• ~1/3 of the world's population has been infected by HBV at some point ^[4].
• ~240 million people worldwide are chronic HBsAg carriers, of which ~75% are Chinese ^[4].
• HBV is more common in Southern China compared to Northern China ^[4].
• HBV is the leading cause of cirrhosis and HCC globally, accounting for ~50% of HCC cases worldwide.

• ~1 in 13 (approximately 8%) of the Hong Kong population are chronic HBsAg carriers ^[4].
• HBV is by far the most common cause of cirrhosis in Hong Kong — WHO pooled analysis estimates 64%, but verbally estimated at ~75% by local hepatologists ^[5].
• Universal neonatal HBV vaccination was introduced in Hong Kong in 1988, which has dramatically reduced the carrier rate in younger cohorts (< 1% in those born after 1988 vs. ~10% in those born before).
• HBV-related HCC remains the 3rd leading cause of cancer mortality in Hong Kong ^[6].

HBV requires at least a mucosal breach for transmission (parenteral transmission) ^[4]:

HBV is a small (42 nm), partially double-stranded DNA virus — unique among hepatitis viruses, which are otherwise RNA viruses. The name Hepadnaviridae literally tells you: "hepa" (liver) + "DNA" (its genome type).

Key structural components:

The HBV genome is remarkably compact (~3.2 kb) with four overlapping open reading frames (ORFs):

1. Gene S (Surface) — Encodes the three envelope proteins: pre-S1, pre-S2, and HBsAg ^[10]

• HBsAg is produced in massive excess (up to 10¹³ particles/mL) — acts as a decoy for HBV-specific humoral and T-cell responses ^[8]

2. Gene C (Core) — Encodes HBcAg ^[10]

• HBcAg is found inside virus or hepatocytes, not in serum — so you cannot detect it directly ^[10]
• The pre-C region helps form HBeAg from HBcAg. The first 19 amino acids constitute a signal peptide for processing HBeAg via the ER and Golgi ^[10]

3. Gene P (Polymerase) — Encodes the viral polymerase (reverse transcriptase)

• Suppresses myeloid differentiation protein → decreases toll-like receptor (TLR) function → decreases immune clearance ^[8]

4. Gene X — Encodes the HBx protein ^[10]

• Products for transactivation — HBV DNA integrates into the host genome; HBx can activate adjacent host genes
• May be related to carcinogenesis — if it activates an oncogene ^[10]
• Inhibits degradation of viral protein → reduces antigen presentation → reduces immune clearance ^[8]

Direct Repeat I and II (DR-I and DR-II) ^[10]:

• Initiate long strand and short strand synthesis respectively
• Form a preferential site for integration into the host genome — this is why HBV can cause HCC even without cirrhosis (direct DNA integration and transactivation of oncogenes)

Understanding this explains why HBV is so hard to cure:

1. Attachment: HBV binds to hepatocyte via NTCP (sodium taurocholate co-transporting polypeptide) receptor on the hepatocyte surface (identified 2012).
2. Entry and uncoating: Virus enters by endocytosis; nucleocapsid releases relaxed circular DNA (rcDNA) into the nucleus.
3. Formation of cccDNA: rcDNA is converted to covalently closed circular DNA (cccDNA) in the nucleus — this is the "minichromosome" that serves as the transcriptional template. cccDNA is the reason we cannot truly "cure" HBV — it persists in hepatocyte nuclei even after HBsAg loss ("functional cure").
4. Transcription: cccDNA is transcribed into pregenomic RNA (pgRNA) and subgenomic mRNAs.
5. Reverse transcription: pgRNA is reverse-transcribed by the viral polymerase into new rcDNA within the nucleocapsid (this is why nucleos(t)ide analogues work — they inhibit the reverse transcriptase step).
6. Assembly and secretion: New virions are enveloped and secreted. Excess HBsAg is also secreted as non-infectious subviral particles.
7. Integration: HBV DNA can integrate into the host genome via DR-I/DR-II → this is independent of cccDNA and is the mechanism for direct carcinogenesis ^[10].

The central concept: HBV is not directly cytopathic. All liver damage is immune-mediated.

1. Innate immunity: HBV is a "stealth virus" that largely evades innate immune detection. The viral proteins (HBeAg, HBx, polymerase) actively suppress innate immune responses:

   • HBeAg down-regulates TLR-2 expression on Kupffer cells, hepatocytes, and monocytes ^[8]
   • HBeAg down-regulates CD28 on T cells and CD86 on monocytes and Kupffer cells ^[8]
   • HBx protein inhibits degradation of viral protein → reduces antigen presentation ^[8]
   • Polymerase protein suppresses myeloid differentiation protein → decreases TLR function ^[8]

2. Adaptive immunity (the real battleground):

   • CD8+ cytotoxic T lymphocytes (CTLs): Recognise viral peptides (primarily HBcAg-derived) presented on hepatocyte HLA class I → kill infected hepatocytes → this killing causes ALT/AST elevation (the "hepatitis").
   • CD4+ T helper cells: Produce cytokines (IFN-γ, TNF-α) that activate macrophages and enhance CTL activity.
   • B cells: Produce anti-HBs (neutralising), anti-HBc, anti-HBe. Anti-HBs is the protective antibody.
   • Non-cytolytic clearance: CTLs can also clear HBV from hepatocytes via IFN-γ and TNF-α without killing the cell — this degrades cccDNA and suppresses replication.

3. Chronicity results from failure of immune clearance:

   • In neonates: immature immune system + viral immune evasion strategies (see below)
   • In adults: strong immune response → usually clears virus (only 2% chronicity)

This is a favourite exam topic. Both host and viral factors contribute ^[8]:

Host factors:

• Failure of host to recognise infected hepatocytes — immature neonatal immune system
• Covering of viral antigens displayed by HLA by maternal anti-HBc — maternal antibodies mask the antigens, preventing T-cell recognition ^[4]

Viral factors (all serve to evade or suppress the immune response) ^[8]:

1. Excessive production of HBsAg → acts as a "decoy" for HBV-specific humoral and T-cell responses → immune system attacks empty viral particles instead of infected cells → modulation of immune signalling with suppression of inflammatory cytokines
2. HBx protein → inhibits degradation of viral protein → reduces antigen presentation
3. Polymerase protein → suppresses myeloid differentiation protein → decreases TLR function
4. Pre-core/HBeAg → down-regulates TLR-2 expression on Kupffer cells, hepatocytes, and monocytes; down-regulates CD28 on T cells and CD86 on monocytes and Kupffer cells

Chronic inflammation → repeated hepatocyte necrosis and regeneration → hepatic stellate cell activation → collagen deposition → fibrosis → diffuse distortion of liver architecture and formation of regenerative nodules surrounded by fibrous bands = cirrhosis ^[5].

Fibrosis staging (Metavir):

• F0: No fibrosis
• F1: Portal fibrosis without septa
• F2: Portal fibrosis with rare septa
• F3: Numerous septa without cirrhosis
• F4: Cirrhosis

HBV causes HCC via two mechanisms — this is critical and distinguishes it from HCV ^[6]:

1. Indirect (via cirrhosis): Chronic inflammation → cirrhosis → regenerative nodules → dysplastic nodules → HCC. Same pathway as any chronic liver disease.
2. Direct (via DNA integration): HBV DNA integrates into the host genome via DR-I/DR-II → insertional mutagenesis can activate oncogenes or inactivate tumour suppressors. HBx protein can transactivate adjacent host genes, potentially including growth-promoting genes ^[10][11].

How to differentiate acute HBV from acute flare of chronic HBV? Sometimes we can't definitively tell. Check HBsAg at 6 months — if HBsAg clears within 6 months, it was acute ^[7]. In adults, acute infection is far more likely to resolve. IgM anti-HBc may help (very high titre favours acute) but is not definitive.

The natural history of chronic HBV is classically divided into phases defined by the interplay between viral replication and immune response. The updated EASL 2017/AASLD 2018 nomenclature is shown alongside the traditional terminology ^[14]:

The fluctuations in Phase 2 are interesting: HBV DNA and ALT/AST CORRELATE with each other ^[12]:

• HBV DNA rises with viral replication → immune system gets more activated → more cytotoxic killing → more AST/ALT release
• More virus killed → HBV DNA falls → immune system calms down → ALT/AST fall → but then virus can replicate again
• The cycle continues until either the immune system wins (e-seroconversion) or fibrosis/cirrhosis develops

There are 10 HBV genotypes (A-J). In Hong Kong:

• Genotype B and C are most common
• Genotype C is associated with worse outcomes (delayed e-seroconversion, higher risk of cirrhosis and HCC)

Most patients with chronic HBV are asymptomatic for decades (especially during the immune tolerance and inactive carrier phases). Symptoms, when present, include:

Depend on the stage of disease:

Compensated cirrhosis (may have NO signs):

Decompensated cirrhosis:

These are immune complex-mediated or related to chronic immune stimulation:

Hepatitis episodes (acute flares) often complicate the course of chronic hepatitis B ^[12]. Causes include:

• AFP is not always a tumour marker ^[7]
• High inflammation in the liver can cause marked elevation of AFP sometimes during acute flares
• Key: see whether AFP comes down after symptoms disappear. If it keeps rising, start worrying about HCC ^[7]
• However, 20-30% of HCC is non-secreting (no AFP elevation) ^[7]
• Normal AFP: < 6 ng/mL (some labs use < 12 ng/mL)

• Liver biopsy is generally not done anymore, rarely performed due to invasiveness ^[7]
• Gold standard but has sampling error and risk of complications (bleeding, pain)
• Metavir fibrosis score: F0-F4

FibroScan (transient elastography) is the standard of care nowadays ^[7]:

Child-Pugh Score classifies cirrhosis severity ^[5]:

• Child A (5-6 points) = Compensated cirrhosis
• Child B (7-9) or C (10-15) = Decompensated cirrhosis ^[5]
• Poor survival once decompensated ^[7]

HBV vaccine is included in the CFB immunisation schedule ^[16]:

• Recombinant HBsAg vaccine (contains only HBsAg → this is why vaccinated individuals only develop anti-HBs, not anti-HBc)
• Universal neonatal vaccination in Hong Kong since 1988 ^[16]
• Schedule: 0, 1, 6 months (3 doses)
• Protective antibody: anti-HBs ≥ 10 mIU/mL ^[16]
• Non-responders (5-10%): may need booster doses or double-dose vaccine
• Duration of protection: at least 20+ years; immunological memory persists even when anti-HBs wanes below 10 mIU/mL

• Hepatitis B Immunoglobulin (HBIG) — provides immediate but temporary passive protection
• Indications:
  • Neonates born to HBsAg+ mothers — HBIG + first dose of vaccine within 12 hours of birth (prevents vertical transmission; efficacy ~90-95% when combined)
  • Post-exposure prophylaxis (needle-stick injury, sexual exposure) — within 24-48 hours
  • Post-liver transplant for HBV — to prevent graft reinfection

• All pregnant women should be screened for HBsAg
• If HBsAg+:
  • Check HBV DNA level
  • If HBV DNA > 200,000 IU/mL (or > 10⁶ copies/mL): start tenofovir in 3rd trimester (week 28-32) to reduce viral load and decrease transmission risk
  • Neonate receives HBIG + HBV vaccine within 12 hours of birth
  • Can breastfeed (HBV in breast milk is not a significant transmission risk when neonate has been vaccinated/given HBIG)

• Acute HBV in adults: 98% will clear spontaneously. Treatment is supportive (antivirals NOT required unless fulminant). You monitor and recheck HBsAg at 6 months ^[22].
• Acute flare of chronic HBV: The patient already has chronic infection. They need antiviral treatment and long-term follow-up. Flares can precipitate decompensation in cirrhotic patients.

Sometimes we simply cannot differentiate definitively ^[7]. The practical approach:

• Definition of chronic HBV = HBsAg persistence > 6 months
• If the patient doesn't die, recheck HBsAg at 6 months: if HBsAg clears → it was acute infection with clearance ^[7]
• Adults with acute hepatitis B are unlikely to become chronic carriers (2%), since the big immune reaction generally clears the virus ^[7]

AFP is not always a tumour marker ^[7]. High inflammation in the liver can also cause marked elevation of AFP during acute flares. The key difference is whether AFP comes down after symptoms disappear — if it keeps rising, start worrying about cancer ^[7]. However, 20-30% of HCC is non-secreting and will have no AFP elevation ^[7].

> 70% of HCC and cirrhosis complications occur in anti-HBe+ patients, even in patients with "normal" ALT ^[12]. This is because:

• Pre-core mutant viruses cause ongoing hepatocyte damage that may not be reflected by markedly elevated ALT
• Fibrosis/cirrhosis can progress insidiously with only mild or intermittent transaminase elevation
• ALT may be within "normal" laboratory range but still be abnormal for that individual

AST > ALT (typically 2:1 ratio) and AST rarely exceeds 500 IU/L ^[19]. If you see transaminases > 1000, alcoholic hepatitis alone is very unlikely — think viral, ischaemic, or drug-induced.

Very rapid rise and fall of transaminases (fall of ~1000 units/day) ^[19]. The ALP is typically normal. Massive LDH elevation is an ancillary clue ^[19]. This occurs in the context of haemodynamic compromise (cardiac arrest, severe heart failure, septic shock). It is NOT a primary liver disease — fixing the haemodynamics fixes the liver.

AIH is very difficult to diagnose, sometimes becomes a diagnosis of exclusion ^[7]. Autoantibodies are not specific and require diagnostic criteria ^[7]. Always exclude viral hepatitis, DILI, and alcoholic liver disease before making this diagnosis ^[22].

Wilson disease can present as acute hepatitis clinically indistinguishable from acute viral hepatitis ^[20]. The clue is the age (5-35 y/o), Coombs-negative haemolytic anaemia, and Kayser-Fleischer rings. Fulminant hepatic failure from Wilson disease characteristically occurs in young patients with unexplained liver failure and the only finding being low haemoglobin ^[21].

Diagnosis requires ^[1][25]:

• HBsAg positive — confirms current HBV infection
• Anti-HBc IgM positive (high titre) — confirms acute/recent infection
• Markedly elevated ALT and AST (typically 200–2000+ IU/L, can reach 5000) — reflects immune-mediated hepatocyte destruction
• HBsAg clearance within 6 months confirms it was indeed acute

The GC 239 Viral Hepatitis lecture slide lists the investigation panel for acute viral hepatitis ^[1]:

HBsAg, Anti-HAV IgM, Anti-HCV, Anti-HEV IgM, ANA/anti-smooth muscle/anti-LKM-1, Ultrasound, Toxicology screen if appropriate

The logic of this panel: you send all viral serologies simultaneously because the clinical presentation of acute hepatitis is identical regardless of the virus — you cannot tell which virus is responsible from symptoms alone ^[3][9].

Definition: HBsAg positive for ≥ 6 months ^[3][25]

Further classification requires ^[3][25]:

• HBeAg and anti-HBe status — determines the natural history phase
• HBV DNA level — the most important marker for treatment decisions; directly quantifies viral replication
• ALT level — reflects degree of liver inflammation
• Liver fibrosis assessment — FibroScan or (rarely) biopsy

• HBsAg negative but anti-HBc total positive (± anti-HBs)
• HBV DNA detectable (in serum or liver tissue) — the diagnostic requirement ^[25][7]
• Clinical importance: can reactivate under immunosuppression; can transmit through liver transplantation ^[25]

• HBsAg negative, anti-HBs negative, anti-HBc IgM positive — the only positive marker during the window period ^[3]
• This occurs in the gap between HBsAg clearance and anti-HBs appearance
• If you only check HBsAg, you will miss the diagnosis

The GI/Hepatology Investigations lecture (GC) teaches that LFTs assess three distinct aspects ^[19][29]:

Key interpretations specific to HBV:

• ALT >> AST in primary liver pathology (most hepatitis). 4 liver pathologies where AST > ALT: alcoholic hepatitis, HCC, congestive heart failure, ischaemic hepatitis ^[19]
• In acute hepatitis, ALT typically 200-2000 IU/L ^[3], sometimes up to 5000
• INR is the best index for monitoring progress and prognosis in acute hepatitis ^[9]. Why? Because Factor VII has the shortest half-life (~6 hours) — it drops first when synthetic function fails and recovers first when function improves
• Falling ALT + improving INR = recovery. Falling ALT + worsening INR = fulminant hepatitis (catastrophic loss of hepatocytes → not enough cells to release ALT, but not enough cells to synthesise clotting factors either) ^[9]
• Bilirubin may remain elevated long after clinical and histological recovery — the cholestatic phase — so it is less helpful for monitoring acute progress ^[9]
• Albumin is usually normal in acute hepatitis (long half-life) but low in cirrhosis (chronic synthetic failure)
• AST/ALT do NOT reflect severity of cirrhosis ^[28] — a cirrhotic patient can have normal transaminases

• Measured by real-time PCR (quantitative)
• Reported in IU/mL (1 IU ≈ 5 copies)
• The GC 239 case shows HBV DNA > 10⁸ IU/mL ^[1]; the DI lecture shows HBV DNA > 640 million copies/mL ^[26] — both indicating extremely high viral loads
• Clinical thresholds:
  • Immune tolerance: typically > 10⁷–10⁸ IU/mL
  • Threshold for treatment consideration: > 2000 IU/mL (HBeAg−) or > 20,000 IU/mL (HBeAg+) with elevated ALT (varies by guideline)
  • Undetectable = successful viral suppression on treatment
• Very high HBV DNA titer → prone to develop cirrhosis and HCC ^[11]

HCC surveillance protocol ^[27]:

• USG + AFP every 6 months
• Mass ≥ 1 cm: triphasic CT
• Mass < 1 cm: repeat USG at 4 months
• Rationale: tumour doubling time of HCC ~140 days; if missed at initial scan (< 1 cm), will be ≤ 2 cm 6 months later and still operable ^[27]

From the approach framework ^[3]:

Initial management monitoring ^[3]:

• DAT (diet as tolerated), Obs Q4h, H'stix BD
• Bloods: CBC, LRFT, INR, NH₃ daily

This framework from the Maksim Medicine Notes ^[27] is a clean way to remember what to monitor and why:

Target patients for HCC surveillance ^[27][13]:

• Asian HBV carriers: male > 40 y/o; female > 50 y/o
• Any HBV carrier with cirrhosis
• Family history of HCC
• Not all patients benefit: e.g., Child C cirrhosis unless transplant candidate, limited life expectancy ^[27]

When a chronic HBV patient is being considered for antiviral therapy, additional baseline investigations include ^[28]:

1. Bloods: CBC, LRFT, INR, ammonia, glucose, amylase
2. Viral serology panel (all at once): HBsAg, anti-HAV IgM, anti-HCV, anti-HEV IgM ^[1]
3. Autoimmune screen: ANA, anti-smooth muscle, anti-LKM-1 ^[1]
4. Toxicology: Paracetamol level if appropriate ^[1]
5. Imaging: USG abdomen (to exclude biliary obstruction) ^[1]
6. If HBsAg positive: Add HBeAg, anti-HBc IgM/IgG, HBV DNA ^[1]
7. Monitor: CBC, LRFT, INR, NH₃ daily; H'stix BD ^[3]
8. At 6 months: Recheck HBsAg to determine if acute vs. chronic ^[7]

1. Viral activity: HBV DNA, HBeAg/anti-HBe (Q6-12 months)
2. Liver inflammation: LFT (Q6-12 months; Q3 months if active)
3. Fibrosis staging: FibroScan (baseline + follow-up)
4. HCC surveillance: USG + AFP Q6 months (if meets criteria)
5. Complications screen: OGD for varices if cirrhosis; renal function if on tenofovir

Acute hepatitis B is largely self-limited — most patients do NOT require antiviral treatment ^[3][31]:

• Full recovery is the most common outcome ^[3]
• Chronic HBV develops in ~10% overall (90% for neonates, 2% for adults) ^[3]
• Acute liver failure in ~1% ^[3]

No specific treatment is needed for uncomplicated acute hepatitis B ^[9]:

Antivirals are NOT required in most cases, EXCEPT ^[31]:

• Drug of choice: entecavir ^[3][30]
• IFN should be avoided in acute hepatitis — increased risk of hepatic necroinflammation (IFN augments immune killing of infected hepatocytes, which in the acute setting worsens liver damage) ^[31]
• Stop treatment after confirmed HBsAg clearance by 2 consecutive tests 4 weeks apart ^[31]

If acute HBV progresses to fulminant hepatic failure ^[32][4]:

Five principles ^[32]:

1. Supportive → standard ICU care
2. Identify and remove/treat the insult — antivirals (entecavir) for HBV
3. Manage complications (encephalopathy, coagulopathy, renal failure, sepsis, raised ICP)
4. High-volume plasma exchange — washes away cytokines causing liver failure; expensive but proven ^[32]
5. Liver transplantation — the final line after exhausting all other treatments ^[32]

Every chronic HBV carrier should receive comprehensive education ^[27]:

This is the most clinically important and exam-relevant topic. The key principle: treat when there is both active viral replication AND active liver disease — this corresponds to the immune clearance (or immune escape) phase, not the immune tolerance phase ^[30][4].

HK Hospital Authority / Internal Medicine Handbook indications for oral antiviral therapy ^[33]:

1. ALT > ULN AND HBV DNA ≥ 2000 IU/mL (if HBeAg-positive, may consider observing 3-6 months for spontaneous e-seroconversion)

2. Significant fibrosis or cirrhosis with detectable HBV DNA

3. Hepatitis B infection with decompensated liver disease

4. HCC with detectable HBV DNA

5. Pre-emptive treatment before certain chemotherapy or immunosuppressive therapy

6. Hepatitis B reactivation during chemotherapy

7. Pregnant women with HBV DNA > 200,000 IU/mL (start at 3rd trimester and continue for up to 12 weeks after delivery) — use TDF

8. Transplant patient with hepatitis B infection

EASL 2017 guidelines (least restrictive — ensures more patients treated) ^[30]:

• All patients regardless of HBeAg status with: ALT > ULN + HBV DNA > 2000 IU/mL + moderate necroinflammation/fibrosis

HBeAg status is crucial for determining whether treatment can be finite or lifelong ^[7]:

Current endpoints for stopping treatment ^[31]:

• Loss of HBsAg (ideal, rarely achieved)
• HBeAg seroconversion (for HBeAg+ patients → continue 12 more months then consider stopping)
• Undetectable HBV DNA by PCR
• Normalisation of ALT < 0.5 ULN

For immune-tolerant patients, management is monitoring ^[4]:

• ALT Q6 months
• HBsAg Q1 year
• HBeAg/anti-HBe Q6-12 months
• Consider treatment if evidence of progression to active disease (↑ ALT, biopsy showing activity)
• HCC screening: USG ± AFP Q6 months (even in immune tolerance, HCC can develop from DNA integration)

These are the mainstay of current treatment. The name tells you the mechanism: they are analogues (mimics) of nucleosides/nucleotides — the building blocks of DNA. They competitively inhibit the HBV polymerase (reverse transcriptase), blocking viral DNA synthesis.

The HA Handbook lists three first-line options ^[33]:

Dose adjustments are needed in patients with renal dysfunction ^[33]

Older/inferior NUCs (important for context but NOT first-line):

Interferons work by a completely different mechanism: they don't directly kill the virus but instead boost the immune system's ability to clear infected hepatocytes and have direct antiviral effects (degrade viral mRNA, inhibit viral protein synthesis).

Advantages of IFN ^[31]:

• No resistant mutation (immune-mediated, not targeting viral polymerase)
• Finite period of treatment (partly related to side effects — you can't tolerate it indefinitely)
• More HBsAg seroconversion (higher chance of "functional cure")
• More HBeAg seroconversion

Disadvantages of IFN ^[31]:

• Moderate side effects (see below)
• Detectable HBV DNA by PCR despite HBeAg seroconversion (doesn't suppress virus as completely as NUCs)
• Unable to decrease incidence of liver cirrhosis (paradoxically, because it increases immune-mediated hepatocyte killing)
• Hepatotoxicity in cirrhosis (augmented immune attack on a liver already damaged)

Contraindications of IFN ^[31]:

• Pregnancy
• Children
• Liver cirrhosis / decompensated liver disease (risk of precipitating hepatic decompensation by enhanced immune killing)

Side Effects of IFN ^[31]:

This is a critical clinical scenario and exam favourite ^[30]:

Screening before immunosuppression ^[30]:

• Check HBsAg, anti-HBs, anti-HBc for ALL patients planned for immunosuppressive therapy
• If HBsAg positive OR anti-HBc positive → check baseline HBV DNA + LFT
• For anti-CD20 (rituximab) / anti-CD52: if ANY HBV marker positive → check baseline HBV DNA + LFT ^[30]

Management of HBsAg+ patients requiring immunosuppression ^[30]:

• Start prophylactic antiviral therapy irrespective of baseline HBV DNA levels
• Superior and safer than monitoring for reactivation and treating when it occurs ^[30]
• Choice of agent: entecavir or TDF/TAF (low resistance profiles) ^[30]
• Duration:
  • Baseline HBV DNA < 2000 IU/mL: continue for 6 months after completion of immunosuppressive therapy (12 months if anti-CD20) ^[30]
  • Baseline HBV DNA > 2000 IU/mL: continue with long-term antiviral therapy ^[30]

For occult HBV (HBsAg−, anti-HBc+) ^[30]:

• Same principle — if in doubt, just start prophylactic antivirals. They are cheap drugs with not a lot of side effects ^[30]

From GC 239 lecture and HA Handbook ^[1][33]:

• All pregnant women: screen for HBsAg
• If HBV DNA > 200,000 IU/mL: start TDF in 3rd trimester, continue up to 12 weeks after delivery ^[33]
• Neonate: HBV vaccine + HBIG within 12 hours of birth
• Post-vaccination serologic testing: test baby for HBsAg and anti-HBs after completing 3-dose vaccination ^[1]
• Breastfeeding is safe if neonate has received vaccine + HBIG

For HBV carriers undergoing liver transplant ^[34]:

• Antivirals × 2 months before transplant + long-term HBIG after transplant to prevent graft reinfection ^[34]

Common in HK (dual liver disease) ^[13]:

• Weight loss of 5-7% sufficient to reduce liver fat in non-fibrosis patients; 10% in fibrosis patients ^[13]
• GLP-1 receptor agonists: emerging evidence for MAFLD, on top of DM and obesity ^[13]
• Coffee: beneficial for fatty liver ^[13]
• Treat HBV and MAFLD concurrently

• Occurs in ~0.1-0.5% of acute HBV infections ^[4]
• Represents massive immune-mediated hepatocyte destruction outstripping the liver's regenerative capacity
• Defined by the development of hepatic encephalopathy within 8 weeks of onset of symptoms in a patient without pre-existing chronic liver disease
• Falling ALT with rising INR is the ominous sign — not enough hepatocytes left to release enzymes, and not enough to synthesise clotting factors ^[9]

Pathophysiology:

• Overwhelming cytotoxic T-cell attack on HBV-infected hepatocytes → massive necrosis → loss of all hepatic functions simultaneously (synthetic, metabolic, excretory, detoxification)
• Complications: cerebral oedema (failure to clear ammonia), coagulopathy (failure to synthesise factors), hypoglycaemia (failure of gluconeogenesis), infection (loss of reticuloendothelial function), renal failure (hepatorenal physiology)

Definition: acute liver insult manifesting as jaundice and INR > 1.5, complicating within 4 weeks by ascites and/or encephalopathy in patients with underlying chronic liver disease ^[35][4].

HBV-related ACLF is the most common cause in HK and the Asia-Pacific region (but is decreasing because the diagnostic rate of chronic HBV is increasing — fewer patients are going unnoticed) ^[35].

Causes of ACLF in HBV carriers ^[35]:

• Severe exacerbation of undiagnosed HBV
• Immunosuppressive agents (steroids, rituximab) — upon withdrawal
• Superimposed HAV/HEV
• Other systemic infections (pneumonia, UTI, soft tissue)
• Hepatotoxic drugs/herbs, alcoholic hepatitis

Prognosis of ACLF — assessed by 6 organ-specific factors ^[35]:

All 3 components of the MELD score (bilirubin, INR, creatinine) are present in the ACLF prognostic criteria — so the MELD score is still useful for prognosticating ACLF ^[35]. 28-day mortality > 20% ^[35].

Repeated flares are a major driver of disease progression. Cirrhosis occurs more frequently in ^[36]:

• Older age — more time for cumulative damage
• Hepatic decompensation during follow-up
• Repeated severe acute exacerbations characterised by:
  • AFP > 100 ng/mL (AFP is produced by regenerating liver cells, not just tumours — so elevated AFP reflects regenerative nodule formation, a hallmark of cirrhosis) ^[36]
  • Bridging necrosis — severe injury where necrosis extends zonally from one lobule to another (portal-portal, central-central, or portal-central) linking vasculature between lobules ^[36]
  • Unsuccessful HBeAg seroconversion — multiple immune attacks without clearance ^[36]
  • HBV reactivation with HBeAg seroreversion ^[36]

• Annual incidence of cirrhosis: 2.4% for HBeAg+ patients, 1.3% for anti-HBe+ patients ^[12]
• For chronic HBsAg carriers, 25% die of liver diseases (50% for males, 14% for females) ^[4]
• > 70% of HCC and cirrhosis complications occur in anti-HBe+ patients, even in patients with "normal" ALT ^[12] — this seems paradoxical but is explained by:
  • The anti-HBe phase spans decades (much longer than the HBeAg+ phase)
  • Pre-core mutant viruses continue causing damage without HBeAg production
  • Cumulative fibrosis from prior immune clearance phase takes time to manifest clinically

Chronic immune-mediated hepatocyte destruction → hepatic stellate cell activation → collagen deposition → fibrosis → diffuse distortion of liver architecture with formation of regenerative nodules surrounded by fibrous bands = cirrhosis ^[5]. The fibrotic bands distort the hepatic vasculature, creating resistance to portal blood flow → portal hypertension → all downstream complications.

Probably — more and more evidence suggesting yes, to some extent ^[5]:

• Can go from F4 to F0 if removing the underlying cause
• HBV cirrhosis: majority is reversible but not all; requires long-term nucleoside-analogue therapy ^[5]
• Depends on aetiology and severity: Child A/B can benefit in reducing complications and hospitalisations; Child C has less impact ^[5]

• Most common primary liver cancer (80%) ^[6][24]
• 80% of HCC in Hong Kong are HBsAg positive ^[24]
• M:F = 4:1; most in age > 50 years but can occur in young patients ^[24]
• 80% associated with liver cirrhosis in HK ^[24]
• 3rd leading cause of cancer mortality in Hong Kong ^[6]

The "80% tumour" mnemonic for HCC ^[6]:

80% of primary liver cancer; 80% due to HBV; 80% associated with liver cirrhosis; 80% treated non-surgically; 80% recur even with surgical resection

Two mechanisms (covered in Part 1, briefly recapped):

1. Indirect (cirrhosis pathway): Chronic inflammation → cirrhosis → regenerative/dysplastic nodules → HCC
2. Direct (DNA integration pathway): HBV DNA integrates via DR-I/DR-II → insertional mutagenesis → oncogene activation (HBx transactivation). This is why HBV can cause HCC without cirrhosis ^[13]

From the complications lecture ^[31]:

Late presentation + absence of pathognomonic symptoms → difficult diagnosis ^[24][6]:

Four reasons for poor prognosis ^[31]:

1. Present in the late stage — asymptomatic when tumour < 8 cm; no nerve fibres in the liver ^[31]
2. Majority have underlying liver cirrhosis which limits scope for resection — 80% in HBV, 100% in HCV/alcohol ^[31]
3. Early venous permeation (HBV is a vascular tumour with high propensity for venous invasion of portal and hepatic veins) → early metastasis and portal vein thrombosis ^[24]
4. Field cancerisation effect — the whole liver is exposed to oncogenic influence of HBV/HCV or cirrhosis → multiple small tumours at sites not yet identified ^[31]

Surveillance should be performed at intervals of 6 months ^[31]:

• 6-month interval based on expected growth rates of HCC (doubling time ~3-4 months) ^[31]
• USG has higher sensitivity than AFP ^[31]
• USG + AFP Q6 months; ≥ 1 cm → triphasic CT; < 1 cm → repeat USG at 4 months ^[27]

• Shortens duration of HBsAg antigenaemia and increases rate of HBsAg seroconversion
• Reduces peak serum aminotransferase and HBV DNA levels
• But increases risk of severe hepatitis, HCC, and fulminant hepatic failure ^[31]
• Treatment of HCV with DAAs may cause increased HBV replication and flare → fulminant liver failure ^[31]
  • Must either give HBV antivirals together with DAAs for HCV, or monitor HBV DNA closely ^[31]

• HDV are ALWAYS dually infected with HBV (HDV needs HBsAg for its envelope)
• Increases risk of more severe liver disease, cirrhosis, and fulminant hepatic failure ^[31]
• Very rare in Chinese ^[12]; more common in Mediterranean, Middle East, and IVDU populations

This has been discussed in management but is also a major complication category. The two highest-risk drugs ^[30]:

• Anti-CD20 (rituximab) — profound B-cell depletion → loss of immune surveillance → HBV replicates from cccDNA → immune reconstitution upon drug cessation → massive immune flare → fulminant hepatic failure ^[30]
  • Reactivation can occur over 11 months after the last cycle of rituximab — because profound depletion of B cells takes 1 year to recover, and once they recover, these B cells prime T cells, which then damage the liver ^[30]
  • Can be FATAL — Prof CL Lai's first case: 78-year-old lady treated with rituximab for lymphoma, recovered from lymphoma but died from fulminant liver failure 11 months after stopping rituximab ^[30]
• Anti-CD52 (alemtuzumab) — used in B-CLL and as 3rd line in relapsing-remitting MS in HA ^[30]

• Lamivudine: highest resistance (up to 70% at 5 years) — emergence of YMDD mutants
• Entecavir: very low resistance (1.2% at 5 years in NUC-naïve); higher if prior lamivudine resistance
• TDF/TAF: no resistance reported to date
• Resistance manifests as virological breakthrough (> 1 log rise in HBV DNA from nadir) followed by biochemical breakthrough (ALT rise)