When is treatment for Hepatitis B (HBV) indicated?

Hepatitis B Treatment Indications

Treatment for Hepatitis B is indicated when HBV DNA is ≥2000 IU/mL with elevated ALT above the upper limit of normal and evidence of at least moderate liver inflammation or fibrosis, or in any patient with cirrhosis and detectable HBV DNA regardless of ALT levels. 1, 2, 3

Core Treatment Criteria

The decision to treat requires assessment of three key parameters:

• HBV DNA levels ≥2000 IU/mL 1, 3
• ALT elevation above the upper limit of normal (>25 IU/mL for women, >35 IU/mL for men) 1, 2
• Moderate to severe necroinflammation and/or at least moderate fibrosis on liver biopsy or non-invasive assessment 1, 3

Immediate Treatment Without Biopsy

Start treatment immediately without liver biopsy in the following scenarios:

• HBeAg-positive patients with HBV DNA >20,000 IU/mL AND ALT >2× upper limit of normal 4, 1, 3
• HBeAg-negative patients with HBV DNA >2000 IU/mL AND ALT >2× upper limit of normal 4, 1, 3
• Any patient with compensated cirrhosis and detectable HBV DNA, even if ALT is normal 1, 2, 5
• Patients with decompensated cirrhosis and detectable HBV DNA require urgent treatment 4, 1

Non-invasive fibrosis assessment should still be performed to confirm or rule out cirrhosis. 1

Treatment Based on Age and Family History

Age and family history modify treatment thresholds:

• Patients >30 years old with HBV DNA >20,000 IU/mL (HBeAg-positive) or >2000 IU/mL (HBeAg-negative) should be treated even with normal ALT if liver biopsy shows moderate inflammation or fibrosis 4, 1, 3
• Patients with family history of HCC or cirrhosis should be treated even with ALT <2× upper limit of normal if HBV DNA is elevated 4, 1
• Patients <30 years old with persistently normal ALT and no family history of HCC/cirrhosis should NOT be treated 1, 3

Gray Zone Patients Requiring Further Assessment

When HBV DNA is elevated but ALT is 1-2× upper limit of normal:

• Perform liver biopsy or non-invasive fibrosis assessment (FibroScan, APRI, FIB-4) 4, 1, 2
• Treat if biopsy shows moderate to severe inflammation or at least moderate fibrosis (≥F2) 4, 1, 5
• If biopsy is not performed, monitor ALT and HBV DNA every 1-3 months and HBeAg/anti-HBe every 2-6 months 4

Special Populations Requiring Treatment

Cirrhosis patients:

• All patients with compensated or decompensated cirrhosis and detectable HBV DNA must be treated regardless of ALT levels or HBV DNA levels 4, 1, 6

Liver transplant recipients:

• HBsAg-positive patients undergoing liver transplantation should receive prophylactic therapy with nucleos(t)ide analogues ± HBIG 4
• HBsAg-negative patients receiving livers from anti-HBc-positive donors require antiviral prophylaxis 4

Immunosuppression/chemotherapy:

• All HBsAg-positive patients should receive entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide before starting immunosuppressive therapy 4, 3
• HBsAg-negative, anti-HBc-positive patients receiving anti-CD20 antibody therapy or stem cell transplantation should receive prophylactic nucleos(t)ide analogues 4

Pregnancy:

• Women with high viral load (HBV DNA >200,000 IU/mL) should receive tenofovir in the third trimester to prevent vertical transmission 3

Acute hepatitis B:

• Treatment is indicated only for fulminant hepatitis B or severe acute hepatitis with total bilirubin >3 mg/dL, INR >1.5, encephalopathy, or ascites 4

Extrahepatic manifestations:

• Patients with HBV-related extrahepatic manifestations and active viral replication should receive antiviral treatment 4, 3

Children and adolescents:

• HBeAg-positive children ages 2-<18 years with evidence of compensated or decompensated cirrhosis should be treated regardless of ALT, HBeAg status, or HBV DNA levels 4
• Children with ALT >2× upper limit of normal for longer than 6 months warrant treatment consideration 1

Patients Who Should NOT Be Treated

Do not treat the following groups:

• Inactive carriers (HBsAg-positive with persistently normal ALT, HBV DNA <2000 IU/mL, no evidence of liver disease) 1, 3
• Young immunotolerant patients (<30 years) without family history of HCC/cirrhosis, with normal ALT despite high HBV DNA 4, 1
• Patients in the immune tolerance phase (typically <30 years, normal ALT, high HBV DNA, minimal liver inflammation) 4

These patients require monitoring every 3-6 months for ALT and HBV DNA, and every 6-12 months for HBeAg/anti-HBe status. 4

Preferred First-Line Treatments

Monotherapy with entecavir 0.5 mg daily, tenofovir disoproxil fumarate 245 mg daily, or tenofovir alafenamide 25 mg daily are the preferred first-line treatments due to high potency and high genetic barrier to resistance. 4, 1, 3

Pegylated interferon alfa for 48 weeks is an alternative for selected patients who prefer finite therapy, though it has more side effects and is contraindicated in cirrhosis. 4, 1 Peginterferon is most effective in genotype A infection and should be considered for compensated patients without cirrhosis. 4

Common Pitfalls to Avoid

Do not delay treatment in patients with apparent or impending liver failure (jaundice, prolonged PT, hepatic encephalopathy, ascites) - these patients should be treated promptly. 4

Do not use lamivudine, telbivudine, or adefovir as first-line therapy due to weak antiviral potency and high frequency of drug resistance. 4, 7

Do not start treatment without assessing for cirrhosis, as this changes monitoring requirements and prognosis. 1, 2

Do not use peginterferon in patients with decompensated cirrhosis - it is contraindicated and can worsen liver function. 4, 8