What is the treatment for Hepatitis B e-antigen (HBeAg) negative patients with high Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels without cirrhosis?

Treatment for HBeAg-Negative Chronic Hepatitis B with High HBV DNA Without Cirrhosis

For HBeAg-negative patients with high HBV DNA levels (≥2000 IU/mL) without cirrhosis, the preferred first-line treatment options are entecavir, tenofovir, or peginterferon alfa-2a, with entecavir or tenofovir being the most commonly recommended due to their high potency and low resistance rates. 1

Treatment Indications

• Treatment is indicated for HBeAg-negative patients with HBV DNA levels ≥2000 IU/mL and elevated ALT levels 1
• If ALT is normal but HBV DNA is ≥2000 IU/mL, a liver biopsy or non-invasive assessment (like transient elastography) should be considered to evaluate for significant liver disease 1
• Treatment should be initiated if there is evidence of moderate-to-severe inflammation or significant fibrosis, regardless of ALT levels 1
• Family history of HCC or cirrhosis should also be considered when making treatment decisions, even with normal ALT 1

First-Line Treatment Options

• Entecavir (0.5 mg daily) is a preferred first-line agent due to its high potency and low resistance rate (1.2% after 5 years in treatment-naïve patients) 1, 2, 3
• Tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) is also a preferred first-line agent with high potency and no documented resistance in treatment-naïve patients 1, 2
• Peginterferon alfa-2a can be considered as a first-line option for a finite treatment course, but has lower response rates in patients with high HBV DNA levels and normal ALT 1

Treatment Duration and Monitoring

• For HBeAg-negative patients, long-term (often indefinite) treatment with nucleos(t)ide analogues is typically required 1, 4
• The American Association for the Study of Liver Diseases (AASLD) recommends continuing nucleos(t)ide analogues until HBsAg loss, which occurs infrequently (approximately 3.4% after 10 years of tenofovir treatment) 1
• European Association for the Study of Liver Diseases (EASL) guidelines suggest that in selected non-cirrhotic HBeAg-negative patients, nucleos(t)ide analogues may be withdrawn if HBV DNA has been undetectable for 3 years and close follow-up is possible 1
• Regular monitoring of HBV DNA levels every 3-6 months is recommended to evaluate virological response 2, 5
• ALT should be monitored every 3 months during the first year of treatment and then every 3-6 months thereafter 1, 2

Medications to Avoid

• Lamivudine is not recommended as first-line therapy due to high resistance rates with long-term use 1
• Adefovir is not recommended as first-line therapy due to inferior efficacy compared to tenofovir 1
• Telbivudine is associated with moderate resistance rates and is not recommended as a first-line agent 1

Treatment Endpoints and Outcomes

• The primary goal of therapy is sustained suppression of HBV DNA to undetectable levels 1, 2
• Long-term nucleos(t)ide analogue therapy has been shown to achieve:
  • Viral suppression in >95% of patients after 5 years 4
  • Biochemical normalization with ALT returning to normal 4
  • Regression of fibrosis on histology 1, 4
  • Prevention of clinical decompensation in those with advanced fibrosis 4
• HBsAg loss, while ideal, occurs infrequently (3-5% after 10 years of treatment) 1

Common Pitfalls and Caveats

• Medication non-adherence is a significant cause of treatment failure, potentially more important than antiviral resistance with newer agents like entecavir and tenofovir 6
• Discontinuation of therapy in HBeAg-negative patients frequently leads to virological relapse, with higher and earlier relapse rates reported after tenofovir discontinuation compared to entecavir 7
• Even with long-term viral suppression, HCC surveillance should continue as the risk is reduced but not eliminated 1, 4
• When switching between nucleos(t)ide analogues, overlapping coverage is important to prevent viral breakthrough and potential resistance 1, 8

Following these evidence-based recommendations will optimize outcomes for HBeAg-negative patients with high HBV DNA levels without cirrhosis, with the goal of preventing progression to cirrhosis, hepatocellular carcinoma, and liver-related mortality.