Hepatitis A virus — Questions

HAV’s single open reading frame is translated as one polyprotein, which is then cleaved into the individual viral proteins.

The 3C protease (3Cpro) is the only viral protease HAV encodes, and it performs every internal cleavage of the polyprotein, producing both the structural (capsid) and non-structural proteins.

A small number of late cleavages are performed by host proteases instead, notably the final maturation cleavage of VP0 into VP4 and VP2 after RNA packaging.

The commercially available HAV vaccines are all inactivated whole-virus vaccines, differing in strain, manufacturer and antigen quantity.

Single-antigen products (all two-dose intramuscular schedules at 0 and 6 to 12 months):

• Havrix (GlaxoSmithKline; HM175 strain)
• Vaqta (Merck; CR326 strain)
• Avaxim (Sanofi Pasteur; GBM strain)

Combination product:

• Twinrix (GlaxoSmithKline): combined hepatitis A and hepatitis B (adult), three-dose schedule at 0, 1 and 6 months, or an accelerated four-dose schedule (0, 7, 21 to 30 days with a 12-month booster) for last-minute travellers. Must not be used for post-exposure prophylaxis (PEP): its HepA antigen dose is half that of the single-antigen formulations.

Live attenuated (H2 strain) vaccines are used in China and several Asian countries as single-dose schedules, and are not available in South Africa.

All inactivated formulations are aluminium-hydroxide adjuvanted, grown in human diploid cells, produce over 99% seroconversion after two doses, and are brand-interchangeable within a course. Long-term immunity is sustained for at least 25 years on serological follow-up.

Seroconversion is reduced in advanced cirrhosis, HIV with CD4 under 300 cells/µL, and post-transplant immunosuppression: a third booster dose at 6 to 12 months is recommended in these populations.

Hepatitis A virus is Baltimore class IV: a positive-sense, single-stranded RNA virus in the family Picornaviridae, genus Hepatovirus.

A class IV genome can be translated directly by host ribosomes after entry, without a transcription step. In HAV this happens cap-independently, from an internal ribosome entry site (IRES) in the 5’ untranslated region (UTR).

Of the five clinically important hepatitis viruses, four are RNA viruses (HAV class IV, HCV class IV, HDV class V, HEV class IV) and one is a reverse-transcribing DNA virus (HBV class VII).

The hepatitis A capsid is built from four structural proteins: VP1, VP2, VP3 and VP4. Sixty copies of each assemble into a naked icosahedral capsid approximately 27 to 28 nanometres in diameter.

These proteins are not synthesised individually but released from a single polyprotein by sequential cleavage. The viral 3C protease performs most cleavages; a late maturation cleavage of VP0 into VP4 and VP2 (after RNA packaging) is performed by an unknown host protease.

TRUE.

The standard inactivated HAV vaccine schedule is two doses, a priming dose at time zero and a booster at six to twelve months, and applies in HIV-positive patients, including those with chronic liver disease. The vaccine is inactivated whole virus and safe at any CD4 count.

Response is reduced in advanced immunosuppression (around 52% to 94% seroconversion versus over 99% in immunocompetent adults), so a third booster dose six to twelve months after the first is commonly recommended in this population to improve seroconversion.

The HAV genome is approximately 7.5 kilobases (around 7,500 nucleotides) of positive-sense, single-stranded RNA. It has a single long open reading frame encoding a polyprotein of approximately 2,227 amino acids that is cleaved by the viral 3C protease into the structural and non-structural proteins.

India is a high-endemicity destination for HAV. The five-day departure window falls inside the two-week threshold beyond which single-dose HAV vaccine cannot be relied on to develop protective antibody before exposure.

The HAV prophylaxis

For a healthy adult traveller:

• HAV vaccine, single dose IM today (Havrix 1,440 ELU or Vaqta 50 U single-antigen), with a second dose on return to complete the two-dose schedule.
• HNIG intramuscular at a separate site for passive cover during the window before the vaccine response develops:
  • 0.02 mL/kg: about three months of protection.
  • 0.06 mL/kg: three to five months of protection.

HNIG matters most where worst-case protection counts: traveller over 40, immunocompromised, chronic liver disease, infant under 12 months, or any short-notice departure.

Wider travel consultation

Address the other travel exposures in the same visit: hepatitis E food and water precautions (no vaccine available in South Africa), hepatitis B (consider Twinrix on the accelerated schedule if non-immune), typhoid, routine vaccines up to date, malaria chemoprophylaxis and bite precautions by itinerary, and rabies or Japanese encephalitis for rural or prolonged stays.

The approach has three steps: characterise the injury, work through the alternative aetiologies, and decide what needs urgent intervention.

Confirm and characterise

• Pattern of liver enzymes: hepatocellular (alanine aminotransferase [ALT]-dominant) versus cholestatic (alkaline phosphatase [ALP] and gamma-glutamyl transferase [GGT]-dominant) versus mixed.
• Severity: bilirubin, international normalised ratio (INR), albumin, glucose, lactate. INR above 1.5 with encephalopathy meets the working definition of acute liver failure and changes the urgency completely.
• Imaging: ultrasound with Doppler to exclude biliary obstruction and vascular causes.

Systematic differential

• Other viral: HEV (especially in returned travellers and with zoonotic exposure, the next-line test); cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV) in the immunocompromised; HIV (always offer the test).
• Drugs and toxins: paracetamol (send a level on every patient), idiosyncratic drug-induced liver injury (DILI: anti-tuberculosis therapy, antibiotics, anticonvulsants, non-steroidal anti-inflammatory drugs), herbal and traditional medicines, recreational substances, Amanita mushrooms.
• Ischaemic hepatitis: shock liver, markedly raised lactate dehydrogenase (LDH), a hypotensive precipitant.
• Autoimmune hepatitis: antinuclear antibody (ANA), anti-smooth-muscle antibody, anti-liver-kidney-microsomal antibody type 1 (anti-LKM1), raised IgG.
• Wilson disease: consider in any patient under 40; Coombs-negative haemolytic anaemia, aspartate aminotransferase (AST) greater than ALT with ALT under 2,000, low alkaline phosphatase, low uric acid.
• Vascular: Budd-Chiari syndrome, portal vein thrombosis, veno-occlusive disease.
• Pregnancy-related: acute fatty liver of pregnancy (AFLP), the HELLP syndrome, intrahepatic cholestasis of pregnancy.
• Biliary obstruction: gallstones or malignancy, confirmed on imaging.

Urgent action

• Acute liver failure: contact the nearest transplant unit early; commence N-acetylcysteine (NAC) even in non-paracetamol acute liver failure.
• Specific antidotes: NAC for paracetamol, penicillamine for Wilson disease, aciclovir for suspected HSV.
• Stop the offending drug in suspected DILI.

The VITAMIN DEFG differential

• Viral (HEV, CMV, EBV, HSV, VZV, HIV-related opportunists)
• Ischaemic
• Toxins
• Autoimmune
• Metabolic (Wilson disease, haemochromatosis, alpha-1 antitrypsin deficiency)
• Idiosyncratic (drug-induced)
• Neoplastic infiltration
• Deposition (amyloid, sarcoid)
• Endocrine (thyroid storm, Addisonian crisis)
• Fetal liver (pregnancy-related)
• Granulomatous

HAV remains a self-limiting acute infection even in profound immunosuppression. There is no chronic carrier state, including in post-transplant patients, advanced HIV, and severe combined immunodeficiency (SCID).

The transplant recipient may have a longer or more severe acute illness because of reduced hepatic reserve and the immunosuppressive regimen, but the virus is cleared and immunity is preserved long-term. Management is supportive, with hepatology and transplant-unit involvement for severe disease.

Acute HAV superimposed on chronic liver disease, particularly chronic hepatitis C, carries a substantially increased risk of fulminant hepatic failure. The chronic-HCV liver has reduced hepatic reserve, and the immune response that mediates HAV liver injury can precipitate decompensation rather than self-limited recovery. This is the rationale for routinely vaccinating patients with chronic liver disease against HAV.

The other options are wrong: HAV does not cause chronic carriage, does not recombine with HCV, and does not produce prolonged infectious faecal shedding.

For a healthy, immunocompetent adult aged 1 to 40 within the 14-day post-exposure window, the recommended post-exposure prophylaxis (PEP) is single-dose HAV vaccine alone.

The stratified algorithm:

• Healthy, aged 1 to 40: vaccine alone.
• Over 40, immunocompromised, or chronic liver disease: vaccine plus human normal immunoglobulin (HNIG) 0.1 mL/kg at a separate site.
• Infants under 12 months or vaccine-contraindicated: HNIG 0.1 mL/kg alone (HAV vaccine is not licensed under 1 year).
• Outside the 14-day window: PEP is not recommended.

Twinrix must not be used for PEP: its HepA antigen dose is half the single-antigen formulations.

HAV vertical transmission is rare and not a routine clinical concern. Acute HAV in pregnancy is generally unremarkable: incidence, clinical severity and complications do not differ meaningfully from the non-pregnant adult.

Standard neonatal care applies and breastfeeding may continue. The 25 to 30% third-trimester case-fatality figure belongs to HEV, not HAV. Caesarean section, neonatal HNIG and neonatal HAV vaccine at birth are not routinely indicated for maternal HAV.

A HAV-positive food handler must be excluded from work and from patient or food contact for 7 days after the onset of jaundice. This reflects the natural history of faecal HAV shedding: peak shedding occurs in the late incubation and early symptomatic phases, falls sharply with the appearance of anti-HAV IgM, and is essentially undetectable by stool culture or PCR by about one week after jaundice appears.

Related public-health steps when an infected food handler is identified:

• PEP for co-handlers at the same establishment: post-exposure prophylaxis (PEP) is vaccine alone (single dose) for healthy adults aged 1 to 40; vaccine plus human normal immunoglobulin (HNIG) 0.1 mL/kg for those over 40, immunocompromised or with chronic liver disease, within the 14-day window.
• PEP for patrons is not routinely indicated unless onward transmission has been documented, or specific circumstances (handling ready-to-eat food after toileting without adequate hand hygiene) make patron exposure plausible.
• Outbreak notification through the Notifiable Medical Condition (NMC) system, involving the local outbreak response team.
• Premises inspection: hand-hygiene practice, kitchen cleaning, and food-storage and temperature controls.

HAV transmission from a food handler is usually mediated by uncooked or post-cooking-handled food (salad ingredients, sandwiches, garnishes, bakery items) rather than by adequately cooked meals, because cooking inactivates HAV. Risk assessment should target the specific food-preparation activities the handler performed in the seven days before symptom onset.

The 7-day post-jaundice exclusion is the operational rule. Anti-HAV IgM, transaminases and stool PCR are not used to gate return to work: they would prolong exclusion and add no public-health value.

In South African practice, immunosuppressed patients (including HIV-positive patients with reduced CD4 counts or chronic liver disease) receive the standard two-dose HAV vaccine schedule plus a third booster dose at 6 to 12 months after the first dose, to improve seroconversion.

Seroconversion in HIV-positive patients falls to between 52% and 94% compared with over 99% in immunocompetent adults, which is the rationale for the extra dose. The inactivated vaccine is safe at any CD4 count.

Anti-HAV IgM should be requested only when there is a clinical syndrome of acute hepatitis: clinical compatibility plus markedly raised transaminases. Outside this context the pre-test probability is low and the positive predictive value (PPV) of the test falls accordingly.

This is a Bayesian fact about any test:

• In a population with 1% prevalence and a test with 95% specificity, the PPV is roughly 16%: most positives are false.
• In symptomatic adults with acute icteric hepatitis (around 50% prevalence), the same test has a PPV over 95%.

The other options are wrong for specific reasons:

• HAV does not reactivate: there is no latent state.
• Recent HAV vaccination produces IgG, not detectable IgM.
• IgM does not persist from remote infection: it falls below the detection threshold within four to six months, leaving lifelong IgG as the marker.
• Cross-reactivity with anti-HEV IgM is uncommon with modern assays.

HAV in endemic South African settings is typically acquired in early childhood, when infection is usually subclinical or mild and confers lifelong immunity. Universal childhood immunisation has historically not been judged cost-effective on these grounds: the burden of clinical disease prevented is small.

The policy is increasingly vulnerable to the epidemiological transition under way in South Africa: as sanitation improves and the age at first infection rises, the susceptible adolescent and adult population grows, and adult HAV is symptomatic and severe.

HAV vaccine is available in the private sector and recommended for defined at-risk groups: chronic liver disease, HIV-positive patients, men who have sex with men (MSM), healthcare workers, food handlers, raw-sewage workers, international travellers to endemic regions, and household, sexual and daycare contacts of acute cases.

HAV belongs to the genus Hepatovirus, family Picornaviridae. Other relevant genera in the family include Enterovirus (poliovirus, coxsackieviruses, rhinoviruses) and Aphthovirus (foot-and-mouth disease virus).

The five clinically important hepatitis viruses belong to five different families, sharing only their clinical syndrome rather than their lineage:

• HAV: Picornaviridae
• HBV: Hepadnaviridae
• HCV: Flaviviridae (genus Hepacivirus)
• HDV: Kolmioviridae (genus Deltavirus)
• HEV: Hepeviridae

The quasi-enveloped form (eHAV) is HAV wrapped in a piece of host cell membrane, released non-lytically from hepatocytes. The membrane lacks viral glycoproteins but renders the virion resistant to neutralising antibody until it is stripped in the endolysosome of the next cell.

Bile salts strip the membrane in the biliary tract: HAV in stool is naked, HAV in blood is cloaked. The cloaked blood form is the predominant viraemic form and helps explain how HAV produces a prolonged transmissible viraemia despite an active humoral response.

HAV circulates as a single serotype worldwide. The species Hepatovirus A contains five genotypes: I, II and III infect humans (subdivided into sub-genotypes IA, IB, IIA, IIB, IIIA and IIIB), while IV and V are non-human primate strains. Despite the genetic diversity, antibodies raised against any one strain cross-neutralise all the others.

This is the basis of universal vaccine efficacy: a vaccine derived from a single strain protects against every wild-type HAV the recipient might encounter anywhere in the world.

In the SA public sector, anti-HAV IgM and anti-HAV IgG enzyme immunoassays are available at all service levels (primary, secondary and tertiary). IgM diagnoses acute infection; IgG marks past infection or vaccination.

HAV RNA reverse-transcription PCR (RT-PCR) is not routinely available at primary level and is used principally for outbreak investigation, genotyping and food or environmental samples rather than for individual patient diagnosis.

South African practice specifies two weeks after the onset of jaundice, provided transaminases are below 100 U/L, as the threshold for an adult to return to work or school after acute hepatitis A.

• Transaminases should ideally normalise before return to full-time work; the 100 U/L threshold is a minimum.
• Return to sport is permitted only after both full-time work tolerance and normal transaminases. Premature return is associated with relapsing hepatitis A.

A separate 7-day post-jaundice exclusion applies to food handlers, targeting the period of infectious faecal shedding. For a food handler who is also an adult worker, both rules apply in parallel, whichever is longer.

Under current ICTV binomial nomenclature (MSL40, 2024), the formal species name is Hepatovirus A: the genus name Hepatovirus plus a single-word epithet. “Hepatitis A virus” remains the everyday common name in clinical and laboratory practice.

In South Africa, viral hepatitis (including types A, B, C and E) is a Category 2 Notifiable Medical Condition (NMC). Suspected or confirmed cases require written or electronic notification to the Department of Health (usually via the NICD NMC App) within seven days of diagnosis by clinicians or testing laboratories.

HAV has an incubation period of 15 to 50 days, with a mean of approximately 28 days.

Two practical implications:

• Post-exposure prophylaxis (PEP) must be given within 14 days of exposure, a short window relative to the incubation period, so PEP decisions need to be made promptly.
• A returned traveller presenting with jaundice two to six weeks after return from an endemic destination fits the HAV incubation window (and the overlapping HEV window of 15 to 60 days).

HAV severity is strongly age-dependent:

• Children under six: about 70% are asymptomatic, the silent paediatric infection that drives HAV transmission in endemic settings.
• Older children and adults: typically develop the classical icteric illness.
• Older adults: progressively more severe disease, with cholestatic, relapsing and rarely fulminant variants concentrating in this group.

This age gradient drives the age-stratified PEP algorithm: healthy 1 to 40-year-olds receive vaccine alone, while those over 40 (or with chronic liver disease) receive vaccine plus human normal immunoglobulin (HNIG).

HAV in pregnancy is generally unremarkable: the clinical course does not differ meaningfully from non-pregnant adults, and vertical transmission is rare.

HEV in pregnancy is dramatically different. HEV genotype 1 (the faecally transmitted genotype endemic in South Asia and parts of Africa) in the third trimester carries a 25 to 30% case-fatality rate driven by fulminant hepatic failure.

In any pregnant patient with acute hepatitis, HEV must be actively tested for, particularly when HAV serology is negative. HEV genotype 3 (the zoonotic genotype in high-income countries) does not carry the same pregnancy mortality.

HAV encodes only one viral protease, 3C (3Cpro), a cysteine protease that performs every internal cleavage of the polyprotein. This is distinctive within Picornaviridae: enteroviruses also carry a 2A protease and aphthoviruses an L protease, but HAV has neither.

Two cleavages are not performed by 3C: the C-terminal trim of VP1, and the late maturation cleavage of VP0 into VP4 and VP2 after RNA packaging. Both are performed by unknown host proteases.

Twinrix contains about half the HepA antigen dose of single-antigen HAV vaccines (720 ELU per Twinrix dose versus 1,440 ELU in the adult Havrix dose). Single-dose vaccine PEP relies on a high antigen load to drive rapid seroconversion within the 14-day window, and the half-dose does not reliably achieve this.

For routine pre-exposure vaccination against both HAV and HBV, Twinrix is fine: the full three-dose course cumulatively delivers a full HAV antigen exposure. For PEP, choose single-antigen Havrix or Vaqta.