Hepatitis B antivirals

Hepatitis B antivirals

Hepatitis B antivirals

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HBV Lifecycle & Targets - Viral Blueprint

Hepatitis B Virus Lifecycle and Antiviral Targets

  • 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.

Practice Questions: Hepatitis B antivirals

Test your understanding with these related questions

A 25-year-old sexually active male presents to an internal medicine physician for a routine health check up after having several unprotected sexual encounters. After appropriate testing the physician discusses with the patient that he is HIV+ and must be started on anti-retroviral treatment. Which of the following medications prescribed acts on the gp41 subunit of the HIV envelope glycoprotein?

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Flashcards: Hepatitis B antivirals

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PEGylation of interferons allows what pharmacological property to be extended?_____

TAP TO REVEAL ANSWER

PEGylation of interferons allows what pharmacological property to be extended?_____

Half Life

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