Hepatitis B virus — Questions

Likely cause. The picture is hepatitis B virus (HBV) reactivation precipitated by withdrawal of antiretroviral therapy (ART). South African first-line regimens (tenofovir plus lamivudine or emtricitabine, with efavirenz or dolutegravir) all contain two HBV-active agents, so ART was incidentally suppressing an undiagnosed or known HBV co-infection. Defaulting removed that suppression, HBV replication rebounded over years, and the eventual immune-mediated flare produced the raised ALT and jaundice.

Expected serology. HBsAg positive and anti-HBc total positive (lifelong exposure marker), with anti-HBc IgM low-positive possible in a severe flare. HBeAg may be positive or negative depending on phase, anti-HBe positive if HBeAg-negative, and HBV DNA very high, often above 10^7 IU/mL, with ALT typically above 5 times the upper limit of normal.

Management.

• Assess severity: full liver profile, HBV DNA, HBeAg/anti-HBe, HIV viral load and CD4, screen other hepatitides, and look for decompensation (encephalopathy, ascites, coagulopathy).
• Restart ART with a confirmed HBV-active backbone (tenofovir plus lamivudine or emtricitabine, plus dolutegravir). Both HBV-active agents must be continued indefinitely, and retained in any future regimen change, because stopping either reactivates HBV.
• Monitor closely: ALT, bilirubin and INR weekly initially, HBV DNA at baseline, week 4 and week 12, watching for an immune reconstitution flare as recovering immunity attacks infected hepatocytes.
• HCC surveillance six-monthly with AFP and ultrasound, and counsel that stopping ART again may be life-threatening; test and vaccinate contacts.

Phase. This is phase 4: HBeAg-negative chronic hepatitis (immune escape): historical HBeAg seroconversion followed by reactivated replication despite continuing anti-HBe positivity.

Supporting findings.

• Prior HBeAg seroconversion (HBeAg-positive two years ago, now anti-HBe positive), which should have delivered immune control.
• HBV DNA 8,500 IU/mL, above the 2,000 IU/mL phase 3 threshold, and rising over time (5,200 to 8,500), whereas phase 3 is a stable low steady state.
• Rising ALT from 28 to 62 U/L (above the male upper limit of 35 U/L), indicating active necroinflammation, where phase 3 has persistently normal ALT.

The underlying driver is usually a precore (G1896A) or basal core promoter (A1762T + G1764A) mutant abolishing HBeAg expression while allowing replication.

Remaining markers. Anti-HBc total positive (lifelong after natural infection, regardless of phase), and anti-HBc IgM negative or only low-positive (it marks acute infection; low-positive can appear in severe flares but is unusual here).

Phase 4 with this HBV DNA and ALT meets NDoH 2019 treatment criteria: start tenofovir or entecavir, usually lifelong, with continued six-monthly HCC surveillance.

(a) HBsAg+, anti-HBc total+, HBeAg+, anti-HBe-, HBV DNA 35,000 IU/mL. HBeAg-positive chronic HBV infection, either phase 1 (immune tolerant) or phase 2 (immune clearance); ALT and fibrosis distinguish them but are not given. Request ALT, APRI or FibroScan, HIV/HCV/HDV, AFP and ultrasound. Management: if phase 1 (normal ALT, no fibrosis, under 30), monitor 3 to 6 monthly. If phase 2 (raised ALT or significant fibrosis), treat with tenofovir or entecavir, since the viral load exceeds the 20,000 IU/mL threshold for HBeAg-positive disease.

(b) HBsAg-, anti-HBs+, anti-HBc total-. Vaccine-induced immunity: the recombinant vaccine contains only HBsAg, so anti-HBc is negative (it is positive after natural infection). No action required; confirm anti-HBs is at least 10 mIU/mL for documented protection.

(c) HBsAg+, anti-HBs+, anti-HBc total+, HBeAg-, anti-HBe+, HBV DNA 6,100 IU/mL, ALT 31 U/L. The simultaneous HBsAg and anti-HBs is unusual; the likeliest explanation is an HBsAg escape mutant (“a”-determinant, notably G145R) circulating while anti-HBs binds the wild-type epitope, with genotype reinfection or heterologous immunity as alternatives. The HBeAg-negative, anti-HBe-positive pattern with detectable HBV DNA and normal ALT fits phase 3 or early phase 4. Management: sequence the S gene and request quantitative HBsAg, confirm on a different assay platform, assess fibrosis, and repeat HBV DNA and ALT in 3 to 6 months; treat if HBV DNA exceeds 2,000 IU/mL with persistently raised ALT or at least F2 fibrosis.

Co-infection is simultaneous acquisition of two viruses in a single exposure, seen most often in people who inject drugs. Superinfection is acquisition of a second virus in someone already chronically infected with the first; the dominant disease driver and the management depend on which virus is established and which is new.

Hepatitis C virus (HCV) suppresses hepatitis B virus (HBV) replication through core-protein-mediated downregulation of HBV transcription. In HBV/HCV co-infection one virus is usually clinically dominant, often with HBV suppressed. In HCV superinfection of chronic HBV, HCV drives the disease, HBV DNA often falls below detection while HBsAg persists, and fibrosis and HCC risk accelerate.

Treatment implications:

• Treat HCV with direct-acting antivirals (sofosbuvir-velpatasvir or glecaprevir-pibrentasvir), as in monoinfection.
• HBV reactivation after HCV cure is a recognised risk: clearing HCV lifts its suppression of HBV, so HBV DNA can rebound with severe flares.
• Screen every HCV-treated patient for HBsAg and anti-HBc. HBsAg-positive patients receive prophylactic tenofovir or entecavir from the start of direct-acting antiviral therapy and for 12 months after cure; anti-HBc-positive, HBsAg-negative patients have HBV DNA and ALT monitored during and after treatment.

Hepatitis B core-related antigen (HBcrAg) is a composite immunoassay marker measuring three overlapping hepatitis B virus (HBV) proteins together: HBeAg, HBcAg and the precore p22cr protein. Its clinical value is that it is the only widely available serum marker correlating with intrahepatic cccDNA transcriptional activity, giving a non-invasive surrogate for the persistence reservoir that would otherwise require liver biopsy.

Its main applications:

• Phasing chronic infection: highest in HBeAg-positive phases and falling progressively to the lowest levels in occult HBV, and identifying HBeAg-negative chronic hepatitis driven by precore or basal core promoter mutants (high HBV DNA and HBcrAg despite HBeAg-negativity).
• Predicting spontaneous HBeAg seroconversion, which falling HBcrAg often precedes by months.
• Predicting safe nucleos(t)ide analogue discontinuation: low end-of-treatment HBcrAg is associated with lower relapse.
• Predicting HCC risk independently of HBV DNA, with levels above ~4 log U/mL carrying higher long-term risk even when HBV DNA is suppressed.

Limitations are cost and availability (not in routine South African public-sector use or the NDoH 2019 guideline), and poor discrimination at very low cccDNA activity. HBcrAg therefore sits in the tertiary-care toolkit alongside quantitative HBsAg and HBV RNA, refining decisions on starting, stopping and HCC surveillance rather than screening.

A reflex algorithm after an HBsAg-positive result must answer three questions: acute or chronic, which phase, and does the patient meet treatment criteria. The NDoH 2019 Viral Hepatitis Guideline sets out a tiered approach.

• Acute versus chronic: anti-HBc IgM (positive in acute, negative in chronic), with anti-HBc total to confirm exposure and exclude a false-positive HBsAg. IgM-positive acute disease enters an acute pathway with serial ALT and bilirubin monitoring.
• Phase the chronic infection: HBeAg and anti-HBe for HBeAg-positive versus HBeAg-negative phases, and HBV DNA quantification, the single most important marker for phase and treatment decisions (thresholds ~2,000 and ~20,000 IU/mL), with sex-specific ALT limits.
• Assess liver disease: full liver profile, platelets, and non-invasive fibrosis by APRI (AST to platelet ratio index) and FIB-4, the South Africa-preferred tests where FibroScan is unavailable; AFP and ultrasound for HCC surveillance.
• Screen co-infections: HIV, hepatitis C and hepatitis D, plus anti-HAV IgG to guide hepatitis A vaccination.
• Determine treatment eligibility: treat for cirrhosis or APRI above 2 (any DNA), HBeAg-positive disease with HBV DNA above 20,000 IU/mL and raised ALT or significant fibrosis, HBeAg-negative disease with HBV DNA above 2,000 IU/mL and raised ALT, HIV co-infection, pregnancy with HBV DNA above 200,000 IU/mL, or planned immunosuppression.

In resource-limited settings the highest-yield reflex is HBV DNA quantification (batched every 3 to 6 months for stable patients), HBeAg/anti-HBe can be once-per-patient after documented seroconversion, and APRI and FIB-4 add no reagent cost. The algorithm sorts patients into treat now, monitor, or investigate further (typically a HBV DNA/ALT discrepancy suggesting precore or basal core promoter mutants).

The immune control phase (formerly “inactive carrier state”) is phase 3 of the AASLD/EASL five-phase classification: HBeAg-negative chronic infection with low replication and minimal liver injury. The expected markers:

Marker	Expected result	Significance
HBsAg	Positive, typically low quantitative level	Ongoing infection, not yet cleared
Anti-HBs	Negative	Cannot coexist with HBsAg in classical infection
Anti-HBc IgM	Negative	Not acute or recently reactivated
Anti-HBc total	Positive	Lifelong marker of past exposure
HBeAg	Negative	Seroconverted away from HBeAg
Anti-HBe	Positive	Confirms the historical seroconversion
HBV DNA	Below 2,000 IU/mL or undetectable	The defining laboratory criterion

ALT is also persistently normal, and histology shows minimal necroinflammation and fibrosis. Clinically this phase carries no immediate treatment indication (exceptions: cirrhosis at any DNA level, HIV co-infection, family history of HCC, or planned immunosuppression), but it is not benign: around 10% progress to HBeAg-negative chronic hepatitis (phase 4) over a decade, so serial HBV DNA and ALT monitoring continues, alongside six-monthly HCC surveillance from age 30. Sustained HBV DNA above 2,000 IU/mL with raised ALT signals progression and the need for treatment.

The defensible recommendation is the hepatitis B virus (HBV) birth dose, which South Africa subsequently adopted into the EPI in April 2020. The case rests on prioritising by disease burden, intervention efficacy, cost-effectiveness and the programmatic gap.

Disease burden favours HBV. HBV prevalence is ~6.7% in the general population and higher in HIV, and genotype A1 confers a roughly four-fold HCC risk in young Black men with early onset; hepatocellular carcinoma is a leading cancer death in this group. Vertical transmission is the principal route of chronic acquisition, with ~90% of perinatally infected infants becoming chronic and a quarter to 40% dying of cirrhosis or HCC. By contrast, primary varicella is largely self-limiting in healthy children, with severe disease concentrated in the immunocompromised.

The birth dose closes a window no other intervention covers. HBV is acquired at delivery and chronicity established within days, so the first hexavalent dose at 6 weeks is too late; only a dose within 24 hours interrupts it. A VZV programme would largely substitute for natural exposure most children already encounter.

Cost-effectiveness strongly favours HBV. The monovalent dose costs ~USD 0.20 and prevents decades of life lost, against ~USD 50 for VZV vaccine preventing a self-limiting illness. It is co-administrable with BCG and OPV already given at birth, minimising added cost.

International endorsement and a real gap. The WHO has recommended a universal birth dose since 2009, and Taiwan’s universal infant programme cut childhood HBsAg prevalence from 9.3% to 0.5% with sharp falls in childhood HCC. Until 2020 South Africa had no systematic perinatal HBV prevention, so the birth dose plus universal antenatal screening closes the major gap.

VZV vaccine would take priority only where HBV burden was low and already controlled, a universal birth dose was in place, and childhood varicella morbidity was high enough to justify a two-dose live-vaccine programme.

A complete answer makes the case for inclusion and situates it against current South African policy. The question framing pre-dates the April 2020 introduction of the monovalent birth dose, so it is best answered as the case for inclusion followed by the policy now in place.

The case for a birth dose

Mother-to-child transmission is the dominant route of chronic hepatitis B virus (HBV) acquisition in high-endemic settings. Without prophylaxis, vertical transmission runs at 70 to 90% from HBeAg-positive mothers and 10 to 40% from HBeAg-negative mothers, varying with maternal viral load. Around 90% of perinatally infected infants progress to chronic infection through HBeAg-induced immune tolerance, and a quarter to 40% of these die from cirrhosis or hepatocellular carcinoma (HCC) in adulthood.

HBV is acquired at delivery, and chronicity is established within days. The pre-2020 South African schedule gave its first dose at 6 weeks, far too late, and the vaccine takes 2 to 6 weeks to raise anti-HBs. Only a birth dose within 24 hours interrupts this window, preventing 85 to 90% of perinatal transmission, rising to ~95% with adjunctive hepatitis B immunoglobulin (HBIG) in HBeAg-positive infections.

The local burden justifies the intervention: HBsAg prevalence is ~6.7% in the general adult population and higher in HIV co-infection, and genotype A1 confers a roughly four-fold higher HCC risk in young Black men, presenting a decade or two earlier than in non-endemic settings.

Feasibility and cost

The monovalent vaccine costs ~USD 0.20 per dose, trivial against the lifetime cost of chronic hepatitis B, and can be co-administered with BCG and oral polio vaccine already given at birth. The WHO has recommended a universal birth dose since 2009 for any country with HBsAg prevalence above 2%, which South Africa exceeds. Universal dosing is cheaper and simpler than a targeted strategy, which would need universal antenatal screening with results available at delivery.

Current South African policy

Universal antenatal HBsAg screening entered the NDoH 2019 Viral Hepatitis Guideline, and a targeted monovalent birth dose entered the EPI in April 2020, given within 24 hours to infants of mothers who are HBsAg-positive or HBeAg-positive at screening. HBIG is reserved for infants of HBeAg-positive mothers on cost grounds, and maternal tenofovir is added from 28 to 32 weeks if HBV DNA exceeds 200,000 IU/mL. The remaining work is implementation: closing coverage gaps, returning antenatal screening results in time for delivery, and expanding HBIG supply.

Extrahepatic manifestations occur in around 20% of chronic hepatitis B virus (HBV) infection and arise predominantly from circulating immune complexes deposited in vascular beds, with a secondary contribution from cytokine-mediated injury. HBsAg-rich complexes lodge in vessel walls, glomeruli and serosa, activating complement and driving vasculitic damage.

Vasculitic and rheumatological

A serum-sickness-like prodrome of fever, arthralgia, urticaria and lymphadenopathy occurs in 10 to 20% during the late incubation or early acute phase, resolving as jaundice appears. HBV is the most important infectious cause of polyarteritis nodosa (PAN), a medium-vessel necrotising vasculitis presenting with abdominal pain, hypertension, mononeuritis multiplex and constitutional symptoms; treatment combines an HBV antiviral with plasma exchange and short corticosteroids, avoiding prolonged immunosuppression. A symmetric non-erosive arthritis, often part of the prodrome, may persist into the icteric phase.

Renal

Membranous nephropathy (children and young adults) presents with nephrotic syndrome and often remits spontaneously in children. Membranoproliferative glomerulonephritis (adults), frequently with cryoglobulinaemia, presents with proteinuria, haematuria and renal impairment. Biopsy shows viral antigens co-localised with IgG and C3. Management is antiviral plus supportive care, with immunosuppression generally avoided.

Other

Mixed (essential) cryoglobulinaemia (HBV accounts for ~5% of cases; HCV is commoner) presents with palpable purpura, arthralgia and neuropathy. Papular acrodermatitis of childhood (Gianotti-Crosti syndrome) is the prototypical acute-HBV skin eruption in children aged 1 to 6, self-limiting over weeks. Aplastic anaemia is a rare, probably immune-mediated complication weeks to months after acute HBV, with high mortality.

Approach

Any patient with new vasculitis, glomerulonephritis or atypical arthritis warrants HBV serology (HBsAg, anti-HBs, anti-HBc, HBV DNA) before immunosuppression, because immunosuppressing presumed primary autoimmune disease can precipitate severe HBV reactivation. Antiviral suppression with tenofovir or entecavir is the cornerstone and usually resolves the syndrome; plasma exchange and cautious, antiviral-covered immunosuppression are reserved for severe vasculitis or cryoglobulinaemia.

Both scenarios combine active and passive measures, but the neonatal aim is to interrupt vertical transmission before chronic infection is established, and the transplant aim is to prevent reactivation under profound immunosuppression.

(a) Neonate born to an HBsAg-positive mother

Without prophylaxis, transmission from HBeAg-positive mothers approaches 90% and over 90% of infected infants become chronic; combined active and passive prophylaxis prevents ~95% of cases.

• Antenatal (NDoH 2019): universal first-trimester HBsAg screening; if positive, quantitative HBV DNA, HBeAg and ALT. Maternal tenofovir from 28 to 32 weeks if HBV DNA exceeds 200,000 IU/mL, continued to 12 weeks postpartum if the only indication is transmission prevention.
• At birth: monovalent HBV birth-dose vaccine within 24 hours (10 micrograms intramuscular), co-administered with BCG and OPV, plus HBIG within 12 to 24 hours only if the mother is HBeAg-positive (the cost-rationed South African policy). EPI doses follow at 6, 10 and 14 weeks.
• Delivery and feeding: caesarean section is not indicated and breastfeeding is not contraindicated in a suppressed mother.
• Follow-up: post-vaccination serology (HBsAg and anti-HBs) at 9 to 18 months; anti-HBs of 10 mIU/mL or more confirms protection.

(b) HBsAg-positive patient before haematopoietic stem cell transplant (HSCT)

HSCT combines conditioning, prolonged neutropenia and graft-versus-host immunosuppression, and essentially all HBsAg-positive patients reactivate without prophylaxis, with high mortality.

• Pre-transplant: HBsAg and anti-HBc total (the latter to detect occult HBV, which still needs prophylaxis); if HBsAg-positive add HBV DNA, HBeAg/anti-HBe, fibrosis and HCC screening, with parallel HCV and HIV testing.
• Prophylaxis: entecavir or tenofovir (high genetic barrier), started before conditioning with HBV DNA ideally undetectable, and continued for at least 12 months after immunosuppression ends, often indefinitely given late-reactivation risk. Lamivudine is acceptable only for short courses at low baseline HBV DNA.
• Monitoring: HBV DNA and ALT every 1 to 3 months on treatment, and monthly for 3 months after stopping, watching for a severe late flare.

The G1896A pre-core stop codon mutation is a single nucleotide change (TGG to TAG) creating a premature stop codon at codon 28 of the pre-core open reading frame. The pre-core protein is normally processed into secreted HBeAg, so the mutation abolishes HBeAg expression while leaving replication intact.

Its stability is genotype-dependent because position 1896 base-pairs with position 1858 in the epsilon stem-loop needed for pregenomic RNA encapsidation. In genotypes B, D and E (thymidine at 1858) the G1896A change strengthens the stem-loop and is selected; in genotype A (cytosine at 1858) it destabilises the stem-loop and is selected against. This is why precore-mutant chronic hepatitis is common in the Mediterranean, East Asia and sub-Saharan Africa but rare in genotype-A infection.

Functional significance: the patient appears HBeAg-negative on routine serology despite active replication, so the classical inverse correlation between HBeAg and viral load no longer holds. Loss of the HBeAg tolerogenic effect permits more aggressive immune-mediated injury, fluctuating ALT and higher HCC risk than wild-type at the same viral load, and spontaneous HBeAg seroconversion is no longer a meaningful endpoint, so patients usually need lifelong nucleos(t)ide analogue therapy.

Expected profile:

Marker	Expected result
HBsAg	Positive
Anti-HBs	Negative
Anti-HBc total	Positive
Anti-HBc IgM	Negative (low-positive possible in flares)
HBeAg	Negative (mutation abolishes expression)
Anti-HBe	Positive (historical seroconversion)
HBV DNA	Detectable, often above 2,000 IU/mL
ALT	Elevated, often fluctuating

The basal core promoter mutation (A1762T + G1764A) produces the same HBeAg-negative phenotype through reduced transcription rather than a stop codon, and the two can co-exist; sequencing confirms the profile where available. Treat with tenofovir or entecavir, lifelong, with six-monthly HCC surveillance.

Hepatitis B virus (HBV) is the prototype of the Hepadnaviridae (Baltimore class VII), unusual in using reverse transcription despite being a DNA virus and in maintaining a persistent nuclear mini-chromosome that current treatment cannot eliminate.

Replication cycle and drug targets

Attachment and entry. Low-affinity binding to heparan sulfate proteoglycans is followed by high-affinity binding of the myristoylated preS1 region to NTCP (sodium taurocholate co-transporting polypeptide), encoded by SLC10A1, delivering the nucleocapsid by endocytosis. Target: bulevirtide, a preS1-derived peptide that blocks NTCP (licensed for hepatitis delta; limited in HBV monoinfection).

cccDNA formation. The relaxed-circular DNA (rcDNA) is repaired into covalently closed circular DNA (cccDNA), which assembles with histones into a mini-chromosome that is the persistence reservoir. Target: cccDNA itself, by CRISPR/Cas9, base editors or epigenetic silencing, all investigational.

Transcription. Host RNA polymerase II transcribes cccDNA into the 3.5 kb pregenomic RNA (pgRNA) and the surface, core, polymerase and HBx messages. Targets: small interfering RNA (siRNA) and antisense oligonucleotides (JNJ-3989, VIR-2218, bepirovirsen) degrade HBV transcripts, lowering HBsAg.

Encapsidation and reverse transcription. pgRNA and polymerase are packaged into nucleocapsids nucleated at the epsilon signal, and polymerase reverse-transcribes pgRNA into rcDNA. Targets: nucleos(t)ide analogues (NUCs) (tenofovir, entecavir) inhibit the polymerase reverse-transcriptase; capsid assembly modulators block encapsidation.

Assembly, egress and integration. Mature nucleocapsids either recycle to the nucleus to amplify cccDNA or are enveloped and secreted as Dane particles alongside vast excess subviral HBsAg, using the ESCRT pathway. HBV DNA integration (X and S sequences) is a replication side-product that continues HBsAg production and contributes to HCC.

Effect on viral markers

Agent class	HBV DNA	HBeAg	HBsAg	cccDNA
Nucleos(t)ide analogues	Rapid 6 to 7 log10 fall, usually undetectable by 48 weeks	Seroconversion ~21 to 32% at 5 years	Slow, HBsAg loss ~1% per year	No direct effect, persists
Pegylated interferon-alpha	Suppressed on therapy, durable response ~30%	Durable seroconversion ~32%	HBsAg loss 3 to 7% (highest genotype A)	Some transcriptional silencing and reduction

Novel agents: capsid assembly modulators lower HBV DNA but not HBsAg; siRNA and ASO reduce HBsAg by 1 to 2 log10, breaking the decoy; immune modulators (TLR7/8 agonists, PD-1 inhibitors, therapeutic vaccines) restore exhausted T cells; cccDNA-targeting tools alone could achieve complete cure.

Endpoints

Sustained virological response (HBV DNA undetectable), HBeAg seroconversion (allowing finite therapy in HBeAg-positive disease), functional cure (sustained HBsAg loss, the realistic ceiling) and complete cure (cccDNA eradication, not achievable). The self-replenishing cccDNA mini-chromosome is the principal barrier to cure, compounded by integrated HBsAg output and T cell exhaustion, which is why the pipeline combines direct-acting and immune-restorative strategies.

A complete answer explains why current treatment suppresses but does not cure hepatitis B virus (HBV), then maps the cure pipeline onto the specific viral and immune barriers.

Three levels of cure are recognised: sustained virological response (HBV DNA undetectable on therapy, achievable now but not curative), functional cure (sustained HBsAg loss off therapy, the realistic target, reached in 3 to 7% on pegylated interferon-alpha and ~1% per year on tenofovir), and complete cure (cccDNA eradication, not achievable with any current agent).

Viral factors

The covalently closed circular DNA (cccDNA) mini-chromosome is the central barrier: a stable nuclear form that is the template for all viral transcripts, self-replenishing through nucleocapsid recycling, and untargeted by any licensed drug. Integrated HBV DNA cannot replicate but continues producing HBsAg and HBx indefinitely, so even a perfect cccDNA-clearing agent may leave residual HBsAg. Massive HBsAg over-production as subviral particles floods the circulation at 1,000 to 10,000 times the concentration of complete virions, acting as a decoy that exhausts HBV-specific B and T cells. Genotype heterogeneity (ten genotypes, A to J) and precore/basal core promoter mutants further modify antigen expression and immune visibility.

Immunological factors

Chronic antigen exposure drives HBV-specific T cell exhaustion, with upregulation of the inhibitory receptors PD-1, TIM-3, LAG-3 and CTLA-4 and loss of effector function, so the response cannot clear infection even under pharmacological suppression. Soluble HBeAg acts as a tolerogen, crossing the placenta to induce neonatal tolerance and dampening T cell costimulation. HBV also achieves innate immune evasion, with HBx and polymerase inhibiting the MAVS, IRF3/7 and STAT1 signalling that would drive type I interferon, earning it a “stealth virus” reputation. Regulatory T cell expansion, myeloid-derived suppressor cells and NK cell dysfunction reinforce the immunosuppressive intrahepatic environment.

The cure pipeline

The likely route to functional cure is combination therapy: an HBsAg-lowering agent (small interfering RNA or antisense oligonucleotide, such as bepirovirsen, VIR-2218 or JNJ-3989) to break the decoy effect, paired with an immune restorer (PD-1 checkpoint inhibitor, TLR7/8 agonist or therapeutic vaccine) to let the host clear residual cccDNA-expressing hepatocytes. Capsid assembly modulators and entry inhibitors (bulevirtide) reduce cccDNA replenishment, while direct cccDNA-targeting tools (CRISPR/Cas9, base editors) remain investigational and are the only strategies that could achieve complete cure.

Each reflex should earn its cost by changing a decision. The five listed vary from essential to near-useless.

• Anti-HBs: drop. HBsAg and anti-HBs cannot coexist in typical infection, and the only exception (S-gene escape mutants such as G145R) is diagnosed by HBV DNA and sequencing, not anti-HBs. It is a useful reflex when HBsAg is negative (immunity versus susceptibility), but not when HBsAg is positive.
• Anti-HBc total: keep. It confirms genuine exposure, excludes a false-positive HBsAg, and is a required baseline before HCV direct-acting antivirals, rituximab or chemotherapy. Inexpensive and useful.
• Anti-HBc IgM: keep. It separates acute (positive) from chronic (negative) infection and flags severe flares, changing the monitoring and treatment pathway.
• HBeAg and anti-HBe: keep, but once per patient. Essential for phasing and treatment, but once HBeAg-negative, anti-HBe-positive seroconversion is documented, repeating adds little unless an unexpected HBV DNA rise or ALT flare prompts reassessment. A once-per-patient strategy saves substantial cost in follow-up.

Two gaps should be closed. HBV DNA quantification, the single most important treatment-decision marker, is absent and should be added as a reflex whenever HBsAg is positive in a treatment-evaluation setting. APRI (AST to platelet ratio index) and FIB-4 should be auto-reported, since both are calculated free from the full blood count and liver profile already requested and inform the treat-or-not decision under NDoH 2019.

The net effect is broadly cost-neutral: dropping anti-HBs and reducing repeat HBeAg/anti-HBe frequency offsets adding HBV DNA, while sharply improving information yield and alignment with the guideline’s treatment criteria.

Occult hepatitis B infection (OBI) is the persistence of HBV DNA in liver (and sometimes serum, usually below 200 IU/mL) despite an undetectable HBsAg by standard assays (Taormina 2008 consensus). It is seropositive (~80%, anti-HBc and/or anti-HBs detectable, resolved infection with cccDNA persistence) or seronegative (~20%, HBV DNA only).

Mechanisms

Three routes produce OBI: true low-level chronic infection where a small cccDNA pool supports HBsAg output below the assay threshold (the commonest); S-gene escape mutants (notably G145R in the “a” determinant) that replicate actively but evade the detection epitope, important in transfusion medicine; and co-infection-mediated suppression by HCV or HIV, with HBV rebound when the co-infection is treated.

Clinical importance

• HCC risk persists, probably through integrated HBV DNA and HBx, with HBV sequences found in 50 to 70% of HBsAg-negative HCC in endemic regions.
• Transfusion transmission drove the adoption of HBV nucleic acid testing (NAT) alongside HBsAg screening, including in South Africa.
• Anti-HBc-positive donor organs (especially livers) transmit HBV, so recipients receive lifelong antiviral cover.
• Immunosuppression-driven reactivation is the key pitfall: rituximab, allogeneic haematopoietic stem cell transplant (HSCT) and other profound immunosuppression can reactivate OBI with severe, sometimes fatal hepatitis, occurring months after treatment ends.

Management (NDoH 2019)

Screen anti-HBc total alongside HBsAg and anti-HBs before high-risk immunosuppression. Treat detectable HBV DNA as HBsAg-positive disease with tenofovir or entecavir. Where HBV DNA is undetectable but anti-HBc positive, give prophylactic NUC before rituximab or allogeneic HSCT and for at least 12 months afterwards, with HBV DNA and ALT monitoring; anti-HBc-positive HSCT recipients always receive prophylaxis because late-reactivation risk is too high to leave unguarded.

HBeAg positive, very high HBV DNA (10^9 IU/mL) and normal ALT identify phase 1: HBeAg-positive chronic infection (immune tolerant). This is typical of adults infected vertically, in whom placental HBeAg induced neonatal tolerance, allowing decades of high replication without immune-mediated injury.

Phase	HBeAg	HBV DNA	ALT
1 immune tolerant	+	Very high	Normal
2 immune clearance	+	High, falling	Elevated
3 immune control	-	Below 2,000	Normal
4 immune escape	-	Fluctuating, often above 2,000	Elevated
5 occult	- (HBsAg-)	Undetectable in serum	Normal

Phase 2 (B) would show elevated ALT; phases 3 and 4 (C, D) require HBeAg negativity; phase 5 (E) requires HBsAg negativity. Phase 1 patients are generally not treated in South Africa, except adults over 30 with HBV DNA above 1,000,000 IU/mL plus significant fibrosis; six-monthly HCC surveillance still applies.

Anti-HBs below 10 mIU/mL defines a non-responder, and the first step is a single booster dose with a recheck; if it stays below 10 mIU/mL, give a complete second three-dose series. A single booster rescues 25 to 50% of initial non-responders, so it is tried before committing to a full second course. Always check HBsAg first to exclude undiagnosed chronic infection as the reason for apparent non-response.

Documenting protection (A) is wrong because 4 mIU/mL is below threshold. A single sub-threshold titre does not define a permanent non-responder (C). There is no live-attenuated HBV vaccine (D); all are recombinant subunit. The 80 microgram single dose (E) is not a standard schedule; the correct next step is a 20 microgram booster then a full re-course if needed. Haemodialysis patients are the exception, receiving 40 microgram doses with annual anti-HBs testing.

The basal core promoter (BCP) double mutation A1762T + G1764A cuts pre-core mRNA transcription more than pregenomic RNA, so the patient is HBeAg-negative yet still replicates. The result is HBeAg-negative chronic hepatitis B (phase 4): HBsAg-positive, HBeAg-negative, anti-HBe positive, HBV DNA often above the 2,000 IU/mL treatment threshold, and fluctuating ALT with increased HCC risk. The classical inverse correlation between HBeAg status and viral load no longer holds.

Option A is phase 1 (HBeAg-positive, high DNA, normal ALT). B is vaccine-induced immunity. C is resolved past infection. D is an internally inconsistent HBeAg-positive but undetectable-DNA combination. Manage as phase 4: tenofovir or entecavir, usually lifelong, with six-monthly HCC surveillance; the precore G1896A mutation produces the same phenotype through a different mechanism and the two can co-exist.

Antiretroviral therapy must contain two agents active against hepatitis B virus (HBV): tenofovir plus lamivudine or emtricitabine, with a third agent such as dolutegravir (the South African first-line single-tablet regimen). Combination cover guards against HBV resistance, and the critical caveat is that the HBV-active backbone must be maintained even if the HIV regimen changes, because stopping either agent reactivates HBV with severe flares.

Adding HBV cover separately (A) risks leaving HBV unaddressed if the regimen lacks it. Lamivudine monotherapy (C) develops rapid HBV resistance and is inadequate for HIV. Abacavir (D) has no HBV activity. Delaying ART (E) is harmful, since HBV does not clear. If tenofovir is contraindicated, switch to tenofovir alafenamide or add entecavir alongside an HIV-active regimen, and monitor ALT for an immune reconstitution flare when starting at low CD4.

The guideline covers three overlapping groups with six-monthly alpha-fetoprotein (AFP) plus abdominal ultrasound: all cirrhotic patients at any age, all chronic HBV patients from age 30, and any patient with a family history of HCC. The age-30 inclusion of non-cirrhotic patients is a South Africa-specific feature reflecting early HCC in genotype A1, and AFP is retained alongside ultrasound because of the multifocal, rapidly doubling HCC pattern.

Option A over-includes by dropping the age-30 threshold for non-cirrhotics. B and D use an incorrect age-50 threshold and the wrong modality (CT, or AFP alone). E is wrong because surveillance is explicitly recommended. Surveillance continues lifelong, including on suppressive therapy, since viral suppression reduces but does not eliminate HCC risk.

Quantify HBV DNA at booking, then start maternal tenofovir disoproxil fumarate (TDF) at 28 to 32 weeks if HBV DNA exceeds 200,000 IU/mL. That threshold identifies women whose neonatal transmission risk remains significant despite HBIG and birth-dose vaccine, and the last-trimester benefit reduces residual transmission to under 2%. Women already on a tenofovir-containing antiretroviral regimen continue unchanged.

Starting TDF at 14 weeks (B) adds drug exposure without extra benefit, since the transmission-reduction effect comes from the third trimester. Awaiting delivery (C) leaves the residual 5 to 10% transmission from high-viraemia mothers unaddressed. Caesarean section (D) is not indicated to prevent HBV vertical transmission, and breastfeeding (E) is not contraindicated in a suppressed mother; transmission through milk is negligible.

Two consecutive QC values beyond 2 SD on the same side of the mean violate the 2-2s rule, indicating systematic error: reject the run and investigate. A consistent one-directional displacement points to a shift rather than random scatter, and the timing immediately after a lot change is the classic signal of an unrecognised lot shift.

Rule	Pattern	Error
1-2s	One value beyond 2 SD	Warning
1-3s	One value beyond 3 SD	Random
2-2s	Two consecutive beyond 2 SD, same side	Systematic
R-4s	Two consecutive spanning 4 SD, opposite sides	Random
10-x	Ten consecutive same side	Systematic trend

A single 2 SD excursion (A) is only a warning; neither value reaches 3 SD (B); R-4s (D) requires opposite sides; 10-x (E) requires ten values. The action is to reject the run, re-establish the QC mean and SD for the new lot from at least 20 in-control measurements, recalibrate, and re-run affected samples.

HBsAg negative, anti-HBs positive, anti-HBc total negative is the signature of vaccine-induced immunity. The recombinant vaccine contains only HBsAg, so it raises anti-HBs but cannot induce anti-HBc; natural recovery always produces both.

HBsAg	Anti-HBs	Anti-HBc total	Interpretation
Negative	Negative	Negative	Susceptible
Negative	Positive	Negative	Vaccine-induced immunity
Negative	Positive	Positive	Immunity from past infection
Positive	Negative	Positive (IgM+)	Acute infection
Positive	Negative	Positive (IgM-)	Chronic infection

Susceptibility (A) is excluded by the positive anti-HBs. Past infection (B) would need anti-HBc positive. The window period (D) would need HBsAg and anti-HBc IgM positive. An escape mutant (E) would need HBsAg with anti-HBs and anti-HBc coexisting. Confirm protection with an anti-HBs titre of at least 10 mIU/mL.

The covalently closed circular DNA (cccDNA) mini-chromosome is the cure barrier. Formed when host enzymes repair the incoming relaxed-circular DNA, it is the template for all viral transcripts, self-replenishing through nucleocapsid recycling, untargeted by any licensed agent, and persists for the lifespan of the long-lived hepatocyte. This is why the realistic ceiling is functional cure (sustained HBsAg loss) rather than complete cure (cccDNA eradication), and why investigational tools (CRISPR/Cas9, base editors, capsid assembly modulators, siRNA plus immune modulators) are built around depleting or silencing it.

The polymerase does mutate (A), but that drives resistance, not the cure barrier. The envelope (C) is an antibody target, not a cure obstacle. Tenofovir (D) has essentially no established resistance after a decade of use. Integration (E) contributes HBsAg and HCC risk but is a replication side-product; cccDNA persistence is the principal barrier.

South Africa is dominated by genotype A, mainly subgenotype A1, which accounts for ~90 to 97% of isolates in rural Black populations. Its significance is a roughly four-fold higher hepatocellular carcinoma (HCC) risk in young Black men compared with non-A genotypes, with a younger onset (third to fourth decade) and HCC often arising without cirrhosis. This is why NDoH 2019 surveillance extends to non-cirrhotic chronic HBV from age 30 and retains alpha-fetoprotein alongside ultrasound. Genotype A also responds better to pegylated interferon than genotype D.

Genotype B (A) and C (B) predominate in East Asia, not South Africa. Genotype E (C) dominates West Africa. Genotype D (E) is Mediterranean and only a minor urban contributor locally.

The high-affinity entry receptor is sodium taurocholate co-transporting polypeptide (NTCP, encoded by SLC10A1), a hepatocyte bile-acid transporter engaged by the myristoylated preS1 region. Low-affinity heparan sulfate proteoglycan binding tethers the virion first, but NTCP confers the species- and tissue-specificity. Bulevirtide (Hepcludex) is a preS1-derived lipopeptide that blocks NTCP; it is licensed for chronic hepatitis delta, with a limited role in HBV monoinfection because it does not clear established cccDNA.

CD4 (A) is the HIV receptor; ACE2 (B) is SARS-CoV-2; the asialoglycoprotein receptor (C) is not the principal entry receptor and sofosbuvir is an HCV drug; heparan sulfate proteoglycan (E) mediates only initial tethering, and tenofovir targets the polymerase, not entry.

Lamivudine resistance is mediated by mutations in the YMDD motif: M204V or M204I, often stabilised by L180M. This is the prototype nucleoside-analogue resistance pattern, reaching ~70 to 80% by five years and making lamivudine unsuitable as first-line monotherapy.

Adefovir resistance (B) is N236T (D domain) and A181T/V, not M204V. Entecavir (C) needs the lamivudine backbone (M204V/I) plus an entecavir-specific mutation, so N236T alone is wrong and naive resistance is very rare. Tenofovir (D) has no clinically established resistance, and M250V is an entecavir mutation. Telbivudine (E) selects M204I (cross-resistant with lamivudine), not T184G. First-line for chronic HBV is tenofovir or entecavir, and tenofovir remains fully active against lamivudine-resistant mutants.

The 45-year-old man (E) has HBeAg-negative chronic hepatitis with HBV DNA above the 2,000 IU/mL threshold, sustained ALT elevation, and APRI 1.4 indicating significant fibrosis, so treatment is indicated. He meets two independent NDoH 2019 criteria (the HBeAg-negative pattern and fibrosis evidence); start tenofovir or entecavir.

Patient A is phase 1 (immune tolerant): high DNA but normal ALT, no fibrosis, under 30, so the immune-tolerant threshold is not met, monitor. Patient B has coexisting HBsAg and anti-HBs with undetectable DNA and no active disease, investigate rather than treat. Patients C and D have no active HBV infection (isolated anti-HBc, and vaccine-induced immunity respectively). Treatment is also indicated regardless of these thresholds for cirrhosis or APRI above 2, HIV co-infection, pregnancy with HBV DNA above 200,000 IU/mL, and planned immunosuppression.