Hepatitis B virus

Hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic infection of hepatocytes. It is the prototype of the family Hepadnaviridae and the only human virus that uses a reverse-transcription step despite carrying a DNA genome. An estimated 296 million people live with chronic hepatitis B worldwide, and the infection accounts for around 820,000 deaths per year from cirrhosis and hepatocellular carcinoma. The unusual replication strategy produces a persistent nuclear mini-chromosome (cccDNA) that current therapies cannot eliminate, which is why infection can be suppressed but not cured. Most adult infections clear spontaneously; most perinatal infections become chronic. The principal late complications are cirrhosis and hepatocellular carcinoma, both of which are largely preventable by vaccination and antiviral therapy.

Discovery and historical significance

For most of the twentieth century, “infectious hepatitis” (faecally transmitted, short incubation) and “serum hepatitis” (parenterally transmitted, long incubation) were recognised as clinically distinct entities, but neither virus was identified. Saul Krugman’s controlled cross-immunity studies in the 1950s and 1960s established the immunological distinction between MS-1 (later identified as hepatitis A) and MS-2 (later identified as hepatitis B), but the agent of serum hepatitis remained elusive.

The breakthrough came from Baruch Blumberg in 1963. While screening sera from haemophiliacs against the sera of populations worldwide for new antigen-antibody systems unrelated to known disease, Blumberg detected an unusual antigen in the serum of an Australian Aboriginal donor that precipitated against the serum of a New York haemophiliac who had received multiple transfusions. He named it the “Australia antigen” and over the next several years established that it was specifically associated with hepatitis. The link was solidified through prospective cohort studies in transfusion recipients, in patients with Down syndrome, and in viral hepatitis outbreaks. Blumberg received the Nobel Prize in Physiology or Medicine in 1976 for the discovery.

David Dane visualised the complete virion by electron microscopy in 1970, identifying the 42 nm enveloped spherical particle that now bears his name (the Dane particle), distinguishable from the abundant 22 nm subviral spheres of HBsAg that had been the original “Australia antigen” preparation.

The first hepatitis B vaccine, derived from purified plasma HBsAg from chronic carriers, was licensed in 1981. A recombinant HBsAg vaccine produced in Saccharomyces cerevisiae (yeast) followed in 1986, becoming the first recombinant vaccine licensed for human use. The WHO recommended universal infant vaccination against HBV in 1992, and universal birth-dose vaccination in high-endemicity settings followed in the 2000s.

The development of effective oral nucleos(t)ide analogue therapy transformed chronic HBV management between 1998 (lamivudine) and 2008 (tenofovir disoproxil fumarate), with tenofovir alafenamide added in 2016. The NTCP receptor for HBV entry was discovered by Yan and Li in 2012, opening a new class of entry inhibitors (bulevirtide, licensed for chronic hepatitis D). The WHO’s 2016 Global Health Sector Strategy on Viral Hepatitis set ambitious 2030 elimination targets that shape current public-health response.

Classification, structure, and genome

Classification

HBV belongs to the family Hepadnaviridae, genus Orthohepadnavirus. Under the 2024 International Committee on Taxonomy of Viruses (ICTV) binomial nomenclature, the species is named Orthohepadnavirus hominoidei (the hominoid hepatitis B virus, encompassing HBV strains of humans and great apes); the older common name “Hepatitis B virus” remains in widespread clinical use.

Ten genotypes (A to J) are defined by at least 8 per cent nucleotide divergence across the full genome. Distribution is geographically structured, with clinically meaningful phenotypic differences:

• Genotype A (subgenotypes A1 and A2): dominant in southern Africa (A1) and in northern Europe and North America (A2). A1 carries a four-fold higher risk of hepatocellular carcinoma in young Black men than non-A genotypes.
• Genotypes B and C: East Asia and the Pacific. C is more aggressive than B.
• Genotype D: Mediterranean basin, Middle East, India. Associated with the precore G1896A stop codon mutation.
• Genotype E: West Africa.
• Genotype F: Central and South America.
• Genotypes G, H, I, J: smaller geographic niches.

Related viruses in the family. The family Hepadnaviridae also contains the genus Avihepadnavirus (duck and other avian hepatitis B viruses) and the Orthohepadnavirus relatives of HBV (woodchuck, ground squirrel, and other rodent hepatitis B viruses), all of which have served as animal models for HBV biology, cure strategies, and immune control.

Hepatitis D virus (HDV) is a defective satellite virus that requires HBsAg for its envelope and cannot replicate without HBV. Co-infection or superinfection of HBV with HDV accelerates fibrosis progression and worsens hepatocellular carcinoma risk. HDV is most common in southern Italy, the Mediterranean basin, parts of central Asia, Mongolia, the Amazon basin, parts of central Africa, and pockets of eastern Europe. South African HDV prevalence has historically been low, but it remains a recognised co-infection in some populations. Bulevirtide, the NTCP-blocking peptide, is licensed in the European Union for chronic hepatitis D.

Virion structure

HBV-infected serum contains three distinct particle types:

• The complete Dane particle (42 nm spherical, enveloped, infectious virion).
• Subviral 22 nm spheres composed of HBsAg only and lacking nucleic acid (non-infectious).
• Subviral filaments of variable length, also composed of HBsAg only.

The subviral particles are secreted in around 1,000 to 10,000-fold excess of complete virions. They function as a humoral and cellular decoy, distracting antibody and T cell responses from infected hepatocytes and contributing to immune exhaustion.

The Dane particle consists of an outer lipid envelope studded with three forms of the surface antigen, enclosing an icosahedral nucleocapsid of HBcAg dimers. Inside the nucleocapsid is the partially double-stranded relaxed-circular DNA (rcDNA) genome, covalently bound to the viral polymerase through its amino-terminal terminal protein domain.

The three HBsAg surface proteins arise from translation initiation at three different start codons within a single open reading frame:

• Large HBsAg (LHBs): preS1 + preS2 + S. Myristoylated at glycine-2; carries the receptor-binding motif required for infectivity.
• Middle HBsAg (MHBs): preS2 + S.
• Small HBsAg (SHBs): S only.

The principal neutralising epitope, the “a” determinant, lies within the S protein. Mutations in this region (notably G145R) produce HBsAg escape mutants that circulate undetected by standard commercial assays, with clinical implications for blood donation, vaccine-induced immunity, and antiviral monitoring.

Genome organisation

The HBV genome is approximately 3,200 base pairs of partially double-stranded relaxed-circular DNA. The genome uses four overlapping open reading frames read off the minus strand to maximise coding density on a small genome:

Open reading frame	Length and position	Encodes
Polymerase (P)	The longest, about 80 per cent of the genome	A multifunctional protein with four domains: terminal protein (a protein primer for reverse transcription), spacer, reverse transcriptase (containing the YMDD active-site motif), and RNase H
Pre-core / Core (C)	Nested within P	HBcAg (the icosahedral nucleocapsid subunit) and HBeAg (secreted soluble form generated by an upstream start codon with signal peptide cleavage)
Pre-S / S (envelope)	Nested within P	The three forms of HBsAg, from different start codons within a single transcript
X	Nested within P	HBx, a 154-amino-acid multifunctional transactivator essential for productive infection in vivo and a major contributor to hepatocellular carcinoma

The overlap between the polymerase and envelope open reading frames has clinical consequences: mutations in the polymerase gene that confer antiviral resistance can simultaneously alter the overlapping envelope sequence, producing concurrent HBsAg escape phenotypes.

Two mutations of central clinical importance:

• The pre-core G1896A stop codon mutation (TGG to TAG at codon 28) abolishes HBeAg expression at the translational level. The mutation is stable only where position 1858 is thymidine (genotypes B, D, E, G, and some C); the consequent HBeAg-negative chronic hepatitis is therefore common in these settings and rare with genotype A or F.
• The basal core promoter A1762T + G1764A double mutation reduces transcription of the pre-core messenger RNA, again producing HBeAg-negative chronic hepatitis but through a transcriptional rather than translational mechanism. The two mutations can co-exist.

Replication cycle

HBV replication is unique among DNA viruses in its use of a reverse-transcription step. The cycle revolves around two key processes: the generation of a persistent nuclear cccDNA from rcDNA, and the reverse transcription of pregenomic RNA back to rcDNA inside the capsid.

Attachment and entry. Low-affinity binding of the HBsAg antigenic loop to heparan sulfate proteoglycans on the hepatocyte basolateral membrane is followed by high-affinity binding of the myristoylated preS1 region (residues 2 to 48) of LHBs to NTCP (sodium taurocholate co-transporting polypeptide, SLC10A1), a bile-acid transporter discovered as the HBV entry receptor by Yan and Li in 2012. Receptor-mediated endocytosis delivers the nucleocapsid into the cytoplasm. NTCP is the target of bulevirtide (Hepcludex), an NTCP-blocking peptide licensed in the European Union for chronic hepatitis delta.

Nuclear import and cccDNA formation. The capsid traffics to the nuclear pore and releases rcDNA into the nucleus. Host enzymes repair the gapped rcDNA into covalently closed circular DNA (cccDNA), which assembles with histones to form a stable mini-chromosome. cccDNA is the persistence reservoir and the principal cure barrier. It is self-replenishing through reflux of new nucleocapsids to the nucleus and survives the lifespan of the infected hepatocyte.

Transcription. Host RNA polymerase II transcribes cccDNA into:

• A 3.5 kb pregenomic RNA (pgRNA) that serves both as the messenger for polymerase and HBcAg and as the template for reverse transcription.
• A 3.5 kb pre-core messenger RNA encoding the HBeAg precursor.
• 2.4 and 2.1 kb messenger RNAs encoding the three forms of HBsAg.
• A 0.7 kb messenger RNA encoding HBx.

Encapsidation and reverse transcription. Cytoplasmic HBcAg dimers and polymerase assemble around pgRNA at the epsilon stem-loop. Inside the capsid, polymerase reverse-transcribes pgRNA into minus-strand DNA (primed by the terminal protein domain of polymerase covalently attached at its 5’ end), then synthesises a partial plus strand to generate the new rcDNA genome.

Two fates of the new genome. Mature nucleocapsids carrying rcDNA can either re-enter the nucleus to amplify the cccDNA pool, or acquire envelope and be secreted as complete Dane particles via the ESCRT pathway. Subviral 22 nm spheres and filaments composed of HBsAg only are simultaneously secreted in vast excess.

Genome integration. A side product of replication is the integration of HBV DNA fragments (particularly X and S sequences) into host chromosomes. Integrated DNA cannot replicate but continues to produce HBsAg and HBx indefinitely, contributing to hepatocellular carcinoma and complicating the definition of cure.

Pathogenesis

HBV is not directly cytopathic. Liver injury is overwhelmingly immune-mediated, driven by CD8+ cytotoxic T cell killing of infected hepatocytes. HBcAg is the principal target epitope. Cytokine-mediated, non-cytolytic suppression of viral replication (by IFN-γ and TNF-α from cytotoxic T cells, natural killer cells, and macrophages) clears most of the viral pool in adult acute infection without massive hepatocyte death.

Three immunological themes shape the clinical phenotype:

• Neonatal tolerance. HBeAg crosses the placenta and induces T cell tolerance in the fetus, allowing the 90 per cent chronicity rate after vertical transmission from HBeAg-positive mothers.
• T cell exhaustion. Chronic antigen exposure progressively disables HBV-specific cytotoxic T cells, with upregulation of the inhibitory receptors PD-1, TIM-3, and LAG-3. This is why chronic infection cannot be cleared by the host even when viral load is suppressed pharmacologically.
• HBsAg decoy effect. The 1,000 to 10,000-fold excess of subviral HBsAg particles distracts both humoral and cellular responses, contributing to immune exhaustion.

Extrahepatic manifestations are predominantly immune-complex diseases driven by circulating HBsAg-anti-HBs complexes deposited in vascular beds:

• Polyarteritis nodosa: medium-vessel necrotising vasculitis; HBV is the most important infectious cause.
• Membranous and membranoproliferative glomerulonephritis.
• Mixed cryoglobulinaemia (less common than with hepatitis C).
• Papular acrodermatitis of childhood (Gianotti-Crosti syndrome): symmetric erythematous papules on face and extremities, classically associated with acute HBV in young children.
• Serum-sickness-like prodrome: fever, arthralgia, urticarial rash in the late incubation or early acute phase.

These syndromes respond to antiviral suppression of HBV replication; immunosuppression alone (without antiviral cover) precipitates HBV reactivation with severe hepatitis.

Epidemiology

An estimated 296 million people are living with chronic hepatitis B globally, with around 820,000 deaths per year from cirrhosis and hepatocellular carcinoma. The disease distribution reflects historical patterns of childhood acquisition before universal vaccination.

Geographic endemicity. The WHO classifies regions by HBsAg prevalence:

• High endemicity (HBsAg prevalence ≥8 per cent): sub-Saharan Africa (especially West and Southern Africa), East Asia, the Pacific, the Amazon basin, parts of central Asia and the Middle East. Perinatal and early-childhood transmission dominate, producing the high chronicity burden.
• Intermediate endemicity (HBsAg 2 to 7 per cent): South Asia, Mediterranean basin, parts of South America and Eastern Europe.
• Low endemicity (HBsAg below 2 per cent): Western Europe, North America, Australia. Adult horizontal transmission (sexual, percutaneous) dominates.

Transmission routes.

• Perinatal (mother-to-child) is the dominant route in endemic settings, accounting for the majority of chronic infections worldwide. Risk approaches 90 per cent without prophylaxis from an HBeAg-positive mother.
• Early-childhood horizontal transmission through household contact, micro-trauma, and shared sharps is a major route in endemic regions.
• Sexual transmission, particularly in men who have sex with men and in unprotected heterosexual contact with chronic carriers.
• Percutaneous transmission: shared injecting equipment, unsafe medical injections, transfusion of unscreened blood products, occupational needlestick injury, tattooing, body piercing.
• Mother-to-child intrauterine transmission accounts for a small minority of vertical transmissions, mostly in high-viral- load mothers.

Key populations and risk groups. People who inject drugs, men who have sex with men, sex workers, healthcare workers in high-prevalence settings, people in custodial settings, dialysis patients, migrants from high-endemic regions, sexual partners and household contacts of chronic carriers, infants born to chronically infected mothers.

Acute hepatitis B incidence has fallen substantially in countries with sustained vaccination programmes; the residual burden is concentrated in unvaccinated migrants, MSM, and PWID in low-endemicity settings.

The global elimination target (WHO 2016 strategy) is a 90 per cent reduction in incidence and 65 per cent reduction in mortality by 2030 relative to 2015, with three operational pillars: birth-dose universal vaccination, three-dose infant vaccination, and prevention of mother-to-child transmission through antenatal screening and antiviral therapy of high- viraemia mothers.

Natural history

The single most important determinant of outcome is the age of acquisition:

• Perinatal infection: around 90 per cent chronicity. The dominant route of chronic HBV acquisition in endemic settings.
• Early childhood infection (age 1 to 5): around 30 per cent chronicity.
• Adult infection: around 5 per cent chronicity; 95 per cent clear spontaneously within months.
• Fulminant hepatitis: less than 0.5 per cent of acute adult infections; mortality around 80 per cent without liver transplantation.

Chronic infection passes through up to five phases distinguished by HBeAg status, HBV DNA, and ALT:

Phase	Former name	HBsAg	HBeAg / anti-HBe	HBV DNA	ALT
1: HBeAg-positive chronic infection	Immune tolerant	+ (very high)	HBeAg+, anti-HBe–	Very high (often above 10⁸ IU/mL)	Normal
2: HBeAg-positive chronic hepatitis	Immune clearance	+	HBeAg+ transitioning to anti-HBe+	High but falling, typically above 20,000 IU/mL	Elevated, often flaring
3: HBeAg-negative chronic infection	Inactive carrier	+ (low)	HBeAg–, anti-HBe+	Below 2,000 IU/mL or undetectable	Normal
4: HBeAg-negative chronic hepatitis	Immune escape	+	HBeAg–, anti-HBe+	Fluctuating, often above 2,000 IU/mL	Elevated and fluctuating
5: HBsAg-negative phase	Resolved / occult	–	–	Undetectable in serum; cccDNA persists in liver	Normal

The phases are not strictly linear. Patients can move between them, particularly between phases 3 and 4 (driven by precore or basal core promoter mutants), and rarely from phase 5 back to active disease under immunosuppression.

Clinical presentations and complications

Acute hepatitis B

Most acute infections are subclinical. Symptomatic cases follow a typical prodromal-icteric pattern over 1 to 4 weeks: malaise, nausea, right upper quadrant discomfort, jaundice, dark urine, and pale stools. The pre-icteric serum-sickness-like prodrome with fever, arthralgia, and urticarial rash precedes the icteric phase in around 10 to 20 per cent of cases.

Around 0.5 per cent develop fulminant hepatic failure with hepatic encephalopathy, coagulopathy, and decompensation. Mortality is around 80 per cent without liver transplantation. Risk factors for fulminant evolution include older age at acquisition, co-infection with hepatitis D virus, and certain HBV genotypes.

Chronic hepatitis B

Most chronic infections are asymptomatic and identified through screening (antenatal, blood donor, pre-employment) rather than through clinical presentation. Symptoms when present are non-specific fatigue and mild abdominal discomfort. Progression to cirrhosis is typically silent until decompensation with ascites, variceal haemorrhage, or hepatic encephalopathy.

Hepatocellular carcinoma

Chronic hepatitis B is one of the most important global causes of hepatocellular carcinoma (HCC). The relative risk of HCC in HBsAg-positive individuals is 7 to 60-fold higher than in HBsAg-negative individuals, depending on cofactors.

Three mechanisms drive HBV-associated HCC:

• Chronic inflammation with repeated cycles of hepatocyte injury and regeneration, leading to dysplastic nodule formation.
• HBV DNA integration into host chromosomes (particularly X and S sequences), causing insertional mutagenesis and altered host gene expression.
• HBx transactivation of cellular promoters and interactions with p53 and other tumour suppressors.

Independent risk factors include HBV DNA above 2,000 IU/mL, elevated ALT, male sex, age, genotype C, HBeAg positivity, basal core promoter mutation, established cirrhosis, and family history of HCC. Importantly, HCC can arise in non-cirrhotic chronic HBV, particularly with genotype A1 in southern Africa.

Surveillance with six-monthly liver ultrasound and serum alpha-fetoprotein is recommended for cirrhotic patients of any age and for chronic HBV patients from the age of 30 in higher-prevalence settings. HCC risk is reduced but not eliminated by viral suppression on therapy. Surveillance is lifelong.

Extrahepatic manifestations

Covered above under Pathogenesis. The most clinically important are polyarteritis nodosa, glomerulonephritis, and Gianotti-Crosti syndrome in children.

Diagnosis

The diagnosis of HBV infection and the phase of chronic disease rest on a five-marker serological framework plus quantitative HBV DNA.

The five serological markers

• HBsAg: the marker of current infection. Persistence above 6 months defines chronic infection.
• Anti-HBs: protective antibody from vaccination or natural recovery. The 10 mIU/mL threshold defines vaccine seroprotection.
• Anti-HBc total (IgG + IgM): lifelong marker of past or current exposure. The HBV vaccine does not induce anti-HBc, which makes this marker the key discriminator between vaccine-induced and natural immunity.
• Anti-HBc IgM: marker of acute infection. Can be low-positive in severe reactivation flares of chronic disease.
• HBeAg / anti-HBe: markers of replication phase in chronic infection.

In addition, HBV DNA quantification by real-time PCR (reported in international units per millilitre) is the single most important marker for treatment decisions.

Common serological patterns

HBsAg	Anti-HBs	Anti-HBc total	Anti-HBc IgM	Interpretation
+	–	+	+	Acute infection
+	–	+	–	Chronic infection
–	+	–	–	Vaccine-induced immunity
–	+	+	–	Recovery from past natural infection
–	–	+	–	Isolated anti-HBc: resolved infection with waned anti-HBs, occult HBV, or late window
+	+	+	–	Unusual; investigate for HBsAg escape mutant
–	–	–	–	Susceptible: never exposed, never vaccinated

Emerging and tertiary markers

• Quantitative HBsAg predicts treatment response and spontaneous HBsAg loss.
• HBcrAg (hepatitis B core-related antigen) is a composite assay that correlates with intrahepatic cccDNA transcriptional activity.
• HBV RNA in serum reflects ongoing cccDNA transcription and is emerging as a marker of treatment response.
• Genotyping and resistance testing by polymerase gene sequencing are reserved for treatment failure investigation.

Management

Current therapy can suppress HBV replication but cannot eliminate the cccDNA mini-chromosome. The realistic ceiling is functional cure (sustained HBsAg loss with or without anti-HBs, off therapy), not complete cure.

Nucleos(t)ide analogues

The first-line agents target the polymerase reverse-transcriptase domain:

• Tenofovir disoproxil fumarate (TDF) 300 mg daily: potent (6 to 7 log10 reduction in HBV DNA), essentially no clinically established resistance. Renal and bone toxicity warrant monitoring on long-term therapy.
• Tenofovir alafenamide (TAF) 25 mg daily: prodrug with less systemic exposure; preferred where renal impairment, osteoporosis, or older age are concerns.
• Entecavir (ETV) 0.5 mg daily, or 1 mg if previously lamivudine-experienced: potent, with a high genetic barrier in naïve patients but compromised by prior lamivudine resistance.
• Older agents (lamivudine, telbivudine, adefovir) have high resistance rates and are no longer first-line.

Nucleos(t)ide analogue therapy is usually lifelong. Finite-course therapy is reserved for HBeAg-positive patients who seroconvert durably and for the rare patient who achieves sustained HBsAg loss. Stopping nucleos(t)ide analogues without substitution can precipitate severe HBV flares.

Pegylated interferon-α

A 48-week finite course of pegylated interferon-α 180 µg subcutaneously weekly achieves durable HBeAg seroconversion in around 30 per cent and HBsAg loss in 3 to 7 per cent. Response is best in genotype A, in HBeAg-positive disease, and in younger patients with elevated ALT. Pegylated interferon is contraindicated in decompensated cirrhosis, autoimmune disease, severe depression, and pregnancy.

The cure pipeline

Investigational agents now in trials include:

• Capsid assembly modulators (JNJ-6379, bay 41-4109).
• Small interfering RNAs and antisense oligonucleotides (JNJ-3989, VIR-2218, AB-729, bepirovirsen) that silence viral messenger RNAs and reduce HBsAg.
• Entry inhibitors (bulevirtide), licensed for chronic hepatitis delta.
• Immune modulators: TLR7 and TLR8 agonists, PD-1 checkpoint inhibitors, therapeutic vaccines.
• cccDNA-targeting agents (CRISPR / Cas9, base editors) at preclinical and early-phase stages.

The probable path to functional cure is combination therapy: an HBsAg-lowering agent (siRNA or ASO) to break the antigen decoy effect, plus an immune restorer (checkpoint inhibitor or therapeutic vaccine). Specific patient-eligibility criteria and agent choice are set at national level and vary by jurisdiction.

Prevention and public health

Vaccination

The HBV vaccine is a recombinant HBsAg protein produced in Saccharomyces cerevisiae (yeast), licensed since 1986. The standard schedule is three doses at 0, 1, and 6 months, with around 95 per cent seroprotection (anti-HBs at least 10 mIU/mL) in young adults. Response falls with increasing age, obesity, smoking, immunosuppression, diabetes, and end-stage renal disease.

The newer TLR9-agonist-adjuvanted vaccine HEPLISAV-B requires fewer doses and is more immunogenic, particularly in non-responders to the standard recombinant vaccine. It is licensed in the United States and Europe.

Universal infant vaccination is recommended by the WHO and implemented in most national EPI schedules. Birth-dose universal vaccination within 24 hours of life is the WHO recommendation for high-endemic settings; coverage varies widely.

Catch-up and risk-group vaccination is recommended for unvaccinated adults at risk: healthcare workers, people who inject drugs, men who have sex with men, dialysis and pre- dialysis patients, household and sexual contacts of chronic carriers, migrants from high-endemic regions, people in custodial settings, and the chronically immunosuppressed.

Post-exposure prophylaxis

Perinatal prophylaxis for the neonate of an HBsAg-positive mother prevents around 95 per cent of vertical transmissions:

• HBV monovalent vaccine within 24 hours of birth (ideally within 12 hours).
• HBV immunoglobulin (HBIG) intramuscularly into a separate anatomical site within 12 to 24 hours.
• Subsequent EPI vaccine doses.
• Maternal antiviral therapy (tenofovir, from the late second or early third trimester) where maternal HBV DNA exceeds approximately 200,000 IU/mL.

Caesarean section is not indicated for HBV vertical transmission prevention. Breastfeeding is not contraindicated when the mother is virally suppressed.

Occupational and sexual exposure. Needlestick, sexual, and mucosal exposure to an HBsAg-positive source require active vaccination (if non-immune) within 12 hours, plus passive immunoprophylaxis with HBIG. Documented prior vaccination with anti-HBs above 10 mIU/mL confers full protection without further intervention.

Treatment as prevention

Suppression of HBV DNA below the limit of detection on nucleos(t)ide analogue therapy substantially reduces sexual, percutaneous, and vertical transmission risk. Universal antenatal HBsAg screening followed by tenofovir for high-viraemia mothers is the operational expression of treatment-as-prevention in the perinatal setting.

Harm reduction

For people who inject drugs, harm-reduction interventions (needle and syringe programmes, opioid agonist therapy) substantially reduce HBV transmission. Vaccination of PWID is integrated into harm-reduction services in most jurisdictions.

Surveillance and notification

Chronic and acute hepatitis B are notifiable conditions in most jurisdictions worldwide. The WHO maintains the Global Health Observatory dataset of HBsAg prevalence, hepatitis-related mortality, and vaccination coverage. National HBV registries support treatment-as-prevention monitoring.

Elimination and eradication

The WHO 2016 Global Health Sector Strategy on Viral Hepatitis sets the target of 90 per cent reduction in new infections and 65 per cent reduction in mortality by 2030, with three operational pillars: birth-dose universal vaccination, three-dose infant vaccination, and prevention of mother-to- child transmission through antenatal screening and antiviral therapy. Achieving elimination requires sustained scale-up of HBsAg testing, linkage to care, and antiviral access in endemic settings.

South African context

HBV in South Africa has a distinctive profile shaped by genotype A1 dominance, the public-sector HIV burden, and recent reforms to the Expanded Programme on Immunisation.

• Prevalence: around 6.7 per cent HBsAg in the general adult population, higher in HIV-positive adults and in mining and migrant labour populations. South Africa sits within the World Health Organization’s high-endemicity classification.
• Genotype A1 accounts for around 90 to 97 per cent of HBV isolates in rural Black populations, and is the principal driver of the distinctive South African HCC phenotype: multifocal HCC with rapid doubling time, often presenting in the third or fourth decade of life and frequently in non-cirrhotic livers.
• HIV co-infection is the dominant clinical scenario for HBV management in South Africa. The standard first-line ART regimen (tenofovir plus lamivudine or emtricitabine plus dolutegravir as a single tablet) provides dual HBV and HIV cover.
• Targeted EPI birth dose: South Africa introduced a targeted HBV monovalent birth-dose vaccine in April 2020, given to infants born to mothers with acute hepatitis B at delivery, or to mothers who are HBsAg-positive or HBeAg-positive at antenatal screening. This is more limited than the WHO recommendation of a universal birth dose for all infants in high-endemic settings, which South Africa has not yet adopted. Universal first-trimester antenatal HBsAg screening (introduced in the 2019 NDoH Viral Hepatitis Guideline) identifies the eligible mother-infant pairs.
• Service delivery: tenofovir and lamivudine are available at all levels of public-sector care; entecavir, tenofovir alafenamide, and pegylated interferon are reserved for tertiary-level practice. HCC surveillance retains serum alpha-fetoprotein alongside ultrasound because of the multifocal rapid-doubling HCC pattern in genotype A1.
• Notification. Viral hepatitis is a Category 2 Notifiable Medical Condition in South Africa, reported to the Department of Health (typically via the NICD NMC App) within seven days of diagnosis.

References and recommended reading

• Wong DJ, Locarnini SA, Thompson AJV. Hepatitis B Virus. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 32. Washington: ASM Press; 2016.
• Burrell CJ, Howard CR, Murphy FA. Fenner and White’s Medical Virology, 5th edition. Academic Press / Elsevier; 2017.
• National Department of Health, South Africa. National Guidelines for the Management of Viral Hepatitis. December 2019.
• World Health Organization. Global Health Sector Strategy on Viral Hepatitis 2016 to 2021. Geneva: WHO; 2016.
• Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 2012;1:e00049.