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 DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure during the replication process. This process inhibits the function of viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure-dependent DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase, resulting in chain termination. All of these medications are administered orally and are excreted by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. 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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
  • Competitively inhibit viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure-dependent DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase (also known as reverse transcriptase)
  • Drug is intracellularly phosphorylated → incorporated into viral DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerization is blocked → chain termination

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys.

Indications

Chronic hepatitis B

Indications for treatment:

  • Without cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis:
    • High viral load
    • Transaminitis
  • With cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis:
    • Decompensation or acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure
    • Compensated with a high viral load
    • Consider in compensated cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis with elevated transaminases
  • Also indicated for concurrent:
    • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
    • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus 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 Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs

Adverse Effects and Contraindications

Adverse effects

  • Nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System:
    • Headache
    • Fatigue
    • Peripheral neuropathy (telbivudine)
  • GI symptoms:
    • Nausea
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. 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 DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase → conformational change → ↓ incorporation of drug into DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
    • 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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