Antivirals for Hepatitis B

Antivirals for hepatitis B include the nucleoside/nucleotide analogs, also known as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Because of their similar chemical structure to nucleosides and nucleotides, NRTIs are able to integrate into viral DNA during the replication process. This process inhibits the function of viral RNA-dependent DNA polymerase, resulting in chain termination. All of these medications are administered orally and are excreted by the kidneys. Indications include chronic hepatitis B infection, and some (such as lamivudine) are also used for HIV. Adverse effects include GI symptoms, evidence of mitochondrial toxicity (such as lactic acidosis), and rebound infection upon discontinuation.

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Chemistry and Pharmacodynamics

Chemical structure

Antivirals for hepatitis B have structures similar to those of nucleotides and nucleosides, thus they are classified as nucleoside/nucleotide analogs (also known as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)).

  • Nucleotide (nucleic acid + sugar + phosphate group) analogs of adenosine:
    • Adefovir
    • Tenofovir
  • Nucleoside (nucleic acid + sugar) analogs of:
    • Cytidine → lamivudine
    • Guanosine → entecavir
    • Thymidine → telbivudine

Mechanism of action

  • Disrupt viral DNA replication
  • Competitively inhibit viral RNA-dependent DNA polymerase (also known as reverse transcriptase)
  • Drug is intracellularly phosphorylated → incorporated into viral DNA
  • DNA polymerization is blocked → chain termination

Pharmacokinetics

Absorption

  • Absorbed orally
  • Tenofovir:↑ absorption with high-fat meals
  • Entecavir: delayed absorption with food

Distribution and metabolism

  • Generally low protein binding
  • Minor metabolism
  • Intracellularly phosphorylated to active forms

Excretion

All of these medications are excreted by the kidneys.

Indications

Chronic hepatitis B

Indications for treatment:

  • Without cirrhosis:
    • High viral load
    • Transaminitis
  • With cirrhosis:
    • Decompensation or acute liver failure
    • Compensated with a high viral load
    • Consider in compensated cirrhosis with elevated transaminases
  • Also indicated for concurrent:
    • Hepatocellular carcinoma
    • Hepatitis C infection
    • Need for immunosuppressive therapy

Differences among medications:

  • Adefovir:
    • Helpful in lamivudine-resistant infections
    • Preferably used in combination with another agent
  • Tenofovir: 
    • May be used as 1st-line for treatment-naive individuals
    • Effective as monotherapy
    • Helpful in lamivudine-resistant infections
  • Lamivudine:
    • Cheap
    • No longer 1st-line owing to high rates of resistance
    • An option for individuals with concurrent HIV
  • Entecavir:
    • May be used as 1st-line for treatment-naive individuals
    • Effective as monotherapy
    • Low resistance rates; however, some cross resistance with lamivudine-resistant infections
  • Telbivudine:
    • Not available in the United States
    • High resistance rates
    • Unfavorable side-effect profile

HIV

  • Most agents also active against HIV (exception: telbivudine)
  • Of this group of medications, lamivudine is most likely to be used:
    • Can be used for treatment or prophylaxis
    • Used in some combination antiretroviral therapy

Adverse Effects and Contraindications

Adverse effects

  • Nervous system:
    • Headache
    • Fatigue
    • Peripheral neuropathy (telbivudine)
  • GI symptoms:
    • Nausea
    • Abdominal pain
    • Diarrhea
  • Musculoskeletal (particularly telbivudine):
    • Arthralgia
    • Myalgia
    • Myopathy
  • Hepatic:
    • Lactic acidosis (due to mitochondrial toxicity)
    • Hepatomegaly with steatosis
    • Hepatitis flare with discontinuation
  • Other:
    • Cytopenias
    • Nephrotoxicity (adefovir)

Contraindications

  • Use with caution in renal failure
  • Entecavir should not be used in lamivudine-resistant infections.

Drug interactions

  • Telbivudine: ↑ toxicity of interferon alfa
  • Medications that ↑ concentrations of tenofovir:
    • Antivirals (e.g., acyclovir, ganciclovir, cidofovir)
    • Aminoglycosides

Mechanisms of Resistance

  • Resistance tends to occur over time with long-term therapy.
  • Resistance to NRTI therapy can occur via:
    • Genetic mutations in viral DNA polymerase → conformational change → ↓ incorporation of drug into DNA
    • Mutations allowing for a compensatory ↑ in viral replication
  • This resistance is due to hepatitis B’s:
    • ↑ Rate of replication
    • Lack of proofreading function
  • Note: Many times, a nucleoside analog can be used for nucleotide analog resistance (and vice versa).

References

  1. Safrin, S. (2018). Antiviral agents. In Katzung, B.G., et al. (Ed.), Basic and Clinical Pharmacology, 14th ed., vol. 1. pp. 870–876 and pp. 885–887. McGraw Hill.
  2. Lok, A.S.F. (2021). Hepatitis B virus: overview of management. UpToDate. Retrieved September 10, 2021, from https://www.uptodate.com/contents/hepatitis-b-virus-overview-of-management
  3. Pyrsopoulos, N.T. (2021). Hepatitis B Treatment & Management. In Anand, B.S. et al. (Ed.), Medscape. Retrieved September 10, 2021, from https://emedicine.medscape.com/article/177632-treatment#showall
  4. Rajbhandari, R., Chung, R.T. (2016). Treatment of hepatitis B: a concise review. ResearchGate. Retrieved September 10, 2021, from https://www.researchgate.net/publication/308172277_Treatment_of_Hepatitis_B_A_Concise_Review
  5. Tripathi, N., Mousa, O.Y. (2021). Hepatitis B. StatPearls. Retrieved September 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK555945/
  6. Taylor, K., Fritz, K., & Parmar M. (2021). Lamivudine. In StatPearls. StatPearls Publishing. Retrieved September 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559252/
  7. Muller, J.T., Al Khalili, Y. (2021). Emtricitabine. StatPearls. Retrieved September 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539853/
  8. Warner, N., Locarnini, S. (2014). Mechanisms of hepatitis B virus resistance development. Intervirology 57:218–224. https://www.karger.com/Article/Fulltext/360940

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