What is hepatitis B, its transmission, diagnosis, treatment, and prevention?

Hepatitis B: Comprehensive Lecture

What is Hepatitis B?

Hepatitis B is a DNA virus from the Hepadnaviridae family that infects over 350 million people worldwide, causing chronic liver disease, cirrhosis, and hepatocellular carcinoma, with an estimated 500,000-700,000 deaths annually. 1, 2

• HBV is a small, partially double-stranded DNA virus with a 3.2 kb genome that replicates through an RNA intermediate, similar to retroviruses 2, 3
• The virus can integrate into the host genome, conferring a distinct ability to persist in infected cells 3
• HBV is concentrated most highly in blood and is approximately 100 times more infectious than HIV and 10 times more infectious than HCV 1
• The virus remains infectious on environmental surfaces for at least 7 days 1

Transmission Routes

HBV is transmitted through percutaneous, mucosal, or nonintact skin exposure to infectious blood or body fluids, with perinatal transmission being the highest risk route (90% chronicity rate). 1

Primary Transmission Routes:

• Perinatal transmission: 80-90% of infants infected at birth develop chronic infection 1
• Sexual transmission: Efficient transmission occurs among heterosexuals and men who have sex with men (MSM) 1
• Percutaneous exposure: Injection drug use and needlestick injuries 1
• Horizontal transmission: 30% of children infected before age 6 develop chronic infection 1

Infectious Body Fluids:

• Blood (highest concentration), semen, vaginal secretions 1
• Saliva, tears, bile, cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, amniotic fluid 1
• Urine, feces, vomitus, sputum, and sweat are NOT efficient transmission vehicles unless they contain blood 1
• Breast milk contains HBsAg but is unlikely to transmit infection; breastfeeding is NOT contraindicated 1

Diagnosis and Serologic Markers

Diagnosis requires HBsAg testing to confirm current infection, with additional serologic markers (anti-HBs, anti-HBc IgM/IgG, HBeAg, anti-HBe) and HBV DNA quantification to classify disease phase and guide treatment. 1, 4, 5

Key Serologic Markers:

Marker	Interpretation
HBsAg positive	Current infection (acute or chronic); if persists >6 months = chronic [1,4]
Anti-HBs positive	Immunity from vaccination or resolved infection [1,6]
IgM anti-HBc positive	Acute infection [1]
IgG anti-HBc positive	Past or chronic infection [1]
HBeAg positive	High viral replication and infectivity [1]
Anti-HBe positive	Lower viral replication (but reversion can occur) [1]
HBV DNA	Measure of viral load and replication [1,4]

Diagnostic Algorithm:

1. Screen with HBsAg and anti-HBs to determine infection status and immunity 4
2. If HBsAg positive: Check HBeAg, anti-HBe, HBV DNA, and ALT to classify disease phase 1, 4
3. If HBsAg negative but anti-HBc positive: Check anti-HBs to distinguish resolved infection (anti-HBs positive) from occult infection (anti-HBs negative, may have detectable HBV DNA) 6
4. Assess liver fibrosis using non-invasive tests (transient elastography) or biopsy 4

Who Should Be Screened:

• All persons born in endemic regions (Asia, Africa, Pacific Islands) 4
• HIV-infected individuals, dialysis patients, healthcare workers 4
• Pregnant women (universal screening) 1
• Injection drug users and MSM 1
• Household and sexual contacts of HBsAg-positive persons 1

Natural History and Disease Phases

Chronic HBV infection progresses through four non-linear phases: immune tolerant, immune active, immune inactive, and reactivation, with 25% of chronically infected persons dying prematurely from cirrhosis or hepatocellular carcinoma. 1

Four Phases of Chronic HBV:

1. Immune Tolerant Phase (HBeAg-positive chronic infection):

   • High HBV DNA (>20,000 IU/mL), normal ALT, positive HBeAg 1, 4
   • Minimal hepatic inflammation or fibrosis 1
   • Most chronically infected children remain in this phase until late childhood/adolescence 1

2. Immune Active Phase (HBeAg-positive or HBeAg-negative chronic hepatitis):

   • Active immune response with hepatic inflammation ± fibrosis 1
   • Prolonged immune active phase = high risk for cirrhosis and HCC 1

3. Immune Inactive Phase (Inactive carrier):

   • Improvement of hepatic inflammation and fibrosis 1
   • Lower HCC risk compared to active phase 1

4. Reactivation Phase:

   • Active liver inflammation ± fibrosis 1
   • Can occur with immunosuppressive therapy or HCV treatment 1

Risk Factors for Disease Progression:

• Age at infection (younger = higher chronicity risk) 1, 7
• Male sex, older age, HBV genotype 1, 7
• Coinfection with HIV, HCV, or HDV 1, 7
• Elevated ALT, alcohol use (>25-30 mL/day), tobacco use 1, 7
• Family history of HCC or cirrhosis 4, 7

Treatment Indications

All patients with cirrhosis and any detectable HBV DNA must be treated immediately, regardless of ALT levels; non-cirrhotic patients require treatment when HBV DNA ≥2,000 IU/mL with elevated ALT or evidence of at least moderate fibrosis. 4, 6

Immediate Treatment Required:

• Decompensated cirrhosis with any detectable HBV DNA 4, 6
• Compensated cirrhosis with HBV DNA >2,000 IU/mL, regardless of ALT 4, 6
• Life-threatening disease (acute liver failure, severe acute hepatitis with coagulopathy) 4, 6
• HBV DNA ≥20,000 IU/mL AND ALT ≥2× ULN (no biopsy needed) 4, 6

Treatment Considerations for Non-Cirrhotic Patients:

• HBV DNA ≥2,000 IU/mL with elevated ALT (>40 IU/L) and at least moderate necroinflammation/fibrosis on biopsy 4, 6
• HBV DNA ≥2,000 IU/mL with normal ALT if at least moderate fibrosis demonstrated (liver stiffness ≥9 kPa with normal ALT or ≥12 kPa with ALT <5× ULN) 4, 6
• HBeAg-positive patients >30-40 years with persistently normal ALT and high HBV DNA may be treated regardless of histology 4, 6

Special Populations Requiring Treatment:

• Pregnant women with HBV DNA >200,000 IU/mL: Start tenofovir DF at 24-32 weeks gestation to prevent perinatal transmission 1, 4, 6
• Immunosuppressive therapy recipients (rituximab, anthracyclines, high-dose steroids): Start prophylaxis 2-4 weeks before therapy 6
• Healthcare workers with HBV DNA ≥2,000 IU/mL performing exposure-prone procedures 4

Treatment Options

First-line treatment consists of nucleos(t)ide analogues with high genetic barriers to resistance: entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF), with long-term potentially indefinite therapy required in most patients. 1, 4, 6

First-Line Agents:

Agent	Dosing	Key Features	Resistance
Entecavir	0.5 mg daily	High potency, high barrier to resistance	<1% at 5 years [4]
Tenofovir DF (TDF)	300 mg daily	High potency, preferred in pregnancy	No resistance at 8 years [4]
Tenofovir AF (TAF)	25 mg daily	Less renal/bone toxicity than TDF	High barrier to resistance [4]

Avoid First-Generation NAs:

• Lamivudine: High resistance rates (up to 70% at 5 years) 1, 6
• Not recommended due to low potency and high resistance 4

Pegylated Interferon Alfa:

• Finite-duration therapy (48 weeks) for selected patients with mild-to-moderate disease 4, 6
• Higher rates of HBeAg and HBsAg loss compared to NAs, especially in genotype A 1
• Absolutely contraindicated in decompensated cirrhosis and pregnancy 4, 6
• Limited by side effects and variable response 4

Treatment Efficacy:

• Viral suppression: 96.7% achieve undetectable HBV DNA with tenofovir at 2 years 1
• HBeAg seroconversion: 27.3% at 10 years with tenofovir 1
• HBsAg loss (functional cure): 3.4-4.9% at 10 years with tenofovir 1
• Cirrhosis regression: 74% of cirrhotic patients show regression after 5 years of tenofovir 4

Treatment Monitoring

Monitor HBV DNA every 3 months until undetectable, then every 6 months; check liver enzymes every 3-6 months; and perform annual quantitative HBsAg testing to assess for functional cure. 4, 6

Monitoring Protocol During Treatment:

• HBV DNA: Every 3 months until undetectable, then every 6 months 4, 6
• ALT/AST: Every 3-6 months 4, 6
• Quantitative HBsAg: Annually to assess for HBsAg loss 6
• Renal function: If on tenofovir (especially TDF) 6
• Bone mineral density: Consider if on TDF with risk factors 4

Monitoring for Patients NOT on Treatment:

• ALT: At least every 3 months 4
• HBV DNA: Every 6-12 months 4
• Fibrosis assessment: Every 12 months using non-invasive tests 4

Treatment Response Definitions:

• Virological response: Undetectable HBV DNA by sensitive PCR assay 4
• Biochemical response: Normalization of ALT levels 4
• Sustained off-therapy response: HBV DNA <2,000 IU/mL for ≥12 months after stopping therapy 4

Treatment Duration and Stopping Criteria

Long-term, potentially indefinite treatment is typically required with nucleos(t)ide analogues, with HBsAg loss being the optimal endpoint but rarely achieved; stopping therapy may be considered in HBeAg-positive patients who achieve HBeAg seroconversion with ≥12 months consolidation therapy. 1, 4, 6

Mandatory Lifelong Treatment:

• All patients with decompensated cirrhosis 4
• Compensated cirrhosis (stopping therapy risks decompensation) 4
• Liver transplant recipients 4

Potential Stopping Criteria (Non-Cirrhotic Patients):

• HBeAg-positive patients: HBeAg seroconversion + undetectable HBV DNA + ≥12 months consolidation therapy 4, 6
• Optimal endpoint: HBsAg loss (functional cure), but rarely achieved (3-5% at 10 years) 1, 4
• Close monitoring required after stopping: Most patients experience viral relapse 1

Hepatocellular Carcinoma Surveillance

Ultrasound examination every 6 months is mandatory for all cirrhotic patients and high-risk individuals (Asian men >40 years, Asian women >50 years, family history of HCC), even during effective antiviral therapy. 4, 6

High-Risk Groups Requiring HCC Surveillance:

• All patients with cirrhosis (regardless of treatment status) 4, 6
• Asian men >40 years 4, 6
• Asian women >50 years 4, 6
• Family history of HCC 4, 6
• Age >40 years with persistent ALT elevation 6
• Moderate-to-high HCC risk scores 4

Surveillance Protocol:

• Ultrasound every 6 months 4, 6
• Alpha-fetoprotein (AFP) measurement at baseline and periodically 1
• Early detection allows for potentially curative interventions (ablation, resection, transplant) 1

Important Caveat:

• Antiviral therapy reduces but does NOT eliminate HCC risk 1, 7
• HBV replication is an independent predictor of HCC, along with male sex, older age, genotype, coinfections, elevated ALT, alcohol, and tobacco 4

Prevention Strategies

Universal hepatitis B vaccination for all infants within 24 hours of birth, combined with postexposure prophylaxis (HepB vaccine + HBIG) for infants born to HBsAg-positive mothers, achieves 90-95% prevention efficacy. 1, 8

Vaccination Strategy:

• Universal infant vaccination within 24 hours of birth 1
• 3-dose series for complete protection 1
• 90-95% effective in preventing chronic infection 1
• Vaccine coverage: 85% worldwide (2019), up from 30% in 2000 1, 8

Postexposure Prophylaxis for Infants:

• HepB vaccine + HBIG within 12 hours of birth for infants born to HBsAg-positive mothers 1
• Reduces infection rate to 0.7-1.1% (from 30-85% without prophylaxis) 1
• Post-vaccination testing at 9-18 months to confirm protection 4
• Infants born to mothers with HBV DNA >200,000 IU/mL remain at highest risk despite prophylaxis 1

Maternal Antiviral Therapy:

• Tenofovir DF starting at 24-32 weeks gestation for pregnant women with HBV DNA >200,000 IU/mL 1, 4
• Further reduces perinatal transmission beyond vaccine + HBIG 1

Postexposure Prophylaxis for Adults:

• Vaccine series initiated within 12-24 hours: 70-90% effective 1
• Vaccine + HBIG for known nonresponders or high-risk exposures 1
• HBIG alone within 7 days for percutaneous exposure in nonresponders 1
• Sexual exposure: HBIG within 2 weeks for exposure to acute hepatitis B 1

Additional Preventive Measures:

• Hepatitis A vaccination for all HBV-infected patients (coinfection increases mortality 5.6-29 fold) 1, 6
• Alcohol abstinence counseling (>25-30 mL/day worsens liver disease) 1, 6
• Screen for coinfections: HIV, HCV, HDV 6
• Identify and vaccinate susceptible contacts of HBsAg-positive persons 1

Special Clinical Scenarios

Acute Hepatitis B:

• >95% of immunocompetent adults recover spontaneously without antiviral therapy 4
• Supportive care is the mainstay for uncomplicated acute infection 1
• Antiviral therapy indicated for severe acute hepatitis (coagulopathy, severe jaundice, liver failure) with entecavir or tenofovir 1, 4
• Fulminant hepatitis: Evaluate for liver transplantation + start nucleos(t)ide analogues 4

Immunosuppressive Therapy:

• HBsAg-positive patients: Start prophylaxis 2-4 weeks before high-risk agents (rituximab, anthracyclines, high-dose steroids) 6
• Reactivation risk: 12-50% without prophylaxis 6
• Continue prophylaxis through treatment and for 12-24 months after completion (24 months for rituximab) 6
• HBcAb-positive/HBsAg-negative patients: Prophylaxis preferred, or monitor monthly HBV DNA if high anti-HBs present 6

HIV-HBV Coinfection:

• All coinfected patients should receive antiretroviral therapy including tenofovir (TDF or TAF), regardless of CD4 count 4, 6
• TDF- or TAF-based ART regimens are mandatory 4

Occult Hepatitis B:

• HBsAg negative but HBV DNA detectable 1
• Can transmit infection 1
• Requires HBV DNA testing for diagnosis 6

Common Pitfalls to Avoid

Diagnostic Pitfalls:

• Do NOT rely solely on traditional ALT cutoffs to exclude liver disease—normal ALT by conventional criteria does NOT exclude significant necroinflammation or fibrosis 4
• Transient HBsAg positivity can occur up to 18 days post-vaccination (52 days in hemodialysis patients)—clinically insignificant 1
• Window period: IgM anti-HBc may be the only positive marker during acute infection when HBsAg has cleared but anti-HBs not yet developed 6

Treatment Pitfalls:

• NEVER use lamivudine as first-line therapy due to high resistance rates 1, 6
• NEVER delay treatment in patients with decompensated cirrhosis—immediate treatment required 4, 6
• Pegylated interferon is ABSOLUTELY CONTRAINDICATED in decompensated cirrhosis and pregnancy 4, 6
• Do NOT stop antiviral therapy in cirrhotic patients—lifelong treatment mandatory 4

Monitoring Pitfalls:

• Do NOT assume HCC risk is eliminated with viral suppression—surveillance remains mandatory 1, 4
• Do NOT forget renal monitoring with tenofovir, especially TDF 6
• Do NOT miss the opportunity to vaccinate susceptible household and sexual contacts 1

Prevention Pitfalls:

• Do NOT delay birth dose of HepB vaccine—must be given within 24 hours, preferably before hospital discharge 1
• Do NOT forget post-vaccination testing for infants born to HBsAg-positive mothers at 9-18 months 4
• Breastfeeding is NOT contraindicated in HBV-infected mothers 1