Hepatitis B antivirals

HBV Lifecycle & Targets - Viral Blueprint

• Core Process: A DNA virus that uniquely replicates via an RNA intermediate using reverse transcriptase.
• Viral Reservoir: Forms a stable, episomal covalently closed circular DNA ($cccDNA$) in the hepatocyte nucleus.
  • $cccDNA$ serves as a persistent template for all viral gene products.
  • Not cleared by current therapies, leading to lifelong infection.
• Primary Drug Targets:
  • Reverse Transcriptase (RT): Targeted by Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTIs) like Tenofovir & Entecavir.
  • Entry: Blocked by Bulevirtide.

⭐ The persistence of nuclear cccDNA is the primary reason for treatment failure and viral rebound after discontinuing NRTIs. It's the key barrier to a sterilizing cure.

Nucleos(t)ide Analogs - The Chain Breakers

• Mechanism of Action: Competitively inhibit HBV DNA polymerase/reverse transcriptase. After incorporation into the growing viral DNA strand, they cause premature chain termination, halting viral replication.

• First-Line Agents:

  • Tenofovir (TDF or TAF): Potent with a high barrier to resistance.
    • TDF: Associated with nephrotoxicity (e.g., Fanconi syndrome) and decreased bone mineral density.
    • TAF (alafenamide): Prodrug with lower plasma levels, resulting in fewer renal and bone side effects.
  • Entecavir: Potent, high barrier to resistance. Must be taken on an empty stomach.

• Other Agents:

  • Lamivudine, Telbivudine: Lower barrier to resistance.
  • Adefovir: Risk of dose-dependent nephrotoxicity.

• Class-wide Warnings:

  • Rare but severe risk of lactic acidosis and hepatomegaly with steatosis.

⭐ Exam Favorite: Abrupt discontinuation of these agents can cause a severe acute exacerbation of Hepatitis B, potentially leading to hepatic failure. Always taper or switch therapy under guidance.

Interferon-Alpha - The Immune Alarm

• Mechanism: A host cytokine that boosts anti-viral immune responses. It doesn't target HBV directly but activates host defenses, like setting off an "immune alarm."
  • Induces expression of MHC class I molecules, enhancing cytotoxic T-cell recognition of infected hepatocytes.
  • Activates natural killer (NK) cells.
• Clinical Use: Finite course of therapy (48 weeks). Often considered in younger patients with well-compensated liver disease and high serum ALT.
• Adverse Effects:
  • Flu-like symptoms (fever, chills, myalgia) are very common.
  • Neuropsychiatric: Depression, anxiety, irritability.
  • Bone marrow suppression.

⭐ Pegylated interferon (Peg-IFN) is conjugated with polyethylene glycol, which ↑ half-life, allowing for once-weekly injections and providing a more sustained therapeutic effect.

• Goal of therapy is HBV DNA suppression, not a cure; lifelong treatment is common.
• First-line agents are Entecavir and Tenofovir (TDF/TAF) due to high potency and a high barrier to resistance.
• All are NRTIs that inhibit HBV DNA polymerase.
• Tenofovir Disoproxil Fumarate (TDF) is associated with nephrotoxicity and decreased bone mineral density.
• Tenofovir Alafenamide (TAF) is a newer prodrug with a better renal and bone safety profile.
• Pegylated interferon-alfa offers a finite treatment course but has significant side effects.