When is treatment indicated for chronic hepatitis B in children older than 2 years and adolescents (e.g., persistently elevated ALT ≥2 × upper limit of normal for ≥6 months, HBV DNA ≥20 000 IU/mL or ≥2 000 IU/mL with documented fibrosis, moderate‑to‑severe fibrosis or cirrhosis, or HBeAg‑positive adolescents with HBV DNA ≥100 000 IU/mL and abnormal ALT)?

Treatment of Chronic Hepatitis B in Children and Adolescents

When to Treat: Core Criteria

Treatment should be initiated in children ≥2 years old with chronic hepatitis B when ALL of the following criteria are met: HBV DNA ≥20,000 IU/mL (for HBeAg-positive) or ≥2,000 IU/mL (for HBeAg-negative), ALT ≥2× upper limit of normal persisting for at least 6 months, and liver biopsy demonstrating moderate-to-severe inflammation or fibrosis (Ishak ≥3/6 for inflammation or ≥F2 for fibrosis). 1, 2

Primary Treatment Indications

Standard criteria requiring all three components:

• Viral load threshold: HBV DNA ≥20,000 IU/mL for HBeAg-positive patients OR ≥2,000 IU/mL for HBeAg-negative patients 1
• Sustained ALT elevation: ALT ≥2× ULN (or >1.5× ULN per some guidelines, whichever is lower, but not <60 IU/L) persisting for ≥6 months 1, 2, 3
• Histologic confirmation: Liver biopsy showing moderate-to-severe necroinflammation or significant fibrosis (≥F2 or Ishak ≥3) 1, 2

The requirement for liver biopsy before treatment is critical because response to therapy is significantly better when moderate necroinflammation or fibrosis is documented histologically 2. This distinguishes true immune-active disease from transient ALT fluctuations.

Immediate Treatment Indications (Regardless of Standard Criteria)

Treat immediately without waiting for 6-month ALT monitoring in:

• Decompensated cirrhosis (any degree of hepatic decompensation) 1, 3
• Compensated cirrhosis with any detectable HBV DNA 1
• Acute liver failure or severe acute hepatitis (bilirubin >3 mg/dL, INR >1.5, encephalopathy, or ascites) 4, 3
• HBV-related extrahepatic manifestations (e.g., HBV-associated glomerulonephritis) 1
• Family history of hepatocellular carcinoma in first-degree relatives 1
• Co-infection with HDV, HCV, or HIV 1
• Planned immunosuppression or chemotherapy 1

When NOT to Treat: The Immune-Tolerant Phase

Do not treat children in the immune-tolerant phase, characterized by HBeAg-positivity, HBV DNA >20,000 IU/mL, persistently normal or minimally elevated ALT (<2× ULN), and minimal/no liver inflammation on biopsy. 1, 2

Rationale for Deferring Treatment

• Antiviral therapies are generally ineffective during immune tolerance 4
• High risk of developing drug resistance with nucleos(t)ide analogues if treated during this phase 4
• Most perinatally infected children remain in immune tolerance for 10-30 years with minimal liver damage 4
• Spontaneous HBeAg seroconversion rates are low (<2% per year if age <3 years) but increase to 4-5% per year after age 3 years 2

Critical pitfall: Children infected horizontally (after the perinatal period) have much higher spontaneous seroconversion rates (70-80% over 20 years), making watchful waiting even more appropriate 4, 2

Monitoring During Immune Tolerance

• Physical examination, ALT, HBeAg/anti-HBe status every 6 months 1, 2, 3
• HBV DNA testing if ALT becomes elevated 2
• Liver ultrasound every 6-12 months depending on risk factors 2, 3
• Complete blood count and comprehensive liver panel annually 2

Special Populations Requiring Modified Approach

HBeAg-Positive Adolescents with High Viral Load

For HBeAg-positive adolescents with HBV DNA ≥100,000 IU/mL and abnormal ALT (even if <2× ULN), consider treatment after histologic assessment shows active disease. 4

This lower threshold recognizes that adolescents may be transitioning into immune-active phase and early intervention may prevent progression.

Inactive Carriers (Do Not Treat)

Children who are HBsAg-positive, HBeAg-negative, anti-HBe-positive with HBV DNA <2,000 IU/mL and normal ALT should NOT be treated. 4

• These inactive carriers have minimal liver inflammation and fibrosis regresses over time 4
• Risk of cirrhosis is very low if no cirrhosis present at time of seroconversion 4
• Continue monitoring every 6 months as 10% may develop HBeAg-negative chronic hepatitis (reactivation) 4

Documented Fibrosis with Lower Viral Loads

Children with HBV DNA ≥2,000 IU/mL and documented moderate-to-severe fibrosis (≥F2) should be treated even if ALT is only mildly elevated or HBeAg-negative. 1

This recognizes that significant fibrosis indicates disease progression regardless of current inflammatory activity.

First-Line Treatment Choice

Entecavir is the preferred first-line treatment for children ≥2 years old due to FDA approval for this age group, high efficacy, and low resistance rate. 1

Alternative Options by Age

• Interferon alfa-2b: FDA-approved for age ≥1 year; finite duration therapy (preferred if meeting criteria for interferon use) 5
• Pegylated interferon alfa-2a: FDA/EMA-approved for age ≥3 years 5
• Lamivudine: FDA/EMA-approved for age ≥3 years, but high resistance rate limits use 1, 3, 5
• Adefovir: FDA-approved for age ≥12 years 5
• Tenofovir disoproxil fumarate: EMA-approved for age ≥2 years; FDA-approved for age ≥12 years 5
• Tenofovir alafenamide: EMA-approved for age ≥12 years or weight >35 kg 5

Interferon remains the treatment of choice for finite-duration therapy in children without cirrhosis who meet treatment criteria, as it offers the possibility of HBsAg loss (10% rate) compared to nucleos(t)ide analogues (2-3%). 4, 6

Predictors of Better Response to Treatment

• Baseline ALT ≥2× ULN (higher is better) 4
• Lower HBV DNA levels (<2 × 10^8 IU/mL) 4
• Higher histologic activity index at baseline 4
• Genotype does not significantly affect response 4

Treatment Duration

For nucleos(t)ide analogue therapy in HBeAg-positive children, continue treatment for at least 1 year after HBeAg seroconversion is achieved. 1

• Monitor every 3 months during active therapy 1
• Virologic response at 24 weeks predicts higher chance of HBeAg seroconversion and lower resistance rates 4
• HBeAg-negative chronic hepatitis may require indefinite treatment 4

Critical Pitfalls to Avoid

Do not treat based on ALT elevation alone without confirming sustained elevation over 6 months and obtaining histologic assessment. 1, 2 Transient ALT flares are common and may represent spontaneous immune activation leading to seroconversion.

Do not initiate nucleos(t)ide analogues during immune-tolerant phase due to high risk of resistance development and poor efficacy. 4

Do not assume all children with elevated ALT need treatment—children infected horizontally have 70-80% spontaneous seroconversion rates over 20 years. 4, 2

Do not stop monitoring inactive carriers—10% will develop reactivation with HBeAg-negative chronic hepatitis requiring treatment. 4

Lifelong Surveillance Regardless of Treatment Status

All children with chronic HBV infection require lifelong monitoring for hepatocellular carcinoma with liver ultrasound every 6-12 months, even if they become inactive carriers, because HCC risk persists throughout life. 4, 2, 3

• HCC occurs in 0.01-0.03% of children with chronic HBV (32 per 100,000 person-years) 4
• Risk factors include male sex (70%), cirrhosis (80%), and paradoxically, early HBeAg seroconversion 4
• Family history of HCC significantly increases risk 4