Elaborate the indications for initiating antiviral therapy in a patient with chronic hepatitis B.

Understanding the Natural History of Chronic Hepatitis B

The natural history of chronic HBV infection is dynamic and complex, evolving through several phases, including immune tolerant, immune active (HBeAg-positive and HBeAg-negative), and inactive carrier phases. Liver injury is primarily immune-mediated, where the host's immune response attempts to clear the virus, leading to inflammation and fibrosis. The progression to severe liver disease is influenced by viral factors (genotype, viral load), host factors (age at infection, immune status, gender), and environmental factors (alcohol, co-infections).

General Goals of Antiviral Therapy in Chronic Hepatitis B

The primary goals of antiviral therapy are:

• To achieve sustained viral suppression (undetectable HBV DNA).
• To prevent or reverse liver fibrosis and cirrhosis.
• To reduce the risk of hepatocellular carcinoma (HCC) and liver-related mortality.
• To improve overall patient survival and quality of life.

Key Indications for Initiating Antiviral Therapy

The decision to initiate antiviral therapy is individualized and based on a combination of factors, including the patient's HBeAg status, HBV DNA levels, Alanine Aminotransferase (ALT) levels, and the degree of liver inflammation and fibrosis/cirrhosis. The 2024 WHO guidelines emphasize simplified treatment criteria, particularly for adults and adolescents.

1. HBeAg-Positive Chronic Hepatitis B (Immune Active Phase)

This phase is characterized by active viral replication and ongoing liver inflammation. Therapy is generally recommended for patients who meet the following criteria:

• HBV DNA Levels: Persistently high, typically > 20,000 IU/mL.
• ALT Levels: Persistently elevated, often > 2 times the Upper Limit of Normal (ULN). The WHO guidelines suggest ALT thresholds of 19 IU/L for women and 39 IU/L for men for treatment decisions, while AASLD recommends 25 IU/L in women and 35 IU/L in men.
• Liver Biopsy/Non-invasive Assessment: Evidence of moderate to severe necroinflammation and/or significant fibrosis (e.g., Ishak score ≥ 2 or METAVIR score ≥ A2F2). Non-invasive methods like FibroScan or APRI (AST to Platelet Ratio Index) are increasingly used to assess fibrosis, especially where viral load testing is not readily available.

2. HBeAg-Negative Chronic Hepatitis B (Immune Active Phase)

In this phase, patients typically have lower HBV DNA levels but still experience active liver inflammation and disease progression due to mutations in the pre-core or basal core promoter regions of the virus. Indications include:

• HBV DNA Levels: Detectable, usually > 2,000 IU/mL.
• ALT Levels: Persistently elevated, > 2 times ULN (using WHO or AASLD specific thresholds).
• Liver Biopsy/Non-invasive Assessment: Significant necroinflammation and/or fibrosis (e.g., Ishak score ≥ 2 or METAVIR score ≥ A2F2).

3. Compensated and Decompensated Cirrhosis

Patients with cirrhosis are at a high risk of liver decompensation and HCC. Antiviral therapy is crucial regardless of their HBeAg status, HBV DNA, or ALT levels.

• Compensated Cirrhosis: Treatment is recommended for all patients with compensated cirrhosis, irrespective of HBV DNA levels, HBeAg status, or ALT levels.
• Decompensated Cirrhosis: Immediate initiation of oral antiviral treatment is recommended, often in conjunction with evaluation for liver transplantation. The goal is to rapidly suppress viral replication to improve liver function and survival.

4. Special Considerations

Beyond the standard criteria, certain patient groups and conditions warrant special consideration for early antiviral therapy:

• Patients with a Family History of HCC or Cirrhosis: Even in cases with less severe liver disease, a strong family history may lower the threshold for treatment due to increased genetic susceptibility.
• Patients Co-infected with Other Liver Diseases: Individuals with co-infection (e.g., HIV, Hepatitis C, Hepatitis D) or other chronic liver conditions (e.g., fatty liver disease, alcohol-related liver disease) may have accelerated disease progression and generally require earlier treatment. For patients coinfected with HCV and HBV who are receiving direct-acting antiviral (DAA) therapy for HCV, there's a risk of HBV reactivation, necessitating careful monitoring and potential antiviral treatment for HBV.
• Immunosuppressed Patients: Patients undergoing chemotherapy, immunosuppressive therapy (e.g., for autoimmune diseases or organ transplantation), or those with HIV infection are at a higher risk of HBV reactivation and progressive liver disease. Prophylactic antiviral therapy is often initiated before or concurrently with immunosuppression, irrespective of baseline HBV DNA or ALT levels.
• Pregnant Women: To prevent mother-to-child transmission (MTCT) of HBV, antiviral prophylaxis is recommended for pregnant women with high HBV DNA levels, typically > 200,000 IU/mL, from the second trimester onward. The 2024 WHO guidelines have expanded eligibility for this prophylaxis.
• Older Patients: In selected individuals over 40 years of age with high HBV DNA (> 1,000,000 IU/mL) but normal ALT, treatment may be considered if liver biopsy shows significant necroinflammation or fibrosis.

The decision-making process for initiating antiviral therapy is dynamic and requires ongoing monitoring of virological, biochemical, and histological markers. The long-term nature of CHB therapy necessitates adherence to treatment regimens and regular surveillance for complications.