studies and Epidemiology

• The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013 · The Lancet · 2016 · 1,124 citations
• Global reporting of progress towards elimination of hepatitis B and hepatitis C · ˜The œLancet. Gastroenterology & hepatology · 2023 · 318 citations
• Adeno-associated virus 2 infection in children with non-A–E hepatitis · Nature · 2023 · 139 citations
• Heterogeneous geographic distribution of human T-cell lymphotropic viruses I and II (HTLV-I/II): serological screening prevalence rates in blood donors from large urban areas in Brazil · Cadernos de Saúde Pública · 2005 · 138 citations
• Genomic investigations of unexplained acute hepatitis in children · Nature · 2023 · 130 citations
• Global temporal trends and projections of acute hepatitis E incidence among women of childbearing age: Age-period-cohort analysis 2021 · Journal of Infection · 2024 · 119 citations
• Acute Hepatitis and Adenovirus Infection Among Children — Alabama, October 2021–February 2022 · MMWR Morbidity and Mortality Weekly Report · 2022 · 115 citations
• Increase in Hepatitis A Virus Infections — United States, 2013–2018 · MMWR Morbidity and Mortality Weekly Report · 2019 · 114 citations
• Adeno-associated virus type 2 in US children with acute severe hepatitis · Nature · 2023 · 114 citations
• Hepatitis A Virus Outbreaks Associated with Drug Use and Homelessness — California, Kentucky, Michigan, and Utah, 2017 · MMWR Morbidity and Mortality Weekly Report · 2018 · 113 citations

Most recent work

• Best practice guidelines for viral hepatitis service delivery in prisons · The Lancet Infectious Diseases · 2026
• Shellfish as a Potential Source of Hepatitis E Virus: Epidemiological Evidence, Biological Plausibility, and Research Gaps · Viruses · 2026
• Evidence of Wild Boars as a Reservoir of Zoonotic Hepatitis E Virus Genotype 3: Implications for Public Health in Argentina · Pathogens · 2026
• Hepatitis E virus-associated neurological injury and neurotropic cellular mechanisms · Frontiers in Cellular and Infection Microbiology · 2026
• Mitochondrial and lipid metabolism rewiring during HEV infection · Cellular and Molecular Life Sciences · 2026
• Nucleotide analogue bemnifosbuvir inhibits hepatitis E virus replication in preclinical models · Gut · 2026
• Hepatitis E virus replication is maintained in proliferative cells within the intestinal crypt · Science Advances · 2026
• Cost-effectiveness of hepatitis A vaccination for adults in China: A decision tree Markov model study · Vaccine · 2026
• P-1842. Clinical Characteristics of Rat Hepatitis E Virus (Rocahepevirus ratti) Infection: an emerging agent of viral hepatitis in humans · Open Forum Infectious Diseases · 2026
• Extrahepatic hepatitis E virus in cerebrospinal fluid of people living with human immunodeficiency virus at an Academic Hospital, South Africa · International Journal of Infectious Diseases · 2026

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