Hepatitis A virus

Hepatitis A is the prototype acute viral hepatitis: a self-limiting faeco-oral infection of the liver that has no chronic phase but real morbidity, particularly in adults and in those with underlying chronic liver disease. The virus is also a deeply unusual picornavirus. It is hepatotropic where its relatives are gut-or-neurotropic, it is innately stealthy where its relatives are cytopathic, and it is the only known picornavirus that uses a quasi-enveloped form to escape antibody during viraemia.

Discovery and historical significance

Hippocratic writings and ninth-century Chinese texts describe icteric illness that may well have been hepatitis A, but cannot be reliably distinguished from other causes of jaundice. The first firmly recognised outbreaks appear in the soldier journals of seventeenth- and eighteenth-century European armies (kriegsikterus and jaunisse des camps), where epidemics of jaundice swept through encamped troops with suspicious regularity.

The modern history begins during the Second World War. Saul Krugman, Joseph Stokes and Sol Havens conducted controlled cross-immunity studies in volunteers that established two distinct entities behind the wartime hepatitis problem: a short-incubation, faecally transmitted infectious hepatitis (the agent later named HAV) and a long-incubation, parenterally transmitted serum hepatitis (HBV). Friedrich Deinhardt’s 1967 transmission experiments in marmosets gave the first reliable animal model. The virus itself was identified in 1973 by Stephen Feinstone, Albert Kapikian and Robert Purcell at the US National Institutes of Health, who visualised 27 nm viruslike particles in stool from convalescent volunteers by immune electron microscopy. Cell culture followed in 1979 (Provost and Hilleman); the full genome was sequenced in 1985; and the inactivated whole-virus vaccines Havrix and Vaqta were licensed in 1995 and 1996 respectively, ending the era of immunoglobulin as the only prophylaxis.

Classification, structure, and genome

Classification

Hepatitis A virus belongs to the genus Hepatovirus, family Picornaviridae. Under the 2022 ICTV binomial nomenclature the species is named Hepatovirus ahepa; the older common name “Hepatitis A virus” remains in widespread clinical use. The species contains five genotypes (I, II and III in humans, further subdivided into sub-genotypes IA, IB, IIA, IIB, IIIA and IIIB; and IV and V in non-human primates). All human strains belong to a single serotype worldwide, which is the virological basis of universal vaccine efficacy: a vaccine derived from a single strain protects against every wild-type HAV anywhere in the world.

Hepatoviruses sit alone in their genus within the Picornaviridae. The family also contains the medically important genera Enterovirus (polio, coxsackie, rhinovirus), Parechovirus, and Aphthovirus (foot-and-mouth). HAV diverges from its picornavirus relatives at almost every level of biology: cell tropism (hepatocytes versus enteric or respiratory epithelium), innate immune profile (stealthy versus cytopathic), and the unique quasi-enveloped form discussed in Virion structure below.

Virion structure

The virion is a naked icosahedral capsid, 27 to 28 nm in diameter, built from sixty copies each of four capsid proteins (VP1 to VP4). The capsid surface is smooth and lacks the receptor-binding canyon of enteroviruses, which is one reason the cellular receptor has been so difficult to identify with certainty.

The capsid is remarkably stable. HAV survives pH below 3.0, 60 °C for ten minutes, drying and most household disinfectants. It is inactivated by autoclaving, sodium hypochlorite, formalin (the basis for vaccine production), quaternary ammonium products and ultraviolet light. This stability underpins HAV’s persistence on hands, surfaces, and in contaminated food and water.

HAV’s most distinctive virological feature is its quasi-enveloped form, eHAV. Virions are released non-lytically from hepatocytes wrapped in a piece of host-cell membrane. Bile salts strip the membrane in the biliary tract, so HAV in stool is naked while HAV in blood is cloaked. The membrane shields eHAV from neutralising antibody and helps explain how a non-cytopathic virus produces a prolonged transmissible viraemia. eHAV is the only known quasi-enveloped picornavirus.

Genome organisation

The genome is a positive-sense, single-stranded RNA of approximately 7,500 nucleotides. A single open reading frame is flanked by structured 5’ and 3’ untranslated regions. The 5’ UTR contains a type III internal ribosome entry site (IRES) for cap-independent translation; a small viral protein, VPg / 3B, is covalently linked at the 5’ end and acts as the genome primer.

The single open reading frame encodes a polyprotein of about 2,200 amino acids that is cleaved by the viral 3C protease, HAV’s only viral protease, into the mature structural and non-structural proteins. The structural proteins are VP1 to VP4 (the capsid components). The non-structural proteins include 2BC (which remodels host membranes into the replication organelle), 3C (protease), 3CD (an active intermediate that cleaves host adaptors in the innate immune pathway), and 3D (the RNA-dependent RNA polymerase).

Replication cycle

The cellular receptor for HAV is unsettled. HAVCR1 (TIM-1) was originally proposed, but recent work points to gangliosides as the essential entry factor. Naked HAV enters via an acidification-independent pathway; quasi-enveloped eHAV enters by endosomal acidification.

After uncoating, the IRES drives cap-independent translation of the polyprotein, which the 3C protease cleaves into the structural and non-structural proteins. RNA replication occurs on host membranes that the virus reorganises into a tubular-vesicular replication organelle.

Egress is non-lytic. Virions exit hepatocytes wrapped in host membrane (eHAV) via the multivesicular body pathway, released both apically into the bile canaliculus and basolaterally into the sinusoid. Bile salts strip the membrane from the canalicular form, leaving naked virions in the gut and stool, while the sinusoidal form circulates in blood as eHAV.

Pathogenesis

HAV is strictly hepatotropic. After faeco-oral ingestion the virus crosses the small intestinal epithelium, drains via the portal vein, and establishes infection in hepatocytes throughout the liver. Kupffer cells also harbour viral antigen.

HAV is not directly cytopathic. Viral loads in the liver reach high levels well before any biochemical or histological evidence of injury. Clinical hepatitis coincides with the emergence of cellular and humoral immunity: the histological injury is immune-mediated, with CD8+ cytotoxic T cells and multifunctional CD4+ T cells acting on infected hepatocytes.

HAV also blunts innate immunity directly by cleaving several host signalling adaptors (MAVS, TRIF, and NEMO), producing minimal type I interferon induction. This innate stealth allows HAV to replicate to high titres for weeks before clinical disease develops, and underlies the long, age-dependent incubation period.

Epidemiology

The WHO estimates approximately 1.5 million symptomatic cases per year globally, with a true infection burden roughly tenfold higher. Epidemiology is dominated by the relationship between sanitation and the age at first infection, which determines whether infection is clinically silent or clinically severe.

Three classical endemicity tiers are recognised:

• High endemicity: sub-Saharan Africa, parts of Asia and South America. Anti-HAV seroprevalence reaches approximately 90 per cent by young adulthood. Almost all infections occur in childhood and are asymptomatic. Outbreaks of clinically apparent disease are rare in this setting precisely because most of the population is immune from childhood.
• Intermediate endemicity: China, parts of Southeast Asia, the Middle East, transitional economies. Adult seroprevalence runs at 50 to 60 per cent and child seroprevalence at 20 to 30 per cent. This is the setting of the largest symptomatic outbreaks, because a large susceptible adolescent and adult population exists alongside continued faecal contamination of food and water. The paradox of improving sanitation is that disease burden initially rises, even as infection burden falls.
• Low endemicity: the United States, Canada and Western Europe. Adult anti-HAV seroprevalence sits below 30 per cent. Outbreaks are imported, food-vehicle-driven or concentrated in specific risk groups.

The same gradient is sometimes expressed through the Age at Midpoint of Population Immunity (AMPI): high endemicity corresponds to AMPI under five years, very low endemicity to AMPI above forty. Sub-Saharan Africa sits in the AMPI-under-five tier.

Outbreak vehicles. HAV is faeco-orally transmitted, principally through contaminated food and water. Shellfish (the 1988 Shanghai outbreak of approximately 300,000 cases linked to clams), frozen berries, salad ingredients and processed produce have all been incriminated; notable food-vehicle outbreaks include the 2012 to 2013 European outbreak linked to Egyptian strawberries and the 2013 US multi-state outbreak linked to frozen pomegranate arils. Person-to-person spread occurs in households, daycare centres and among men who have sex with men; faecally contaminated drug paraphernalia transmits among people who inject drugs and methamphetamine users. Large outbreaks in high-income countries between 2016 and 2020 were concentrated in MSM, people who use drugs and people experiencing homelessness.

Natural history

HAV is self-limiting. There is no chronic carrier state, even in profound immunosuppression (advanced HIV, post-transplant, severe combined immunodeficiency). Acquired immunity is robust and lifelong; documented second symptomatic infections are essentially unknown. Viraemia and faecal shedding decline as anti-HAV IgM appears and clinical hepatitis emerges. Viral RNA can persist in liver tissue for months in chimpanzee models, but this represents non-infectious residual genome rather than chronic replication. Recovery is complete: there is no cirrhosis, no hepatocellular carcinoma, no measurable late sequelae.

Clinical presentations and complications

The incubation period is 15 to 50 days, with a mean of approximately 28 days. Disease severity is strongly age-dependent and is the single most important determinant of clinical phenotype.

Children under six are usually asymptomatic and anicteric: approximately 70 per cent of paediatric infections in this age group produce no recognised illness. This silent infection is the epidemiological engine of HAV transmission in high-endemicity settings.

Older children and adults typically develop a recognisable triphasic illness. The prodrome is the abrupt onset of fatigue, malaise, anorexia, nausea, vomiting, low-grade fever and right-upper-quadrant abdominal discomfort, lasting several days. The icteric phase begins with darkening of the urine, followed within one to two days by scleral icterus and skin jaundice; pale stools follow. Tender hepatomegaly is present in approximately 80 per cent of icteric cases, jaundice in 70 per cent and splenomegaly in roughly 9 per cent. Extrahepatic features such as maculopapular rash, arthralgia, and leukocytoclastic vasculitis occur occasionally. The convalescent phase brings progressive symptomatic recovery over four to eight weeks, with full biochemical recovery in one to three months.

Liver biochemistry. Transaminases rise into the thousands; ALT exceeds AST (the opposite pattern to alcoholic hepatitis); values above 2,000 U/L are common in symptomatic adults and can exceed 20,000. Alkaline phosphatase is mildly elevated unless cholestasis dominates. Bilirubin and INR support severity assessment.

Variant syndromes and complications

Three variant syndromes deserve specific recognition:

• Cholestatic hepatitis A: approximately four per cent of cases. Prolonged jaundice for up to 18 weeks with bilirubin between 12 and 29 mg/dL, severe pruritus and slow ALT recovery. Steroids can shorten the cholestatic course but are not used in typical HAV.
• Relapsing hepatitis A: 3 to 20 per cent of cases. A second milder peak after apparent recovery, with HAV detectable in stool during the relapse. The mechanism is unknown and there are no chronic sequelae. Premature return to full-time work increases the risk.
• Fulminant hepatic failure: rare. HAV accounts for roughly 3 per cent of acute-liver-failure presentations in cohort series. Spontaneous recovery occurs in 30 to 60 per cent of cases; up to half die or require transplantation. Risk factors are older age and pre-existing chronic liver disease, particularly chronic hepatitis C.

In pregnancy, HAV is generally unremarkable, an important contrast with hepatitis E, where third-trimester case-fatality reaches 25 to 30 per cent.

Extrahepatic complications (optic neuritis, transverse myelitis, aplastic anaemia, pancreatitis, thrombocytopenia) are rare.

Diagnosis

Anti-HAV IgM by ELISA is the gold standard for acute hepatitis A. It is positive at symptom onset, peaks within the first month, and persists for approximately four to six months. A positive anti-HAV IgM in a patient with a compatible clinical syndrome and raised transaminases is diagnostic.

Pre-test probability matters. Anti-HAV IgM should be requested when there is a clinical syndrome of acute hepatitis, not as part of a routine liver screen. In low-prevalence screening, the positive predictive value of the test is low and most positives are false; acting on them generates unnecessary contact tracing, occupational exclusion and follow-up investigation.

Anti-HAV IgG (total anti-HAV) appears together with IgM and persists for decades, marking past infection or successful vaccination. It is used for pre-vaccination screening (particularly cost-effective where background seroprevalence is high) and for confirming response to vaccination.

HAV RNA by RT-PCR is the most sensitive HAV-specific test but is not used for routine clinical diagnosis. Its principal applications are outbreak investigation, genotyping to link cases molecularly, and detection in food, water and environmental samples. For example, the molecular epidemiology of the 2013 US frozen-pomegranate-aril multistate outbreak relied on RT-PCR and sequencing.

Approach to acute hepatitis with negative routine serology

When HAV, HBV and HCV serology are all negative, the differential ordered by frequency in clinical practice:

• Hepatitis E virus: particularly in returned travellers from South Asia and zoonotic exposures (undercooked pork, game).
• Other systemic viral infections: CMV, EBV, HSV-1 and HSV-2, VZV, parvovirus B19. The clinical clue is markedly elevated transaminases with leukopenia and low bilirubin, often in an immunocompromised host.
• Drugs and toxins: paracetamol overdose, idiosyncratic drug reactions, herbal preparations, Amanita mushroom poisoning. The clinical clue is very high transaminases with low bilirubin and a drug-exposure history.
• Ischaemic hepatitis: ALT in the thousands with markedly raised LDH, in a patient with a hypotensive episode.
• Autoimmune hepatitis: positive ANA, ASMA or anti-LKM1; female preponderance; raised IgG.
• Wilson’s disease: Coombs-negative haemolytic anaemia, ALT under 2,000 with AST exceeding ALT, low alkaline phosphatase and low uric acid; consider in patients under 40.
• Vascular causes: Budd-Chiari syndrome or portal vein thrombosis; diagnose with Doppler ultrasound.
• Pregnancy-related: acute fatty liver of pregnancy (AFLP), HELLP syndrome.
• Returned travellers: yellow fever, viral haemorrhagic fevers (Ebola, Marburg, Lassa) where the exposure history fits.

Management

Management is supportive. There is no licensed antiviral. Patients with mild illness are managed at home; admit for severe symptoms, dehydration, biochemical evidence of coagulopathy or any encephalopathy.

The therapeutic principles are simple. Maintain hydration. Avoid alcohol and unnecessary hepatotoxic drugs, including therapeutic paracetamol where alternatives exist; review all current medication for hepatotoxicity. Corticosteroids are not used in typical HAV but may shorten protracted cholestatic disease in selected patients. Anti-emetics for nausea; analgesia tailored to the hepatic context.

Bed rest is unnecessary. Work or school exclusion until clinical and biochemical recovery is typical practice; transaminases should normalise before adults return to full-time work, and return to sport is permitted only after both full-time work tolerance and normal transaminases. Premature return is associated with relapsing disease.

Isolation is reserved for patients who are faecally incontinent; standard contact-with-faeces precautions otherwise apply. Hand hygiene is paramount: HAV survives at least four hours on hands and is resistant to many alcohol-based hand rubs at standard concentrations, so soap and water hand-washing is preferred for known contacts.

Fulminant hepatic failure. Trials of corticosteroids, prostaglandin E, interferon and ribavirin have all been inconclusive. Liver transplantation is the only effective intervention in fulminant HAV, with 55 to 75 per cent one-year survival in transplant series. There is no evidence of HAV reinfection in the graft. Tertiary referral should be considered for non-settling disease, encephalopathy, an INR above 1.5 with jaundice, and any patient where transplantation may become necessary.

Prevention and public health

Vaccination

Two single-antigen inactivated whole-virus vaccines dominate global use.

• Havrix (GlaxoSmithKline; HM175 strain grown on MRC-5 cells; US licensure 1995). Paediatric (1 to 18 years): 720 ELU IM at zero and six to twelve months. Adult (19 years and over): 1,440 ELU IM at zero and six to twelve months.
• Vaqta (Merck; CR326 strain; US licensure 1996). Paediatric (1 to 18 years): 25 U; adult (19 and over): 50 U IM at zero and six to eighteen months.

A combination HAV / HBV vaccine is available for adults:

• Twinrix (GlaxoSmithKline; ≥18 years). Standard three-dose schedule at zero, one and six months; an accelerated four-dose schedule (zero, seven, 21 to 30 days, with a twelve-month booster) is licensed for last-minute travellers.

Both Havrix and Vaqta produce protective antibody in over 90 per cent of recipients one month after the first dose and in over 99 per cent after the two-dose course. Brands are interchangeable; interrupted series do not need restarting. Long-term immunity is sustained for at least 25 years on serological follow-up, and modelled to be lifelong.

Live attenuated vaccines (the H2 strain) have been used in China since 1992 with good population-level effectiveness; further attenuated H2 and LA-1 vaccines are licensed in India, Guatemala, the Philippines, Bangladesh, Nepal and Chile.

Diminished response is seen in advanced cirrhosis (approximately 66 per cent seroconversion in decompensated versus 98 per cent in compensated disease), in HIV with a CD4 count below 300 cells/µL (52 to 94 per cent seroconversion), and in post-transplant immunosuppression. A third booster dose at six to twelve months after the first dose is commonly recommended in these populations to improve seroconversion.

Universal childhood immunisation has been adopted in many high-endemicity and intermediate-endemicity countries, and is endorsed by current global guidance. Where universal immunisation is not in place, vaccination is recommended for defined risk groups:

• Household and sexual contacts of acute cases.
• Daycare attendees, staff and volunteers working with children.
• Healthcare workers (pre-vaccination anti-HAV IgG screening is cost-effective where background seroprevalence is high).
• Men who have sex with men.
• Residents and employees of closed institutions.
• International travellers to high- or intermediate-endemicity regions.
• Refugees from endemic regions.
• Patients with chronic liver disease (not at higher risk of acquiring HAV but at substantially higher risk of severe disease if they do).
• Raw sewage workers.
• Food handlers, where occupational risk and outbreak transmissibility justify it.

Pre-travel use. A healthy traveller departing in more than two weeks needs single-dose vaccine pre-departure for protection during the trip, with a second dose on return to complete the schedule. The traveller over 40, immunocompromised or with chronic liver disease, departing in under two weeks, gets vaccine plus HNIG 0.1 mL/kg at a separate site. The vaccine-contraindicated or under-1-year-old traveller gets HNIG alone.

Infection prevention and control

HAV survives at least four hours on hands and weeks on dry surfaces at low temperatures. Effective disinfection includes chlorination (free chlorine at 1 ppm), household bleach diluted 1:100, quaternary ammonium products, autoclaving, and ultraviolet light. Standard alcohol-based hand rubs have variable efficacy against non-enveloped viruses and are not a substitute for soap-and-water hand washing in known HAV contacts.

Healthcare worker exposure. There is no documented nosocomial excess of HAV seroprevalence in HCWs who use standard precautions. Risk is defined by contact with infectious faeces (the diapered child in paediatric units, the incontinent patient in geriatrics) and is managed by routine hand hygiene, PPE for faecal exposure, and pre-employment vaccination where IgG screening is negative.

Post-exposure prophylaxis

Human normal immunoglobulin (HNIG) is polyclonal antibody pooled from donor plasma. It provides passive immunity for several months and is 80 to 90 per cent effective when given within 14 days of exposure.

Doses:

• 0.02 mL/kg IM: approximately three months of protection.
• 0.06 mL/kg IM: three to five months of protection; the pre-exposure dose for sustained risk (long-stay travellers).
• 0.1 mL/kg IM: the post-exposure dose used in combination with vaccine for higher-risk groups.

The stratified PEP algorithm:

• Healthy, immunocompetent, aged 1 to 40: single-dose HAV vaccine alone, within 14 days of exposure.
• Age over 40, immunocompromised, chronic liver disease: vaccine plus HNIG 0.1 mL/kg at a separate site, within 14 days. Individual risk assessment.
• Infants under 12 months or vaccine-contraindicated patients: HNIG 0.1 mL/kg alone.
• Twinrix must not be used for PEP: its HAV antigen dose is half that of the single-antigen formulations.

Surveillance and notification

HAV is a notifiable disease in most jurisdictions worldwide. Suspected and confirmed acute cases must be reported to the relevant public-health authority to trigger contact tracing, outbreak investigation and PEP within the 14-day window. The WHO has placed acute hepatitis A under the International Health Regulations event-based surveillance umbrella for outbreaks of unexplained jaundice.

Outbreak response

Outbreak investigation typically combines case finding with anti-HAV IgM serology, environmental and food sampling, and molecular epidemiology by HAV RNA sequencing. Contact tracing covers household, sexual, daycare, shared-needle and food- establishment co-worker contacts; PEP is offered within the 14-day window.

Food-handler management. A HAV-positive food handler must be excluded from work and from patient and food contact for seven days after the onset of jaundice. PEP is offered to co-handlers at the same establishment. PEP is not routinely offered to patrons unless onward transmission has been documented: the absence of viral shedding from inadequately washed hands typically does not justify mass prophylaxis, and population-level intervention should follow public-health risk assessment.

South African context

HAV is highly endemic in South Africa: up to 80 per cent of children in low-socioeconomic communities are anti-HAV IgG-positive by the age of eleven to thirteen. The country is undergoing the epidemiological transition toward intermediate endemicity as sanitation access improves. No recent national seroprevalence survey has been published, so the precise current position in the transition is unknown.

Viral hepatitis is a Category 2 Notifiable Medical Condition in South Africa. Suspected or confirmed cases are notified to the Department of Health (typically via the NICD NMC App) within seven days of diagnosis.

HAV vaccine is not part of the South African EPI. It is available in the private sector and recommended for the defined at-risk groups listed under Vaccination above. In immunosuppressed patients (including HIV-positive patients with reduced CD4 counts and patients with chronic liver disease), a third booster dose six to twelve months after the first dose is recommended.

National operational guidance excludes affected adults from work or school for two weeks after the onset of jaundice, provided transaminases are below 100 U/L. The 2019 NDoH Viral Hepatitis Guideline is the primary source for the South African operational framework.

References and recommended reading

• Williford SE, Lemon SM. Hepatitis A virus. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 48. Washington: ASM Press; 2017.
• Valaydon ZS, Locarnini SA, Thompson AJV. Viral Hepatitis. In: Richman DD et al. (eds.), Clinical Virology, 4th edition, Chapter 5. Washington: ASM Press; 2017.
• South African National Department of Health. National Guidelines for the Management of Viral Hepatitis (first edition). Pretoria: NDoH; December 2019.
• Hofmeister MG, Weng MK. Hepatitis A. In: CDC Yellow Book: Health Information for International Travel, 2026 edition. US Centers for Disease Control and Prevention; 2025.