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Hepatitis E

Hepatitis E is an acute viral infection of the liver caused by the hepatitis E virus (HEV), a small, non-enveloped, single-stranded belonging to the family Hepeviridae. The virus primarily spreads through the fecal-oral route, often via ingestion of contaminated in areas with poor , though zoonotic transmission from animals like pigs occurs with certain genotypes in developed regions. There are four main genotypes infecting humans: genotypes 1 and 2 are human-exclusive and cause large waterborne outbreaks in developing countries, while genotypes 3 and 4 are zoonotic and more common in industrialized nations. Globally, hepatitis E is a leading cause of acute , with an estimated 19.47 million incident cases and 3,450 deaths in 2021, predominantly in and . In endemic areas, infections often occur in young adults aged 15–40 through sporadic cases or epidemics, while in low-endemic regions like the and , it is rare but increasingly recognized in travelers or via undercooked meat consumption. The typically lasts 2–6 weeks, after which most infections are self-limiting, resolving within 1–6 weeks without long-term liver damage in immunocompetent individuals. Clinical symptoms, when present, include fever, fatigue, nausea, abdominal pain, and , affecting 5–30% of cases; however, the infection can be asymptomatic or severe, particularly in high-risk groups. Pregnant women, especially in the third , face a of up to 20–25% due to fulminant hepatic failure with genotypes 1 and 2, while immunocompromised patients (e.g., organ transplant recipients) may develop chronic with genotypes 3 and 4. Extrahepatic manifestations, such as neurological disorders like Guillain-Barré syndrome, have also been associated with HEV infection. Diagnosis involves detecting anti-HEV IgM antibodies for acute infection or HEV RNA via nucleic acid amplification tests in blood or stool, with IgG indicating past exposure. There is no specific antiviral treatment for acute cases, which are managed supportively; is used for chronic infections in immunocompromised patients, though it is contraindicated in pregnancy. Prevention focuses on ensuring access to safe drinking water, proper , and practices to interrupt fecal-oral transmission. A recombinant (HEV 239, marketed as Hecolin) is licensed in and , with WHO recommending its use in specific high-risk outbreak settings, and has shown over 95% efficacy in healthy adults, with recent use in outbreak responses like those in in 2022–2023, including campaigns in 2023 in Fangak County, following WHO's 2024 recommendations for targeted in outbreak settings. In developed countries, avoiding raw or undercooked and helps mitigate zoonotic risks.

Signs and symptoms

Acute infection

Acute hepatitis E typically follows an of 2 to 8 weeks after exposure to the hepatitis E virus (HEV). The illness progresses through distinct phases, beginning with a prodromal (pre-icteric) phase characterized by nonspecific symptoms such as mild fever, anorexia, , , and , which usually last 2 to 10 days. These early symptoms reflect the initial and in the liver and , often resolving as the advances. The prodromal phase transitions into the icteric phase, marked by the onset of , dark urine, pale stools, and pruritus due to . Physical examination may reveal in 10% to 85% of cases, along with right upper quadrant tenderness. Laboratory findings during this phase include markedly elevated serum (ALT) and aspartate aminotransferase (AST) levels, often peaking at 10 to 20 times the upper limit of normal, alongside increased concentrations. These hepatic enzyme elevations indicate hepatocellular injury and are typically accompanied by positive IgM anti-HEV antibodies, which serve as a key serological marker for acute . The overall duration of acute hepatitis E is generally 1 to 6 weeks, with the icteric phase lasting several days to weeks before symptoms subside. In immunocompetent individuals, full clinical and biochemical recovery occurs in 95% to 99% of cases, and the infection is self-limiting without progression to chronicity. However, a substantial proportion of HEV infections—often the majority—are and only identified through serological testing or incidental detection during screening.

Chronic infection

Chronic hepatitis E is defined as persistent hepatitis E virus (HEV) lasting more than 3 months, primarily affecting immunocompromised individuals. In such populations, including solid organ transplant recipients and those with hematologic malignancies, the risk of developing ranges from 10% to 60%, with higher rates observed in solid organ transplant patients exposed to genotype 3 HEV. This contrasts with immunocompetent hosts, where acute infections typically resolve spontaneously within 4-6 weeks. As of 2025, improved diagnostics have contributed to rising reported HEV cases in , emphasizing its status as a neglected cause of in immunocompromised groups. Symptoms of chronic hepatitis E are frequently absent or mild, with being the most common manifestation reported in up to 24% of cases, alongside occasional or . Key risk factors include , , high-dose immunosuppressive therapy such as , and underlying conditions like infection. In developed countries, 3 HEV predominates in these chronic cases, often linked to zoonotic transmission from swine reservoirs. Untreated chronic hepatitis E can lead to progressive liver and in approximately 10% of affected individuals within 2 years, potentially advancing to end-stage . Extrahepatic complications, such as immune complex-mediated , have also been documented, particularly in kidney transplant recipients with persistent . As of 2025, chronic hepatitis E is increasingly recognized as a "neglected liver killer," with rising incidence noted in , where the average annual increase in hepatitis E cases has been around 7% from 2002 to 2021, driven partly by genotype 4 strains in immunocompromised groups.

Extrhepatic manifestations

Hepatitis E (HEV) can lead to various extrhepatic manifestations, affecting systems beyond the liver, with neurological involvement being among the most frequently reported. These manifestations are often linked to immune-mediated processes and are more common in 3 prevalent in developed regions. Neurological complications occur in approximately 5-30% of acute HEV cases, depending on study populations, with Guillain-Barré syndrome (GBS) and neuralgic amyotrophy (also known as Parsonage-Turner syndrome) being the predominant presentations. GBS, characterized by acute ascending paralysis and areflexia, has been documented in multiple cases associated with acute HEV, particularly genotype 3, where anti-HEV IgM positivity confirms the temporal link. Neuralgic amyotrophy presents with severe shoulder pain followed by muscle weakness and atrophy, reported in up to 10% of symptomatic HEV infections in some cohorts. , involving brain inflammation with altered mental status and seizures, is rarer but has been observed in immunocompromised patients with chronic HEV. These neurological events are predominantly peripheral but can extend to central involvement, with most cases resolving with supportive care and in chronic settings. Renal manifestations are less common but significant, especially in chronic HEV infections among immunocompromised individuals, where (MPGN) and predominate. MPGN features mesangial proliferation and immune deposits leading to and , often confirmed by showing subendothelial deposits. has been reported in approximately 50-70% of chronic HEV cases in solid-organ transplant recipients, with higher rates (up to 67%) in transplant patients; recent 2024 studies highlighting HEV ORF2 protein-antibody complexes in glomerular deposits as a key pathogenic feature. These renal effects are more prevalent in 3 and 4 infections, contributing to progressive dysfunction if untreated. Hematological abnormalities, though rare, include and , observed in acute outbreaks and chronic cases. Thrombocytopenia, with platelet counts below 100,000/μL, affects up to 20% of acute HEV patients and may result from or immune destruction. , including autoimmune forms, is infrequent but documented in outbreaks, particularly in glucose-6-phosphate dehydrogenase-deficient individuals, leading to and fatigue beyond hepatic involvement. These events typically resolve with HEV clearance but can exacerbate severity in vulnerable populations. Other extrhepatic effects encompass and , alongside post-infection autoimmune associations. , marked by elevated and , has been reported in symptomatic HEV cases, often self-limiting but potentially severe. , presenting with and arrhythmias, is exceptional but reported in acute infections, with histopathological evidence of myocardial inflammation. Post-infection autoimmune phenomena, such as or , have been noted in follow-up studies, suggesting persistent immune dysregulation. The underlying mechanisms for these extrhepatic manifestations primarily involve immune-mediated pathways, including molecular mimicry—where HEV epitopes cross-react with host proteins, as proposed for neurological disorders—and immune complex deposition, evident in renal and . Direct in extrahepatic tissues may contribute in chronic cases, but indirect immune responses predominate, with recent from confirming antigen-antibody complexes in affected organs. Cryoglobulinemia prevalence in chronic HEV remains around 10% in high-risk groups, with no major shifts reported in early 2025 data.

Complications in pregnancy

Hepatitis E virus (HEV) poses a significantly heightened during , particularly in the third , where it can lead to fulminant hepatic failure and maternal mortality rates of 20-30%. This severe outcome is more common with HEV genotypes 1 and 2, prevalent in endemic regions of and , compared to genotypes 3 and 4 found in developed countries. The often progresses rapidly from acute hepatitis symptoms such as and to life-threatening complications including and , with the interval from to as short as 1-3 days in many cases. Risk factors for severe disease include infection in the third , where mortality can reach 21-32%, as well as hormonal and immunological changes during that impair viral clearance and exacerbate liver injury. Inadequate antenatal care and poor in endemic areas further amplify vulnerability. Obstetric complications such as premature and preterm delivery occur in over 70% of affected pregnancies, contributing to poor maternal-fetal outcomes. Fetal effects are profound, with stillbirth and miscarriage rates ranging from 20-50%, and intrauterine fetal demise reported in up to 77% of cases in some cohorts. Vertical transmission occurs in 30-50% of cases, often leading to , , and neonatal hepatic issues, though the virus's impact on the is mediated more through placental dysfunction than direct infection in many instances. Recent studies from 2024 have assessed the HEV239 vaccine's safety in ; while no increased risk of fetal loss was observed overall and benefits outweigh risks in high-risk settings, a higher rate of spontaneous was noted if administered within 90 days before or during early , supporting strategies to avoid exposure in early .

Virology

Classification and genotypes

Hepatitis E virus (HEV) is classified within the family Hepeviridae, specifically in the genus Orthohepevirus A, as a single-stranded, positive-sense RNA virus with a non-enveloped or quasi-enveloped structure and a genome approximately 7.2 kilobases in length. This taxonomic placement reflects its enterically transmitted nature and close relation to other mammalian-infecting hepeviruses, distinguishing it from genera like Piscihepevirus (fish viruses) or Rocahepevirus (rat viruses). HEV is further divided into eight recognized genotypes (1 through 8), based on phylogenetic analysis showing sequence divergences typically exceeding 20-25% between genotypes. Genotypes 1 and 2 are exclusively pathogens, primarily spread through contaminated in endemic regions with poor . In contrast, genotypes 3 and 4 are zoonotic, with pigs serving as the main , facilitating to s via undercooked meat or direct contact. Genotype 7 is associated with camels as the primary host and has been linked to infections, while genotypes 5 and 6 have been identified exclusively in wild boars, particularly in , with no confirmed infections to date; genotype 8 has been detected in Bactrian camels in , also without confirmed cases as of 2025. Within genotypes, subtypes are defined by lower divergence thresholds (around 15-20%), with genotype 3 exhibiting the greatest diversity, encompassing at least 14 recognized subtypes (3a through 3m and 3ra) and numerous unclassified variants. These subtypes can influence pathogenicity and geographic prevalence; for instance, subtype 3f predominates in and has been linked to foodborne outbreaks, potentially due to variations in host adaptation and immune evasion. As of 2025, ongoing reclassification proposals under the International Committee on Taxonomy of Viruses (ICTV) emphasize metrics greater than 20% for genotype boundaries, incorporating emerging sequences from animal reservoirs to refine zoonotic risk assessments.

Geographic distribution

Hepatitis E virus (HEV) genotypes 1 and 2 are predominantly associated with endemic transmission in developing regions of and , where they cause both epidemic outbreaks and sporadic cases through fecal-oral routes. In , particularly , and sub-Saharan , these genotypes lead to hyperendemic patterns with seroprevalence often exceeding 3% in general populations, and higher rates in high-risk groups such as rural communities with poor . For instance, studies in , , and parts of report anti-HEV IgG seroprevalence ranging from 15% to over 50% in adults, reflecting ongoing environmental contamination and waterborne spread in these areas. In contrast, genotypes 3 and 4 are linked to sporadic and zoonotic infections in industrialized regions like and , where human cases are typically autochthonous and associated with consumption of undercooked or meat. Seroprevalence for these genotypes in these areas generally falls between 1% and 20%, with higher rates observed in older adults and rural populations exposed to animal reservoirs; for example, in the United States and , anti-HEV antibodies are detected in 5-18% of blood donors as of 2024, while in , rates vary from 0.6% in southern countries to over 20% in parts of and . 3 predominates in and , often transmitted via swine products, whereas genotype 4 is more common in but has been increasingly reported in European cases. Emerging patterns include the detection of 7, primarily in the , where it circulates in camels and has been linked to human infections through consumption of meat or milk. Cases of 7 have been reported in the , , and , marking it as a potential new zoonotic threat in arid regions with husbandry. Additionally, autochthonous infections by genotypes 3 and 4 are rising in developed countries, driven by local animal reservoirs and foodborne transmission from wild game such as boar. As of 2025, HEV infections show increasing trends in specific regions, with genotype 4 cases rising in due to expanding swine reservoirs and changing dietary habits, contributing to over 28,000 reported annual cases nationwide. In , genotype 3 infections linked to game meat consumption, particularly wild boar, have surged, with notifications doubling in some countries since 2020. The estimates approximately 20 million new HEV infections globally each year, underscoring the virus's persistent burden across diverse geographic settings.

Transmission routes

Hepatitis E virus (HEV) is primarily transmitted through the fecal-oral route, particularly in endemic areas where contaminated serves as the main vehicle for spread. This mode of transmission is most common with genotypes 1 and 2, which are predominantly human pathogens and cause large waterborne outbreaks in regions with poor sanitation, such as parts of , , and . Contaminated food, including raw or undercooked , vegetables irrigated with sewage-contaminated water, or fruits, can also facilitate via this route. The infectivity of HEV is dose-dependent, with the lowest observed infectious dose estimated at approximately 7 × 10^3 international units (IU), though higher doses of 10^4 to 10^6 particles are typically required for reliable transmission in experimental models. In non-endemic regions, particularly in developed countries, zoonotic predominates for genotypes 3 and 4, which are shared between humans and animals. Consumption of undercooked , , or deer meat is a key , as the can persist in these animal tissues even after . Occupational among farmers, veterinarians, and workers increases susceptibility through direct contact with infected animal or blood, highlighting the role of as a major in these events. Other transmission routes are less common but documented. Blood transfusion poses a risk in endemic areas, where viremic donors can transmit HEV; in high-prevalence settings like parts of , HEV RNA prevalence in blood donors is approximately 0.1-0.14% as of 2023. Vertical transmission from mother to fetus occurs rarely, primarily with genotype 1 during , contributing to high fetal mortality but not routine spread. Unlike , routine person-to-person or sexual transmission is not observed, though sporadic household contacts have been noted in outbreak settings. The for HEV infection typically ranges from 2 to 10 weeks, with a mean of 5 to 6 weeks, during which the replicates in the liver without symptoms. The infectious period follows, lasting about 1 to 2 weeks after symptom onset, when fecal shedding peaks and declines rapidly, limiting secondary spread. surveillance data indicate ongoing foodborne HEV cases, particularly 3 infections.

Animal reservoirs

Hepatitis E virus (HEV) maintains its zoonotic potential through various animal reservoirs, with domestic pigs and wild boars serving as primary hosts for 3 strains prevalent in , , and . These animals facilitate viral persistence and spillover to humans, with seroprevalence rates in domestic pigs reaching approximately 60% globally and 27% in wild boars, though individual herd rates can vary widely from 1% to 89% depending on and management practices. In herds, HEV often occurs asymptomatically in pigs aged 2-4 months, with documented from infected sows to piglets, contributing to sustained circulation within farms. Camels act as key reservoirs for genotype 7 HEV, particularly dromedary camels in the and Bactrian camels in , where the virus has been detected in fecal samples and linked to human infections via consumption of camel products. Rabbits harbor genotype 3ra variants, a subtype of genotype 3, with evidence of natural infection in feral and domestic rabbits across and , raising concerns for zoonotic transmission due to genetic similarity with strains. Zoonotic spillover from these reservoirs involves cross-species adaptation facilitated by the viral protein encoded by 2 (ORF2) and the multifunctional from ORF3, which aid in virion and host cell interactions. Experimental studies have demonstrated HEV infectivity in non-primary hosts, including chickens and rats, highlighting the virus's broad potential beyond established reservoirs. Genotype 3 subtypes exhibit varying degrees of adaptation, with some strains showing enhanced replication in pigs or s, influencing their zoonotic efficiency. risks are elevated in settings involving close animal contact, such as and wild boar hunting, where occupational exposure through contaminated environments or undercooked meat has led to documented human cases. Recent 2025 analyses of chirohepeviruses in bats reveal genetic relatedness to (including HEV) but position them as distant relatives rather than direct reservoirs for human-pathogenic strains.

Genome structure

The Hepatitis E virus (HEV) genome is a single-stranded, positive-sense molecule approximately 7.2 kilobases (kb) in length, featuring a 5' cap and a 3' polyadenylated tail that mimic eukaryotic mRNA to facilitate and stability. This non-enveloped virus belongs to the family Hepeviridae, and its organization is conserved across genotypes, enabling efficient replication in host cells. The contains three partially overlapping open reading frames (ORFs). ORF1, the largest at about 5,082 , encodes a 1,699-amino-acid nonstructural polyprotein that serves as the replicase complex, incorporating such as methyltransferase (for 5' capping), a Y domain (of unknown function), papain-like , X domain (macrodomain for ADP-ribose binding), , and (for replication). ORF2 spans 1,983 and produces a 660-amino-acid protein essential for virion assembly and host cell attachment. ORF3, overlapping with ORF2, encodes a 123-amino-acid multifunctional that regulates viral egress and interacts with host components. A key feature within ORF1 is the (HVR), a proline-rich (approximately 711-798 in genotype 1) that exhibits pronounced sequence and length variability through insertions and deletions, enabling immune evasion and adaptation to host pressures without compromising overall replication. This region's heterogeneity, including host-derived insertions like those from the RPS17 in the Kernow-C1 strain, enhances viral fitness and persistence. HEV genotypes display 20-40% divergence, with zoonotic genotypes 3 and 4 showing greater intra-genotypic variability (up to 25%) compared to human-specific genotypes 1 and 2, reflecting evolutionary pressures from diverse reservoirs. Recombination is rare but documented, often occurring in the HVR and contributing to emergent strains with altered pathogenicity. Recent analyses of genotype 3 genomes indicate constrained in core functional (e.g., low in methyltransferase and Y domain), where variability is compartmentalized to the HVR to balance stability and adaptability. Updates from 2024-2025 research identify specific genetic determinants in HVR insertions—such as nuclear localization signals and sites—that drive chronicity in immunocompromised patients by boosting replication efficiency, as seen in zoonotic strains with human gene integrations. These findings, coupled with HVR's high mutation rates aligning closely with full-genome phylogenies, underscore its value for tracking and .

Replication cycle

Hepatitis E virus (HEV) initiates its replication cycle by entering host through . The (ASGPR) facilitates attachment and entry by interacting with the viral capsid protein encoded by 2 (ORF2), as demonstrated in studies using hepatocyte cell lines. proteoglycans (HSPGs) also serve as attachment factors for non-enveloped HEV particles, promoting initial binding to the cell surface. Both non-enveloped and quasi-enveloped forms of HEV are internalized via clathrin- and 2-dependent pathways, with quasi-enveloped particles (eHEV) additionally requiring endosomal trafficking through Rab5- and Rab7-positive compartments and lysosomal degradation mediated by Niemann-Pick C1 protein. Following , the viral uncoats in the endolysosomal compartment, releasing the positive-sense, single-stranded genome into the . Replication occurs exclusively in the , often associated with modified membranes forming replication complexes. The (RdRp) within the non-structural polyprotein encoded by ORF1 first synthesizes a complementary negative-sense strand using the genomic as a template. This negative strand then directs the production of new positive-sense genomic RNAs for packaging and subgenomic RNAs (sgRNAs) via a subgenomic promoter located in the junction region between ORF1 and ORF2/ORF3. The sgRNAs are translated into the ORF2 protein and ORF3 protein, which functions as a viroporin to modulate membranes. factors such as the eukaryotic initiation factor 4F (eIF4F) complex support translation of the genomic , while microRNA-122 enhances replication efficiency. The (HVR) within ORF1 contributes to replication by tolerating insertions and deletions that aid in adapting to restrictions and evading innate immune detection through sequence variability. HEV exhibits a characteristically slow replication rate in models, producing on the order of 10^3 to 10^4 genomic copies per infected cell per day, which limits peak titers compared to more robustly replicating viruses. Viral assembly begins with the non-glycosylated form of the ORF2 protein self-assembling into empty icosahedral T=1 in the , which subsequently package the positive-sense genomic to form mature non-enveloped virions. The ORF3 protein recruits these to intracellular membranes, enabling two distinct particle types: non-enveloped virions released into and quasi-enveloped particles (eHEV) in circulating , where the is acquired from host endosomal without incorporating viral glycoproteins. This quasi-envelopment shields the from neutralizing antibodies, enhancing systemic persistence. Mature virions are released primarily through . Quasi-enveloped HEV egresses via multivesicular body (MVB) fusion with the plasma membrane, dependent on the components such as Tsg101, Hrs, and Vps4, as well as Rab27a-mediated trafficking. Non-enveloped particles are secreted apically into canaliculi. HEV can persist intracellularly within lysosomal compartments, potentially contributing to in susceptible hosts.

Pathogenesis

Initial infection and immune response

Hepatitis E virus (HEV) primarily enters the host through the fecal-oral route, with the virus crossing the intestinal mucosa and reaching the liver via the . Recent studies indicate that entry into hepatocytes involves (ITGB1) facilitating interaction with the ORF2 protein. Once in hepatocytes, HEV replicates efficiently, leading to low-level that typically peaks shortly before symptom onset and persists for about 1-2 weeks. In contrast, fecal shedding is robust and prolonged, often beginning 1-2 weeks before and continuing for 2-4 weeks after, facilitating high transmissibility during the early infection phase. The innate immune response to HEV is notably subdued, characterized by a weak type I interferon (IFN) production that fails to mount a robust antiviral defense. HEV achieves this evasion primarily through its ORF1-encoded products, which inhibit the and activation of , thereby suppressing downstream IFN-β induction. This interference with IRF3 signaling, along with potential modulation of IRF1 pathways, allows the virus to replicate with minimal early innate restriction in hepatocytes. Adaptive immunity plays a critical role in controlling acute HEV infection, with humoral and cellular components emerging sequentially. Anti-HEV IgM antibodies targeting the protein (ORF2) and (ORF3) appear within 1-4 weeks post-infection, marking the acute phase. These are followed by neutralizing IgG antibodies against ORF2, which correlate with viral clearance. Analyses as of 2025 reveal evolutionary drivers in HEV, such as immune escape considerations in neutralization epitopes of ORF2, where glycosylated decoys may partially evade recognition, though potent glycan-sensitive broadly neutralizing antibodies (bnAbs) confer protection. Concurrently, + T cells specific to ORF2 epitopes expand and target infected hepatocytes, contributing substantially to the resolution of and fecal shedding. In over 95% of immunocompetent individuals, HEV resolves asymptomatically within 4-8 weeks, driven by the of protective neutralizing that persist long-term. This efficient clearance underscores the effectiveness of the adaptive response in most cases, with and shedding ceasing as titers peak.

Progression to chronic disease

Hepatitis E virus (HEV) typically resolves spontaneously in immunocompetent individuals, but progression to chronic disease occurs primarily through impaired viral clearance mechanisms. Persistence is facilitated by an inadequate T-cell response, particularly in immunosuppressed hosts, where HEV-specific + T cells fail to mount an effective cytotoxic attack, allowing ongoing viral replication and high levels. Additionally, insertions in the (HVR) of the HEV , such as host-derived sequences from genes like TRIM22 or SERPINA1, enable immune evasion by altering viral antigenicity and enhancing replication efficiency, thereby sustaining high viral loads that overwhelm initial immune control. Host factors play a critical role in this progression, with being the dominant risk. In solid organ transplant recipients, regimens involving are associated with higher rates of chronicity compared to cyclosporine, as tacrolimus more potently inhibits T-cell activation and proliferation, leading to prolonged (e.g., tacrolimus trough levels >9 ng/mL correlate with chronic infection in up to 60% of cases). Similarly, in HIV-infected individuals, CD4 counts below 200 cells/mm³ significantly elevate the risk, with seroprevalence reaching 16% in this subgroup versus 4.5% in those with higher counts, due to diminished adaptive immunity that permits viral persistence despite antiretroviral therapy. Viral factors further influence chronic progression, notably through genotypic differences and intra-host variability. Genotype 3 HEV exhibits greater quasispecies diversity in the capsid's M and P domains during acute infection, with higher nucleotide entropy and genetic distances predicting chronic outcomes by enabling antigenic variation and immune escape under selective pressure (e.g., lower Ka/Ks ratios indicate purifying selection favoring persistent variants). Genotype 4, while less commonly zoonotic in Western settings, demonstrates slower viral clearance in some immunocompromised hosts, potentially due to similar quasispecies dynamics, though chronic cases remain rarer than with genotype 3. The timeline of progression is marked by prolonged , defined as detectable HEV beyond 3 months post-infection, which signals a high likelihood of ity and histological damage; by 6 months, it is formally classified as . This drives liver , with studies showing Ishak fibrosis scores exceeding 3 in approximately 20% of untreated cases within the first year, progressing to bridging or early in up to 67% by 2 years in severe instances. Recent genetic analyses of strains highlight evolutionary constraints, where host gene insertions in the HVR promote adaptation for but limit overall genomic diversification due to bottlenecks in immunocompromised environments, underscoring the virus's constrained path to ity.

Factors influencing severity

The severity of hepatitis E virus (HEV) infection varies widely, with an overall case-fatality rate of 0.5-4% in the general population globally, though this rises dramatically to 20-30% among pregnant women, particularly in the third . factors play a critical role in determining outcomes. Advanced age, especially over 50 years, is associated with increased acute severity, particularly for genotypes 3 and 4 prevalent in developed regions, due to diminished immune responses and higher rates of symptomatic disease. Pre-existing , such as chronic or , markedly elevates the risk of acute-on-chronic , with mortality rates reaching up to 70%. In endemic areas of low- and middle-income countries, exacerbates disease progression by impairing immune function and increasing susceptibility to fulminant hepatitis. Viral factors also influence severity. HEV genotypes 1 and 2, which predominate in endemic regions of and , are linked to higher mortality rates compared to genotypes 3 and 4, often due to their association with large-scale waterborne outbreaks and more aggressive acute hepatitis. Additionally, a high viral inoculum dose correlates with greater , as demonstrated in models where larger doses led to more pronounced hepatic damage and clinical manifestations. Environmental and co-morbid factors further modulate disease course. Co-infections, such as with virus, can amplify severity, leading to in rare cases through synergistic hepatic stress. Pregnancy acts as a significant amplifier of severity, independent of , likely due to hormonal and immunological changes that promote and fulminant outcomes. Genetic elements contribute to inter-individual variability. Host polymorphisms in (IFN) signaling pathways, including type I IFN immunity genes, are enriched in symptomatic cases and impair antiviral responses, increasing the likelihood of severe acute hepatitis. Recent studies highlight HEV's genetic adaptations to hosts, such as insertions in 3 strains that enhance replication efficiency and potentially worsen clinical outcomes in susceptible individuals; broadly neutralizing antibodies targeting conserved epitopes provide protective effects against severe disease.

Diagnosis

Clinical evaluation

Clinical evaluation of suspected hepatitis E begins with a detailed history to identify potential exposure risks and epidemiological context. Key elements include recent travel to endemic regions such as parts of , , or , where fecal-oral transmission via contaminated water is common; consumption of undercooked meat from animals like pigs or wild game, associated with zoonotic strains; and underlying , such as in organ transplant recipients or those on , which increases the risk of infection. The typically ranges from 2 to 10 weeks, with an average of 5 to 6 weeks following exposure. Symptom assessment focuses on the prodromal phase, characterized by nonspecific signs such as mild fever, anorexia, , , and lasting a few days, followed by icteric symptoms including , dark , and pale stools, which usually persist for 1 to 6 weeks. In acute cases, and are prominent, while infections in immunocompromised individuals often present with milder or absent symptoms, primarily , without typical fever or . Risk factors like , particularly in the second or third , warrant urgent evaluation due to heightened severity and mortality risk of 20-25%. duration and overall symptom progression help gauge acuity. Physical examination may reveal icteric , right upper quadrant tenderness, and in 10-85% of symptomatic cases, reflecting liver . is rare and not a finding. In or presentations, physical are often minimal or absent. For patients with fulminant hepatitis E progressing to , the are applied to assess prognosis and guide triage for potential . These criteria for non-acetaminophen-induced include unfavorable etiology (such as hepatitis E), age greater than 40 years, duration of more than 7 days before , international normalized ratio (INR) greater than 6.5, or a combination of three or more factors like INR greater than 3.5, age over 40, over 7 days, and non-A, non-B hepatitis. In outbreak settings, 2025 WHO protocols emphasize rapid clinical using case definitions for suspected hepatitis E, integrating history of exposure in endemic areas with acute or elevated liver enzymes to prioritize cases for further investigation and .

Serological and molecular tests

Serological tests for hepatitis E (HEV) primarily detect antibodies produced in response to infection, with anti-HEV IgM indicating acute or recent infection and anti-HEV IgG signifying past exposure or immunity. Anti-HEV IgM typically appears within 1-2 weeks of symptom onset, peaks during the acute phase, and persists for 4-12 weeks before declining, making it a key marker for diagnosing active . enzyme-linked immunosorbent assays (ELISAs) for anti-HEV IgM exhibit sensitivities of 80-97% and specificities of 74-100%, though performance can vary by and , with some rapid diagnostic tests (RDTs) achieving comparable sensitivity to in acute cases. Anti-HEV IgG emerges shortly after IgM, often within 2-4 weeks, and confers lifelong immunity in most individuals, with detection sensitivities ranging from 87-92% in validated kits; however, IgG levels may wane over years in some cases, leading to seroreversion rates of up to 9% after five years. Molecular diagnostics rely on reverse transcription polymerase chain reaction (RT-PCR) to detect HEV , targeting conserved regions such as the overlapping ORF2/ORF3 junction for broad coverage across HEV-1 to HEV-4. Real-time RT-PCR assays, often one-step protocols, offer high sensitivity for and fecal shedding, with fecal samples generally yielding higher viral loads and longer detection windows than due to prolonged enteric . Quantitative RT-PCR is particularly useful for viral loads in infections, where persistent levels above 10^3-10^4 IU/ may indicate ongoing replication, though it requires standardized units for accurate interpretation. In acute HEV infection, typically peaks around week 2 post-onset at levels of 10^4-10^6 /mL before becoming undetectable by week 6 in most immunocompetent individuals, while fecal shedding begins approximately one week prior to symptoms and can persist for 2-4 weeks thereafter. These timelines underscore the need for early sampling, as detection windows are narrow, with positivity rates dropping below 50% after onset. Diagnostic challenges include potential cross-reactivity in serological assays, where IgM may persist or appear in non-HEV contexts like , though most commercial tests show minimal interference with other viral hepatitides. Molecular assays face issues with genotype-specific primer inefficiencies, particularly for divergent strains like HEV-3 subtypes, necessitating broadly reactive targets to avoid false negatives across the eight known genotypes. Recent advances as of 2025 include point-of-care RT-PCR platforms for rapid outbreak detection in resource-limited settings, offering results in under with sensitivities approaching laboratory standards, and the use of short fragments from ORF2 for enhanced diversity assessment in .

Differential diagnosis

The of E (HEV) is crucial due to its clinical overlap with other causes of acute , including , , and elevated liver enzymes, necessitating serological and molecular testing to distinguish it from mimics. Viral etiologies must be excluded first, as HEV shares fecal-oral transmission with virus (HAV) but differs in ; acute HAV is identified by anti-HAV IgM positivity, whereas HEV relies on anti-HEV IgM or HEV RNA detection, with no between the two. Unlike (HBV), which is confirmed by and anti-HBc IgM and can lead to chronic without fecal shedding, HEV typically causes self-limited acute disease with detectable viral RNA in stool.30155-7/fulltext) Similarly, (HCV) is bloodborne, diagnosed via anti-HCV antibodies and HCV RNA, and lacks fecal shedding, helping differentiate it from HEV in non-endemic settings. Non-viral causes include , characterized by a history of heavy alcohol consumption and elevated gamma-glutamyl transferase (GGT) levels, without viral markers or fecal-oral transmission. Drug-induced liver injury, such as from acetaminophen overdose, is suggested by recent exposure and resolves upon discontinuation, contrasting with HEV's epidemiological links to contaminated water.30155-7/fulltext) presents with positive antinuclear antibodies (ANA) and often progresses chronically, unlike the acute, self-resolving nature of most HEV cases, though histological similarities can occur. Other infectious mimics include leptospirosis, which involves renal and multi-organ failure alongside hepatitis and is diagnosed by Leptospira serology or PCR, without HEV's characteristic fecal shedding. In endemic overlap regions, malaria may cause hemolytic jaundice and fever, confirmed by blood smear parasitemia, but lacks HEV-specific serology. Key differentiators for HEV include a travel history to endemic areas, high specificity of HEV PCR for viral RNA, and its unique propensity for fulminant hepatitis in pregnancy, with mortality rates of 20-25% in the third trimester—far exceeding risks from other hepatitides. Serological cross-reactivity with cytomegalovirus (CMV) or Epstein-Barr virus (EBV) can complicate acute HEV diagnosis, but HEV RNA testing resolves this.30155-7/fulltext) As of 2025, multiplex panels, such as the VIDAS Hepatitis Panel for simultaneous detection of HAV, HBV, HCV, and HEV markers, are enhancing diagnostic resolution in co-endemic areas by allowing rapid exclusion of multiple pathogens in a single assay. These advancements, including multiplex RT-PCR assays targeting HEV alongside other enteric viruses, improve specificity in resource-limited settings where co-infections occur.

Prevention

Water and sanitation measures

Access to clean water is a cornerstone of preventing hepatitis E (HEV) transmission through the fecal-oral route, particularly in endemic areas where water sources are often contaminated. Methods such as and effectively inactivate HEV in ; for instance, maintaining a free residual chlorine level of at least 0.5 mg/L throughout the distribution system has been shown to reduce HEV viability significantly, aligning with (WHO) guidelines for safe that emphasize the absence of fecal to protect against waterborne pathogens like HEV. In high-risk regions, WHO targets include universal access to safely managed services by 2030, which for HEV-endemic areas means treating water to eliminate viral risks through community-level interventions like point-of-use and to achieve less than 1% fecal prevalence. Improved sanitation infrastructure plays a critical role in breaking the cycle of HEV contamination by isolating from sources. Upgrading to improved latrines, such as ventilated pit latrines or pour-flush toilets, and implementing systems can reduce environmental fecal contamination by 50-80% in low-resource settings, thereby lowering HEV transmission risks in communities reliant on shared supplies. These measures, endorsed by WHO, focus on preventing leakage into and , which is essential in areas with high and limited . Community-based programs further enhance prevention by promoting hygiene behaviors tailored to outbreak scenarios and resource constraints. Initiatives emphasizing handwashing with after defecation and before food preparation, combined with boiling water during acute outbreaks, have proven cost-effective in low-income settings, with studies showing up to a 30-50% reduction in diarrheal diseases—including those linked to HEV—through simple, scalable interventions. Such programs, often integrated into broader water, sanitation, and (WASH) strategies, prioritize education and low-cost supplies to sustain long-term adherence in vulnerable populations. The impact of these WASH measures is evident in regions undergoing , where enhanced water and infrastructure has contributed to declining HEV incidence rates in parts of ; for example, improvements in urban sewage systems in countries like and have correlated with reduced outbreak frequency over the past two decades. In response to the 2024-2025 hepatitis E outbreak in Chad's Ouaddai region, which reported over 2,000 suspected cases, international organizations implemented rapid interventions, including provision, construction, and promotion, to curb further spread in camps and surrounding communities. These efforts underscore the potential of targeted programs to achieve metrics like less than 1% household fecal , serving as a for effective HEV in endemic low-income areas.

Food safety practices

Preventing foodborne transmission of hepatitis E (HEV) relies on proper cooking methods that ensure the is inactivated, as HEV is highly heat-sensitive. Thorough cooking of potentially contaminated to an internal temperature exceeding 71°C effectively eliminates , with studies showing complete inactivation after exposure to 71°C for at least 20 minutes or higher temperatures for shorter durations. Consumers should avoid consuming raw or undercooked products, such as sausages, pâté, or , which are common sources of zoonotic HEV genotypes 3 and 4, and like oysters or mussels harvested from contaminated waters, as these can harbor viable even after minimal processing. Hygiene practices during food preparation are essential to minimize cross-contamination and reduce HEV risk. Washing fruits and under running water removes potential viral contaminants from or handling, while separating raw meats from ready-to-eat foods using distinct cutting boards and utensils prevents transfer of HEV from infected animal products. of milk, typically at 72°C for 15 seconds, inactivates enveloped and non-enveloped viruses like HEV, making it a safe option if sourced from potentially infected such as pigs or goats in endemic areas. Regulatory measures in regions with high HEV prevalence support by monitoring and controlling contaminated products. In the , the recommends surveillance of and for HEV, with guidelines urging thorough cooking of liver products, though routine screening is not mandatory but implemented voluntarily by some processors. Similarly, in the United States, the monitors imported for viral pathogens, advising against raw consumption of high-risk items like in areas with elevated reservoirs. In high-prevalence regions, such as parts of Europe and , authorities recommend avoiding meat altogether due to frequent HEV detection in species like deer and boar. Consumer education initiatives have proven effective in curbing HEV incidence through awareness of safe handling. A key challenge in food safety is HEV's environmental stability, as the virus remains infectious in contaminated foods subjected to freezing, with viability preserved at -20°C for extended periods, including over a decade in some fecal-contaminated samples. This persistence underscores the need for post-thaw cooking rather than reliance on cold storage alone.

Vaccination strategies

The primary vaccine available for hepatitis E is Hecolin (HEV 239), a recombinant based on the protein encoded by 2 (ORF2) of hepatitis E (HEV) 1. It was approved for use in in 2011 following a phase 3 trial demonstrating 95.5% (95% 85.6–98.6) against symptomatic HEV infection caused by 1 and 4. The standard regimen consists of three intramuscular doses administered at 0, 1, and 6 months, which induces in nearly all healthy recipients and provides long-term protection, with efficacy sustained at 86.6% over 10 years. Hecolin has shown cross-protection against 4 and partial protection against 1, though its efficacy against 3 and 7 remains under evaluation. Hecolin is generally well-tolerated, with clinical trials reporting no significant differences in adverse events compared to , aside from mild injection-site reactions. In , the (WHO) confirmed its safety in , finding no increased risk of among women vaccinated more than 90 days prior to conception, based on data from mass campaigns. strategies emphasize targeted deployment in high-risk settings. Mass campaigns have been implemented during outbreaks, such as the initiative by in South Sudan's Old Fangak region, where over 12,000 women and girls of childbearing age were vaccinated to curb transmission among vulnerable populations; this used a two-dose regimen (0 and 1 month) approved by WHO in for outbreak response. For non-endemic areas, is recommended for travelers to high-prevalence regions and immunocompromised individuals, including those with , due to their elevated risk of severe outcomes. In solid organ transplant recipients and other immunosuppressed groups, pre-exposure is advised to prevent chronic infection, particularly from genotypes 3 and 4. Despite its promise, Hecolin lacks global regulatory approval outside and . Investigational candidates, including those designed for broader coverage against genotype 3—the predominant strain in developed countries—are in early-phase trials; for example, a hepatitis E from was in phase II in as of 2024, while Urihk Pharmaceuticals launched Hevrevac, India's first licensed HEV , in August 2025 for individuals aged 18–65. In 2025, studies reported 72.1% effectiveness of Hecolin against symptomatic HEV in co-infected individuals, supporting its use in comorbid populations. The WHO's 2015 , along with the April 2025 update, endorses in endemic areas for high-risk groups, including pregnant women in outbreaks, to reduce .

Treatment

Supportive care for acute cases

Supportive care for acute hepatitis E focuses on alleviating symptoms and supporting liver recovery in uncomplicated cases, as is typically self-limiting. Patients are advised to observe to conserve energy and promote healing, alongside a high-calorie diet rich in carbohydrates to meet increased metabolic demands without overburdening the liver. is essential to prevent from or reduced intake, and nutritional support should emphasize easily digestible foods while avoiding hepatotoxins such as and limiting acetaminophen to no more than 2 g per day to minimize additional liver stress. Symptom management includes the use of antiemetics like for and , which is preferred due to its minimal hepatic , and antihistamines such as hydroxyzine for pruritus associated with when present. Over-the-counter analgesics should be used cautiously, prioritizing non-hepatotoxic options, and patients are encouraged to maintain electrolyte balance through oral rehydration solutions if needed. Monitoring involves weekly assessment of , including () levels and parameters, to track resolution and detect progression to severe disease. Hospitalization is indicated if exceeds 1000 IU/L or if (e.g., international normalized ratio >1.5) develops, signaling potential requiring closer intervention. In over 95% of immunocompetent individuals, acute hepatitis E resolves spontaneously within 2–6 weeks without the need for antiviral .

Antiviral therapy for chronic cases

Antiviral therapy is indicated for chronic hepatitis E virus (HEV) infection, typically defined as persistent exceeding 3 months accompanied by rising (ALT) levels, particularly in immunocompromised patients such as solid organ transplant recipients. Prior to initiating , efforts should focus on reducing immunosuppressive regimens to enhance immune clearance, as this approach alone resolves infection in approximately 20-30% of cases. Ribavirin remains the first-line antiviral agent for chronic HEV, administered orally at a dose of 400-800 mg per day (typically 600-1000 mg daily in divided doses, weight-based at 8-12 mg/kg/day) for an initial duration of 3 months, which may be extended to 6 months if persists. Sustained virologic response (), defined as undetectable HEV 12 weeks post-treatment, is achieved in 78-85% of treated patients, with higher rates upon retreatment for initial non-responders. The most common adverse effect is , occurring in up to 50% of patients and often necessitating dose reduction, support, or transfusion. As an alternative to , particularly in non-transplant immunocompromised patients intolerant to ribavirin, pegylated interferon-alpha (Peg-IFN-α) can be considered, though it is generally contraindicated in transplant recipients due to the risk of graft rejection. Peg-IFN-α is administered at standard doses (e.g., 180 μg weekly for Peg-IFN-α2a) for 3 months, yielding SVR rates of 40-60% in small case series. Treatment response is monitored via monthly quantitative real-time (RT-PCR) assays for HEV in and , with confirmed by negative results at the end of therapy and 3-6 months thereafter; genotype 3 HEV, which predominates in chronic cases in developed regions, exhibits the best response to . As of , clinical trials are evaluating -based combinations, such as plus , for ribavirin-refractory chronic HEV, showing preliminary additive antiviral activity against genotype 3 and small studies, though larger phase 2/3 data remain pending. Ribavirin resistance is rare, primarily linked to (HVR) insertions or mutations (e.g., Y1320H, G1634R), which emerge under selective pressure and may reduce but occur in fewer than 10% of cases.

Management in special populations

Management of hepatitis E virus (HEV) infection requires tailored approaches in special populations to address heightened risks of severe outcomes. In pregnant women, particularly those in the second or third infected with HEV genotypes 1 or 2 in endemic areas, the focus is on supportive care including hospitalization for symptomatic cases to monitor for , which carries a mortality risk of 20-25%. Intensive monitoring of liver function and fetal well-being is essential, with delivery timing considered based on maternal stability to mitigate complications like obstetric hemorrhage, though no specific antiviral therapy is approved; is contraindicated due to its teratogenicity. Post-partum vaccination with the recombinant HEV vaccine (e.g., Hecolin) may be considered once data confirm its suitability, as preliminary analyses suggest it is safe but long-term efficacy in this group remains under study. For immunocompromised patients, such as solid organ transplant recipients or those on , acute HEV often progresses to chronic infection (lasting >3 months) in up to 70% of cases with genotype 3. Initial management involves reducing doses (e.g., ) where feasible, achieving viral clearance in about 30% of cases without further intervention. If persists, monotherapy at 600-1000 mg/day for 12 weeks is recommended as first-line , yielding sustained virologic response rates of 78%; extension to 6 months or pegylated interferon-alpha may be considered for non-responders. monitoring of HEV via is crucial to guide therapy adjustments. In children, HEV infection is typically milder and self-limiting, with many cases asymptomatic or presenting without , requiring only supportive care; infection is rare except in immunocompromised pediatric patients. Elderly individuals over 60 years face higher mortality from acute HEV, particularly 3 in sporadic cases affecting older males, with severe outcomes linked to underlying ; management emphasizes prompt hospitalization for and supportive measures to prevent . For travelers returning from HEV-endemic regions (e.g., , ) with acute hepatitis symptoms, early diagnosis via for HEV is advised alongside prophylactic guidance on avoiding contaminated and undercooked meat to prevent acquisition. In outbreak settings, such as refugee camps, mass with the HEV 239 has been deployed effectively (e.g., in 2022-2023), achieving high efficacy in preventing cases, combined with enhanced measures. Updated protocols as of 2025 for HBV/HEV co-infection emphasize routine HEV screening in HBV patients, especially elderly or rural high-risk groups, due to increased (up to 18.7%) and exacerbated , including higher rates of and impairment. Management prioritizes close monitoring of and parameters, with integrated antiviral strategies for HBV while addressing acute HEV supportively to prevent progression to .

Epidemiology

Global burden and risk groups

Hepatitis E virus (HEV) imposes a significant burden, with an estimated 19.47 million incident cases of acute hepatitis E and 3,450 deaths in (latest available data). In , HEV accounted for about 8% of global acute cases, with age-standardized incidence rates showing minimal decline since 1990, and responsible for 5.4% of disability-adjusted life years (DALYs) related to acute hepatitis. The burden is disproportionately high in , where genotype 1 predominates and drives elevated incidence and mortality rates due to endemic waterborne transmission in areas with poor . Certain populations face heightened risks from HEV infection. Pregnant women, particularly in the third trimester, experience severe outcomes with a of up to 25%, often linked to hepatic failure and obstetric complications. Immunocompromised individuals, such as solid organ transplant recipients, are prone to chronic infection in roughly 30% of cases, which can progress to if untreated. Travelers to endemic regions in and also represent a vulnerable group, with imported cases contributing to sporadic transmission in non-endemic areas. Epidemiological trends indicate shifts in transmission patterns. Waterborne outbreaks associated with genotype 1 have declined in some developing regions due to sanitation improvements, while zoonotic transmission via genotype 3 has risen in western countries through consumption of undercooked pork or contact with infected animals. In the European Union, seroprevalence among pigs ranges from 10% to 20%, underscoring the reservoir role of swine in sustaining local cycles.

Recent outbreaks and trends

In 2024, Chad experienced a significant hepatitis E outbreak in refugee camps in the Ouaddai province, hosting Sudanese refugees and Chadian returnees, with over 2,000 suspected cases reported by late April, including seven deaths and a case fatality ratio of 0.3%. The outbreak was attributed to genotype 1 hepatitis E virus, facilitated by overcrowded conditions and inadequate sanitation, leading to fecal-oral transmission through contaminated water sources. Response efforts emphasized water, sanitation, and hygiene (WASH) interventions, alongside discussions on deploying hepatitis E vaccines to curb further spread in vulnerable populations. Similarly, in during 2024-2025, ongoing hepatitis E outbreaks in flood-prone areas like and Aweil resulted in over 30 deaths, with (MSF) treating more than 500 cases since April 2023, primarily among women and children. Transmission was linked to contaminated water amid seasonal flooding and displacement, exacerbating risks in internally displaced persons camps. MSF initiated mass campaigns using the HEV239 , achieving high efficacy with two doses and demonstrating effectiveness in reducing expected case numbers during the . In , genotype 4 hepatitis E virus has emerged as predominant, with a 10-year active study in Dongtai (eastern ) from 2013 to 2022 revealing an overall incidence of approximately 12.7 per 100,000 population, higher among males (20.95 per 100,000) and those aged 50-69 years (37.47 per 100,000). This analysis of over 11,000 cases highlighted a rising trend in sporadic zoonotic transmissions, often linked to undercooked consumption. Broader epidemiological projections indicate sustained increases in acute hepatitis E incidence through 2030, underscoring the need for enhanced measures. Zoonotic transmission trends show increasing hepatitis E virus prevalence in wild boars across the and , with detection rates in boar liver ranging from 2% to 38%, posing risks through undercooked meat consumption. In , nationwide wildlife surveys reported anti-HEV prevalence of 12.4% in wild boars, particularly higher in larger individuals over 50 kg. In , silent spread of 1 hepatitis E continues through contaminated sources, contributing to the majority of acute cases without large-scale outbreaks, as evidenced by a 2025 comprehensive review emphasizing underreported endemic transmission in urban and rural settings. Climate-driven factors, such as flooding and , can exacerbate water contamination and hepatitis E transmission, particularly in low-resource settings, as shown by studies linking higher ambient temperatures and to increased incidence in regions like Province, .

History and evolution

Discovery and historical outbreaks

The earliest documented outbreak of what is now known as hepatitis E occurred in , , from December 1955 to January 1956, involving over 29,000 cases of acute linked to contaminated water from the River during flooding. This , initially classified as infectious hepatitis not caused by or B viruses, highlighted the role of fecal-oral transmission in and spurred early investigations into improvements in urban areas. Hepatitis E was first suspected as a distinct enterically transmitted non-A, non-B hepatitis (ET-NANB) during a major waterborne outbreak in the Kashmir Valley, India, in 1978–1979 in Gulmarg, a ski resort area, which affected an estimated 20,000 people and resulted in around 600 deaths (part of regional epidemics from 1978–1982 totaling ~52,000 cases and 1,700 deaths), primarily due to poor water quality. The etiological agent was identified in 1983 when Russian virologist Mikhail Balayan self-inoculated with filtered stool from infected patients during an investigation of unexplained hepatitis among Soviet soldiers in Afghanistan, leading to the visualization of virus-like particles in his stool via immune electron microscopy. This marked the initial isolation of the hepatitis E virus (HEV), confirming its role in epidemic non-A, non-B hepatitis. In the 1980s, multiple outbreaks further defined HEV's epidemiology, including epidemics in the former (1985–1987) with thousands of cases among military personnel and civilians, and in parts of such as and , where water contamination drove transmission in endemic regions. The virus was officially named hepatitis E in 1990 at an international workshop, distinguishing it from other forms of based on its enteric transmission and clinical features. The full-length genome of HEV was cloned and sequenced in 1991 from a Burmese strain, enabling molecular studies and diagnostic development. Key milestones in the included the of HEV into four main genotypes, with genotype 1 identified from Asian outbreaks like the 1955 Delhi , establishing its hyperendemicity in developing regions. In the , the zoonotic potential of HEV was recognized, particularly for genotypes 3 and 4, following the isolation of swine strains closely related to human isolates, shifting understanding from purely waterborne human transmission to animal reservoirs. These historical events underscored HEV as the first recognized waterborne , prompting global advances in water and practices to mitigate outbreaks in high-risk areas. Prior to 2020, major epidemics persisted in , including the 1978–1979 Kashmir event and a 1990–1991 outbreak in with approximately 79,000 cases due to contaminated water sources. In , floods frequently exacerbated transmission, with post-monsoon surges in acute hepatitis E cases reported in the 1980s and 1990s, linking sewerage overflow to increased incidence.

Viral evolution and genetic diversity

The common ancestor of modern hepatitis E virus (HEV) strains is estimated to have emerged approximately 6,000 years ago, coinciding with the post-agricultural period that facilitated animal and zoonotic transmissions. This timeline aligns with the rise of swine farming, which likely contributed to the virus's adaptation to human hosts. HEV exhibits an evolutionary rate of approximately 3.4 × 10^{-3} substitutions per site per year across its s, reflecting moderate variability typical of es. is particularly constrained in 2 (ORF2), the capsid-encoding region, due to strong purifying selection that preserves structural integrity for virion assembly and host interaction. in HEV is driven by recombination events concentrated in the (HVR) of ORF1, where insertions, deletions, and rearrangements allow the virus to evade immune responses and adapt to new environments. Host jumps, such as from pigs to s for genotype 3 strains, further promote adaptation through interspecies transmission, leading to phylogenetic intermingling of and lineages. A 2023 study highlighted hidden evolutionary drivers, including intra-host quasispecies dynamics that generate variant populations enabling rapid adaptation under selective pressures like antiviral treatments. Bat-associated chirohepeviruses represent basal relatives in HEV phylogeny, forming a distinct that underscores the family's ancient diversification among mammals. Looking ahead, ongoing host jumps and HVR recombination raise the potential for emergence of novel HEV , as evidenced by a 2025 analysis of genotype 3 strains revealing frequent insertions that enhance replication efficiency and zoonotic potential.