When is treatment indicated for chronic hepatitis B infection based on alanine aminotransferase levels, hepatitis B virus DNA levels, liver fibrosis or cirrhosis, family history of hepatocellular carcinoma, or HIV/hepatitis C/D co‑infection?

When to Treat Hepatitis B Infection

All patients with chronic hepatitis B should be treated when HBV DNA ≥2,000 IU/mL combined with ALT above the upper limit of normal (>40 IU/L) and evidence of at least moderate liver necroinflammation or fibrosis. 1

Immediate Treatment Indications (Treat Regardless of HBV DNA or ALT)

Start antiviral therapy immediately in the following scenarios:

• Any patient with compensated or decompensated cirrhosis and detectable HBV DNA – even if ALT is normal 1, 2
• Life-threatening liver disease: acute liver failure, decompensated cirrhosis, or severe acute exacerbation of chronic hepatitis B 1, 2
• Patients requiring liver transplantation – to reduce post-transplant HBV recurrence risk 1, 2

Treatment Based on HBV DNA and ALT Levels (Non-Cirrhotic Patients)

High Viral Load with Elevated ALT

Treat immediately without liver biopsy if:

• HBV DNA ≥20,000 IU/mL (for HBeAg-positive) or ≥2,000 IU/mL (for HBeAg-negative) AND ALT ≥2× upper limit of normal 1

Moderate Viral Load with Elevated ALT

Consider treatment when:

• HBV DNA ≥2,000 IU/mL AND ALT >1× upper limit of normal (>40 IU/L) – assess fibrosis by biopsy or non-invasive methods; treat if moderate-to-severe necroinflammation (≥A2) or significant fibrosis (≥F2) is present 1

Normal ALT with Elevated HBV DNA

Treatment may be indicated if:

• HBV DNA ≥2,000 IU/mL with at least moderate fibrosis (≥F2) on biopsy or non-invasive assessment – even when ALT is normal 1, 3

Special Populations Requiring Treatment Consideration

Age-Based Criteria

• Patients >30 years old with HBeAg-positive chronic infection (high HBV DNA, normal ALT) may be treated regardless of histological severity, particularly if family history of HCC or cirrhosis exists 1, 2
• Patients >40 years with persistently high HBV DNA should be considered for therapy due to increased cirrhosis and HCC risk 2, 3

Family History

Treat patients with HBeAg-positive or HBeAg-negative chronic infection who have:

• Family history of hepatocellular carcinoma or cirrhosis – even if typical treatment indications are not fulfilled 1

Co-Infections

• All HIV-HBV co-infected patients should start antiretroviral therapy with tenofovir-based regimens regardless of CD4 count 2
• Hepatitis C or D co-infection warrants treatment consideration with lower thresholds 1

Pregnancy

• Pregnant women with HBV DNA >200,000 IU/mL should receive tenofovir disoproxil fumarate starting at 24-32 weeks gestation to prevent mother-to-child transmission 2

Immunosuppression

• Patients receiving immunosuppressive therapy or chemotherapy (including rituximab, anti-TNF agents) require prophylactic antiviral therapy to prevent HBV reactivation 2

Patients Who Should NOT Be Treated (Monitor Only)

Do not treat the following groups:

• Inactive carriers: HBsAg-positive with persistently normal ALT, HBV DNA <2,000 IU/mL, no evidence of liver disease 1, 3
• Young immune-tolerant patients <30 years: high HBV DNA (≥10^7 IU/mL), persistently normal ALT, no family history of HCC or cirrhosis 1, 2, 3
• HBeAg-negative patients with HBV DNA <2,000 IU/mL and normal ALT without evidence of liver disease 1, 3

Monitoring Schedule for Untreated Patients

For patients not meeting treatment criteria:

• Immune-tolerant patients <30 years: ALT and HBV DNA every 6-12 months 2
• Immune-tolerant patients ≥30 years: ALT and HBV DNA every 3-6 months 2
• HBeAg-negative patients: ALT every 3 months during first year, then every 6-12 months with HBV DNA testing 2
• Non-invasive fibrosis assessment: every 12 months 2

First-Line Treatment Options

Preferred agents:

• Entecavir 0.5 mg daily, tenofovir disoproxil fumarate 245 mg daily, or tenofovir alafenamide 25 mg daily – high genetic barrier to resistance 2, 3, 4
• Pegylated interferon alfa-2a – alternative for selected patients preferring finite therapy (48 weeks), but contraindicated in cirrhosis and pregnancy 2, 3

Critical Pitfalls to Avoid

Common errors in hepatitis B management:

• Do not assume normal ALT excludes significant liver disease – patients with HBV DNA ≥2,000 IU/mL and normal ALT may have moderate-to-severe fibrosis requiring treatment 1, 2
• Do not delay treatment in cirrhotic patients – any detectable HBV DNA mandates immediate therapy regardless of ALT 1, 2
• Do not overlook immune-tolerant patients >40 years – they have higher HCC risk and should be evaluated for treatment despite normal ALT 2, 3
• Do not use traditional ALT cutoffs alone – assess fibrosis with non-invasive methods or biopsy when HBV DNA is elevated 2