Hepatitis E virus (HEV) infection is an important cause of acute viral hepatitis worldwide and represents a uniquely severe threat in pregnancy in areas where genotypes 1 and 2 circulate. In low-resource tropical settings, and particularly in the World Health Organization (WHO) Southeast Asia region, HEV infection during pregnancy is associated with disproportionately high maternal case fatality, frequent progression to acute liver failure, and devastating foetal and perinatal outcomes. This narrative review synthesises contemporary evidence on epidemiology, pathogenesis, clinical presentation, maternal and foetal outcomes, management challenges, and prevention strategies with a focus on tropical practice. Critical gaps in diagnostic capacity, access to critical care, and vaccine deployment are highlighted, and practical recommendations are offered to clinicians and health systems working in endemic settings. Strengthened surveillance, outbreak preparedness, inclusion of pregnant women in vaccine policy deliberations, and improved antenatal counselling are essential to reduce preventable deaths from HEV in pregnancy.

Chronic viral hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) remains a leading global public health burden, driving progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) through complex interactions between viral replication, host immune responses, and extracellular matrix (ECM) remodelling. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that serve as central regulators of ECM homoeostasis and immune modulation in the liver. While physiological MMP activity is essential for tissue repair and immune surveillance, dysregulation of the MMP/TIMP (tissue inhibitors of metalloproteinases) axis during viral hepatitis promotes hepatic fibrogenesis, immune evasion, and malignant transformation, positioning MMPs as both drivers of disease progression and promising therapeutic targets. This review comprehensively examines the molecular and cellular mechanisms governing MMP/TIMP dysregulation across the spectrum of viral hepatitis, with particular focus on HCV and HBV. We address the reciprocal interactions between these viruses and MMP/TIMP expression, the roles of MMPs in liver fibrosis, viral replication, hepatocarcinogenesis, and immunomodulation of the tumour microenvironment, and the accelerated fibrogenic mechanisms in HIV-HCV and HIV-HBV coinfection. The review also extends to acute viral hepatitis (HAV and HEV), where direct MMP/TIMP data remain scarce but mechanistic and indirect ECM evidence indicate significant involvement. Finally, we critically evaluate current and emerging MMP-targeted therapeutic strategies including selective inhibitors, nanoparticle delivery systems, and RNA-based approaches and highlight key unresolved questions to guide future research towards disease-tailored interventions against viral hepatitis-driven liver damage and malignant progression.

Florida has the second-highest rate of acute hepatitis C virus (HCV) infection cases in the United States. However, HCV care cascade outcomes among individuals seeking care in Florida emergency departments (EDs) remain unknown. To assess HCV care cascade outcomes and identify HCV infection predictors among individuals tested for HCV in Florida EDs. This retrospective study used electronic health records (2016-2023) linked to the Agency for Healthcare Research and Quality on Social Determinants of Health regional data. Adults aged 18-79 years tested for HCV infection in Florida EDs. Outcomes included the proportions of individuals completing each HCV care cascade step: (1) HCV screening; (2) HCV diagnosis; (3) linkage to care; and (4) treatment initiation. A multivariable logistic regression model was used to identify predictors of HCV infection. Among individuals seeking care in EDs, 4.98% (n=18,444) were tested for HCV, of whom 4.97% were confirmed HCV-positive. Among HCV-positive individuals, 11.24% were linked to care, and 2.84% initiated treatment. Significant predictors of HCV infection included having Medicaid insurance (OR=1.53, 95% CI: 1.14-2.07) or being uninsured (OR=2.88, 95% CI: 2.02-4.12), coinfection with human immunodeficiency virus (OR=28.99, 95% CI: 22.31-37.67), opioid injection drug use (OR=3.62, 95% CI: 2.76-4.75), opioid overdose (OR=3.89, 95% CI: 2.32-6.52), and residing in communities characterized by lower educational attainment (fourth quartile OR=1.95, 95% CI: 1.27-2.98). Significant gaps persist across the HCV care cascade among individuals tested in Florida EDs. Innovative public health interventions are needed to support these vulnerable populations.

Oropouche virus (OROV), a member of the Peribunyaviridae family endemic to South America, is a current public health threat. The recent OROV outbreak driven by a novel reassortant strain has caused a dramatic increase in cases in 2024 (13,785 in Brazil, versus only 261 from 2015 to 2022) with sustained levels of transmission in 2025. Previously underreported outcomes have been recognized, including miscarriage, microcephaly, encephalitis, and death. OROV lethality in humans has been attributed to severe coagulopathy with liver involvement, and epidemiological data suggest that acute hepatitis occurs in mild cases of Oropouche fever, highlighting the underrecognized role of the liver in OROV pathogenesis. We present two discrete mouse models of OROV hepatic disease-a lethal model that is similar to the severe coagulative liver necrosis seen in fatal human cases and a model of self-resolving acute hepatitis, which is similar to mild human disease. In both models, OROV causes focal hepatic necrosis in mice, which progresses to massive necrosis and death when the Type I interferon receptor is antagonized. Additionally, we found that a contemporary OROV isolate is less pathogenic in mice than a historic prototypical strain. These studies enhance our understanding of OROV pathogenesis and provide additional models for potential therapeutic development and evaluation.IMPORTANCEThe disease burden of Oropouche fever has been underrecognized and underreported, as highlighted by the increased testing seen in an ongoing outbreak in South America. Specifically, the role of the liver in Oropouche virus pathogenesis has been understudied. Given the recent increase in cases and severe disease manifestations, there is a present need to understand Oropouche virus pathogenesis and provide models to test potential therapeutics. The mouse models of Oropouche-induced hepatitis presented here provide a means to understand how Oropouche virus causes liver damage in both a lethal and sublethal context. These models will be useful for the preclinical evaluation of vaccines and therapeutic treatments. Additionally, we compare the pathogenicity of a historical Oropouche virus isolate to a contemporary human isolate in a lethal mouse model.

In a phase 3b study, glecaprevir/pibrentasvir (G/P) for 8weeks was well tolerated and effective in treatment-naive adults with acute hepatitis C virus (HCV) infection. Here we analyze the efficacy and safety of G/P in adults with acute HCV infection with a history of prior HCV infection. Participants with acute HCV were stratified by presence of prior HCV infection. Efficacy was assessed in the intention-to-treat population (ITT; all patients receiving ≥ 1 G/P dose) and modified ITT virologic failure population, which excluded non-virologic failures (mITT-VF). Safety (adverse events [AEs] and laboratory values) was assessed, as well as viral kinetics. Among 286 participants, 52 (18.2%) had ≥ 1 prior HCV infection and 234 (81.8%) did not. High-risk characteristics in those with prior infection versus those without: human immunodeficiency virus (HIV) coinfection, 92.3% versus 40.2%; unprotected male-male sexual activity, 78.8% versus 63.7%; and current/recent injection drug use, 23.1% versus 12.4%, respectively. In the ITT, SVR12 was 98.1% (95% confidence interval [CI] 89.9-99.7) in those with a prior infection and 95.7% (95% CI 92.3-97.7) in those without. There were no virologic failures (SVR12 = 100% in the mITT-VF). Rates of serious AEs (5.8% versus 3.0%) and treatment-related AEs (17.3% versus 15.4%) were similar in those with or without prior HCV infection. Individuals with acute HCV infection with a history of prior HCV infection can be successfully treated with G/P. Risk of reinfection in high-risk populations, such as high-risk sexual activity or injection drug use, highlights the need for ongoing testing for reinfection along with subsequent treatment. ClinicalTrials.gov identifier: NCT04903626.

Herpes simplex virus (HSV) infection is common worldwide, but hepatic involvement is rare. HSV hepatitis is an uncommon yet frequently catastrophic cause of acute hepatitis and acute liver failure (ALF), accounting for < 1% of ALF cases while carrying very high mortality when diagnosis and antiviral therapy are delayed. Although classically associated with profound immunosuppression and late pregnancy, HSV hepatitis is increasingly recognized in patients with less obvious or "non-traditional" forms of immune dysfunction. We describe three cases of HSV hepatitis presenting with distinct risk profiles and clinical manifestations and review the diagnostic and therapeutic challenges associated with this condition. Clinical presentation was nonspecific in all cases, and mucocutaneous lesions were absent or delayed, contributing to diagnostic uncertainty. All patients exhibited marked aminotransferase elevation with relatively modest hyperbilirubinemia ("anicteric hepatitis"), frequently accompanied by cytopenias and coagulopathy. Delayed recognition was associated with rapid clinical deterioration, whereas earlier initiation of intravenous acyclovir was associated with biochemical and clinical improvement. Diagnosis was established using polymerase chain reaction-based detection of HSV DNA in blood and tissue samples. HSV hepatitis remains an under-recognized cause of ALF across a broad spectrum of immunocompromised and seemingly immunocompetent patients. Given the narrow therapeutic window and favourable safety profile of acyclovir, empiric intravenous antiviral therapy should be considered in patients with ALF of indeterminate aetiology while diagnostic testing is pending, particularly in high-risk clinical settings. Increased awareness of this overlooked diagnosis may improve outcomes and prevent avoidable mortality.

Autoimmune Hepatitis (AIH) is a liver disease with a wide clinical spectrum, driven by an abnormal immune response against the liver parenchyma. Challenges persist especially in terms of accurate diagnosis of acute onsets and differential diagnosis, outlined by the European Association for the Study of Liver guidelines. Our training cohort comprised 170 untreated AIH and 232 control cases with a variety of differential diagnosis. Ground Truth was the integrative diagnosis of the clinical, histological, biological and treatment response data. We trained a multiple-instance deep-learning model (DLM) from Whole Slide Images alone for the initial diagnosis of AIH. The model was then tested on an external dataset of 61 AIH and 124 controls. Prospective real-life testing of the model was conducted between January and June 2025. Our DLM "Artificial Intelligence On Liver Immunity (AIOLI)" achieved an AUC of 0,92 ± 0,02 on the training dataset and an AUC of 0,74 on the external dataset; in detail, it achieved an AUC of 0,89 for the differential diagnosis of AIH vs. acute alcoholic hepatitis, 0,98 vs. MASH, 0,42 vs. Hepatitis B Virus and 0,76 vs. drug-induced liver injuries. Retrieval of the five most predictive tiles allowed to identify patterns used by the model for prediction and provided interpretability. In the prospective setting, AIOLI achieved a Sensibility of 0.86, a Specificity of 0.76, a F1-score of 0.69 and an AUC of 0.73. AIOLI is an interpretable DLM able to segregate AIH from a variety of control cases with performances comparable to those of an expert liver pathologist, setting a benchmark for future research. We plan to enhance our performances by enriching our dataset, and to validate this approach with a multicentric deployment.

BackgroundDrug‐induced liver injury (DILI) refers to hepatotoxicity caused by conventional chemical drugs or xenobiotics, whereas herb‐induced liver injury (HILI) is attributed to herbal and dietary supplements. Both these conditions pose diagnostic challenges, particularly when concurrent etiologies such as acute viral hepatitis are present. Hurler syndrome (mucopolysaccharidosis Type I) causes hepatocyte and Kupffer cell vacuolization and can predispose to DILI. Early diagnosis is critical given the high fatality rates associated with DILI.Case ReportWe present a case of a 28‐year‐old male with Hurler syndrome who presented with acute onset of nausea, vomiting, and jaundice. Liver function tests (LFTs) revealed markedly elevated liver enzymes. Serological workup identified newly acquired acute hepatitis C virus (HCV) infection. The patient had recent amoxicillin use and was taking hibiscus tea daily. Causality assessment using the updated Roussel Uclaf Causality Assessment Method (RUCAM) of 2016 yielded a score of 6 (probable DILI). Liver biopsy confirmed DILI. The patient showed clinical improvement with N‐acetylcysteine and corticosteroids, with progressive normalization of liver enzymes.ConclusionsThis case highlights the importance of differentiating DILI from acute viral hepatitis: strong clinical suspicion, temporal relation with offending drug, liver biopsy, and treatment response assessment. Clinicians should have a high index of suspicion for DILI even in the presence of concurrent acute HCV infection, especially in patients with underlying hepatic dysfunction such as Hurler syndrome in our case.

Orthohantavirus infections are classically associated with hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. However, accumulating evidence indicates that the clinical spectrum is considerably broader, with frequent involvement of organ systems beyond the kidney and lung. Hepatic manifestations, in particular, may mimic acute viral hepatitis, leading to diagnostic challenges and underrecognition. This paper synthesizes published evidence on hepatic involvement in orthohantavirus infection, with a focus on clinical presentation, pathogenic mechanisms, differential diagnosis, biomarkers, and public health implications. Relevant literature was identified through searches of peer-reviewed articles, with emphasis on studies reporting hypertransaminasemia, hepatitis-like illness, and liver injury in confirmed hantavirus infections. Mild to moderate elevations in aminotransferases are common during acute orthohantavirus infection, and in some patients the clinical picture may be dominated by fever, thrombocytopenia, and hepatitis-like abnormalities, closely resembling dengue, leptospirosis, or classical viral hepatitis. Hepatic injury appears to result primarily from systemic endothelial dysfunction, immune-mediated inflammation, and microvascular leakage rather than direct hepatocytopathic effects. Emerging biomarkers of severity, including thrombocytopenia, neutrophil-to-lymphocyte ratio, soluble thrombomodulin, and IL-6 trans-signaling, reflect widespread vascular and inflammatory activation. Diagnostic delays are frequent, particularly in non-endemic regions, due to low clinical awareness and overlapping features with more common febrile hepatotropic syndromes. Orthohantavirus infection should be considered in the differential diagnosis of acute febrile illness with unexplained hypertransaminasemia and thrombocytopenia, especially when epidemiological clues suggest rodent exposure or compatible environmental contexts. Recognizing hepatic involvement as part of a systemic endothelial syndrome may improve diagnostic accuracy, reduce underreporting, and facilitate earlier supportive management. Increased awareness among hepatologists, infectious disease specialists, and emergency physicians is warranted.

Hepatitis E virus genotype 3 (HEV-3) is a major cause of acute hepatitis in Europe. However, the clinical burden of symptomatic infection in routine practice and the relative contribution of host and viral factors to disease severity remain incompletely defined. We aimed to characterise the clinical burden, molecular epidemiology and determinants of adverse outcomes in patients with symptomatic HEV-3 infection. Prospective multicentre study including patients with suspected HEV infection from ten hospitals in southern Spain between 2022 and 2025. Samples were analysed at a central laboratory using a standardised diagnostic algorithm based on HEV IgM and HEV RNA testing, with molecular characterisation of viraemic cases. Demographic, clinical and outcome data were extracted from medical records. Multivariable logistic regression analyses were performed to identify factors associated with hospital admission and severe acute hepatitis. Among 1124 tested patients, 267 HEV infections were diagnosed (23.7%). Overall diagnostic positivity remained consistently high throughout the study period. Of the 267 patients, 111 (41.6%) required hospital admission, 14 (5.2%) developed severe acute hepatitis and three died (overall mortality 1.1%), all of whom had major comorbidities. Major comorbidity was independently associated with hospital admission and severe acute hepatitis, whereas HEV-3 clade was not. Symptomatic HEV-3 infection in southern Spain was associated with a substantial clinical burden. Adverse outcomes were driven primarily by host comorbidity rather than by the viral features assessed in this cohort, while molecular surveillance provided useful epidemiological context on circulating strains.

Hepatitis A virus (HAV) remains an important cause of acute viral hepatitis worldwide, with its epidemiology shifting in countries undergoing socioeconomic development. In Turkey, improvements in sanitation and the introduction of routine childhood vaccination in 2012 have reduced early-life exposure, potentially creating a susceptible population among adolescents and young adults. This study aimed to evaluate current HAV seroprevalence, acute infection rates, and age-specific susceptibility patterns. This retrospective study included individuals tested for anti-HAV IgG and IgM between January 2021 and January 2026 in a tertiary care hospital. Serological analyses were performed using chemiluminescence microparticle immunoassay. Demographic characteristics, clinical unit distributions, and temporal trends were analyzed. Statistical analyses were conducted using SPSS v22.0, with p < 0.05 considered significant. A total of 7,147 individuals were included (median age: 32 years; 57.8% female). Acute HAV infection (IgM positivity) was detected in only 0.25% of cases, with no significant differences by age or gender. Overall HAV-IgG seropositivity was 63.03%, significantly higher in adults than in children (p < 0.001). The lowest immunity was observed in adolescents aged 15-18 years (12.5%), while seropositivity peaked at 100% in individuals ≥ 60 years. A significant temporal fluctuation was noted, with seropositivity declining to 49.5% in 2022 before rising to 68.5% in 2025 (p < 0.001). Susceptibility to infection was highest among adolescents aged 15-18 years (88.6%) and young adults aged 19-30 years (60.0%). Despite low acute infection rates, a substantial immunity gap exists, particularly among adolescents and young adults (specifically the 15-30 age cohort). This shift reflects changing endemicity patterns and highlights the need for targeted catch-up vaccination strategies to prevent future outbreaks and severe disease in susceptible populations. Not applicable.

Retraction of: P-1835. Dual burden of infections: seroprevalence of acute viral hepatitis among dengue patients in northern India

Retraction of: P-1833. Acute Viral Hepatitis in Hospitalized Children: Clinico-Biochemical, Ultrasonographic and Etiological Findings from North India

Acute Hepatitis B (AHB) remains a significant global health challenge, with complex interactions between metabolic and immune responses influencing disease progression. This study aimed to investigate the causal relationships between immune cell-mediated plasma metabolites and acute hepatitis B using Mendelian Randomization (MR) analysis. A two-sample MR analysis was conducted using genome-wide association study data from the FinnGen consortium (133 AHB cases and 451,214 controls) to examine relationships between 1,400 plasma metabolites and 731 immune cell phenotypes. Inverse variance weighting, MR-Egger regression, and weighted median analyses were employed to assess causal relationships. Mediation analysis was performed to explore the role of immune cells in metabolite-AHB associations. A total of 49 circulating metabolites were identified as being significantly associated with AHB risk, including 32 risk factors (e.g., 4-methylguaiacol sulfate, N-formylmethionine) and 17 protective factors (e.g., indoleacetylglutamine, beta-hydroxyisovalerate). Mediation analysis revealed 12 pairs of immune cell-metabolite relationships significantly associated with AHB. Notably, phenyllactate levels negatively regulated AHB through CD39+ secreting Treg AC (MP=- 4.83%) and B cell AC (MP=-12.1%), while 4-methylguaiacol sulfate levels positively mediated AHB through CD38 on IgD+ CD24- (MP=6.41%) and naive-mature B cells (MP=7.37%). The study's findings provide genetic evidence for causal relationships between specific plasma metabolites and acute hepatitis B risk through immune cell-mediated pathways. The identification of phenyllactate as a protective factor via CD39+ regulatory T cells and 4-methylguaiacol sulfate as a risk factor through CD38+ B cells offers insights into the immunometabolic mechanisms underlying AHB pathogenesis. This Mendelian randomization study reveals novel causal associations between plasma metabolites and acute hepatitis B mediated by specific immune cell phenotypes, providing potential biomarkers and therapeutic targets for future hepatitis B management strategies.

Neutralizing Antibodies as A Therapy for Hepatitis E Virus: Advances, Challenges and Opportunities.

Seroprevalence and risk factors of Hepatitis A virus among Palestinian refugees in North Lebanon: A pilot study to inform vaccination and public health policy

Despite the transformative impact of direct-acting antivirals (DAAs) on hepatitis C control, acute/recent hepatitis C virus (HCV) infections continue to be diagnosed in contemporary clinical practice. We describe acute/recent HCV cases diagnosed at a tertiary hospital in Madrid among men who have sex with men (MSM), including people living with HIV (PLHIV) and pre-exposure prophylaxis (PrEP) users. We conducted a retrospective, single-centre descriptive study including acute/recent HCV cases reported between January 2023 and January 2025. Cases were defined by detectable HCV RNA following a previously negative HCV serology or after a cured HCV infection (reinfection). Chemsex was defined as intentional use of psychoactive substances in sexual contexts; slamsex as injecting drugs in sexual contexts. Patients initially managed with watchful waiting were reassessed at 12 weeks to assess spontaneous clearance. Ninety-two cases were included; median age was 43 years (IQR 36-52) and 24 (26.1%) were >50 years. In total, 91 out of 92 (98.9%) were MSM; 70 (76.1%) were PLHIV and 19 (20.7%) were PrEP users. Among 84 patients with genotype data, 55 (59.8%) had genotype 1a, 8 (8.7%) 1b, and 21 (22.8%) genotype 4. HCV RNA was >6 log in 41 (44.6%) and >7 log in 18 (19.6%). Chemsex was reported by 72 (78.3%); among them, 38 (52.8%) reported slamsex. Among those with available data, 17 out of 54 (31.5%) had another sexually transmitted infection. Watchful waiting was initially adopted in 73 (79.3%); 5 out of 73 (6.8%) achieved spontaneous clearance at 12 weeks. Of those observed, 68 (93.2%) initiated DAAs; 9 (9.8%) were treated at diagnosis. Ten (10.9%) were lost to follow-up before treatment initiation; sustained virological response was achieved in treated patients. Acute/recent HCV diagnoses occurred predominantly among MSM, including PLHIV and PrEP users, with frequent reporting of chemsex/slamsex. Low spontaneous clearance and losses before treatment initiation highlight the need for targeted HCV testing and linkage to care in HIV/PrEP and sexual health services, alongside harm reduction and substance use support.

To describe a case of severe acute hepatitis in an adolescent in whom fosfomycin was identified as the highly probable cause of drug-induced liver injury (DILI) and to highlight the potential hepatotoxicity of fosfomycin. A previously healthy 17-year-old male presented with nausea, vomiting, fever, and progressive epigastric pain over 3 days, accompanied by fatigue and malaise. Laboratory testing revealed marked hepatocellular injury, coagulopathy, metabolic acidosis, mild pre-renal acute kidney injury, and elevated inflammatory markers. Imaging demonstrated hepatomegaly with ascites, without biliary obstruction or vascular abnormalities. Extensive evaluation excluded viral hepatitis, autoimmune liver disease, Wilson's disease, ischemic hepatitis, zoonotic infections, and other potential hepatotoxic exposures. Within the 15 days before symptom onset, the patient had completed a 7-day course of oral fosfomycin 500 mg every 8 hours for renal colic-associated dysuria, with no other medications linked to liver injury. Clinical deterioration with hypotension and oliguria required admission to the intensive care unit, where the patient improved with supportive management during a 4-day stay. Using the Roussel-Uclaf Causality Assessment Method (RUCAM), the score was 9, indicating a highly probable association between fosfomycin and the liver injury. Levels of liver enzymes gradually normalized, and the patient was discharged with full recovery. Although fosfomycin is widely used and generally well tolerated, clinicians should remain vigilant for this rare but potentially serious adverse effect. Early recognition and prompt discontinuation of the suspected agent are essential. Reporting uncommon adverse reactions helps strengthen pharmacovigilance and supports safer therapeutic decision-making.

Dysregulated transcription in core- and pol-specific CD8 T cells can be targeted by HDAC inhibition to improve T-cell function in chronic hepatitis B.

Duck hepatitis virus (DHV) continues to pose a substantial threat to duck production worldwide, causing acute hepatitis, neurological manifestations, and elevated mortality rates, even in vaccinated flocks. During 2022-2023, a significant outbreak involving DHV-1 and DHV-3 was reported in duck farms across five governorates in North Egypt. The outbreaks primarily affected Pekin ducklings aged 4-15 days, with mortality rates ranging from 50% to 70%. Affected ducklings exhibited characteristic pathological lesions, including hepatomegaly with haemorrhages, splenomegaly, and renal enlargement. A total of 30 liver and spleen samples collected from affected farms were analysed using reverse transcription PCR (RT-PCR) targeting the 3' untranslated region (3'UTR) and the VP1 gene. DHV was detected in 56.7% (17/30) of the samples. Among the positive cases (n = 17), DHV-1 was identified in 29.4% (5/17), whereas DHV-3 accounted for 70.6% (12/17). Phylogenetic analysis based on whole-genome sequencing revealed that DHV-1 strains clustered within sub-clade 1a, demonstrating high genetic similarity (99.2-99.8%) with previously reported Egyptian isolates and Chinese reference strains (e.g., DHAV-1-CH-2012). In contrast, DHV-3 strains grouped within sub-clade 3a and showed close genetic relatedness to Chinese strains (97.1-98.7%), while showing marked divergence (75.9-76.3% nucleotide identity) from currently used vaccine strains. Genetic analysis identified multiple mutations in both viral types. DHV-1 exhibited amino acid substitutions within VP0, VP3, and non-structural protein regions, alongside five mutations in hypervariable region 1 (HVR1) and one mutation in HVR2 of the VP1. DHV-3 demonstrated distinct mutations within the VP1, including a unique E681K substitution identified in the Egyptian strain ND3. The findings demonstrate ongoing genetic evolution of DHV circulating in Egyptian duck farms, characterized by the predominance of genetically distinct DHAV-3 strains, with significant divergence from currently used vaccine strains. This genetic divergence may contribute to altered vaccine performance and continued disease outbreaks; however, its impact on vaccine-induced protection requires further experimental validation. Continuous genomic surveillance and the development of updated, strain-matched or multivalent vaccines are therefore essential to control DHV infections and minimise economic losses in Egypt's duck industry.