Antivirals for Hepatitis C

Antivirals against hepatitis C include a wide range of drug classes. The previous treatment regimen included interferon alfa (IFN-α) and ribavirin, which target viral entry, immune modulation, and viral replication. New, direct-acting antiviral (DAV) agents target specific nonstructural (NS) proteins of hepatitis C virus (HCV), which are important for viral replication. These agents include NS3A/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors. DAVs are often given in combination therapy and are the preferred management of hepatitis C due to their high success rate and milder side effect profile.

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Overview

Hepatitis C virus (HCV)

  • Single-stranded RNA virus 
  • Family: Flaviviridae
  • Transmitted via: 
    • Parenteral
      • Blood and blood products
      • Intravenous drug use
    • Perinatal
    • Sexual intercourse
  • Infection can lead to: 
    • Acute and chronic hepatitis
    • Cirrhosis
    • Hepatocellular carcinoma (HCC)

Viral proteins

Hepatitis C virus RNA encodes:

  • 3 structural proteins: 
    • Core (contains viral RNA)
    • Envelope 1 and envelope 2 (on the lipid envelope)
  • 6 nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B)
    • Important for viral replication 
    • Targets of the newer antiviral agents
HCV genome

Viral structure of hepatitis C and the proteins that are translated from its genome:
Structural proteins include core, envelope 1 (E1), and E2. NS2, NS3, NS4A, NS4B, NS5A, and NS5B are nonstructural (NS) proteins, most of which are the targets for direct-acting antiviral therapy.

Image: “HCV genome” by Mostafa H. Elberry, Noureldien H. E. Darwish, and Shaker A. Mousa. License: CC BY 4.0

Treatment regimens

  • Acute infection: interferon alfa (IFN-α)
  • Chronic infection:
    • Depends on the genotype
    • Previously used treatments: 
      • IFN-α
      • Ribavirin
    • Now replaced with direct-acting antivirals (DAVs):
      • NS3/4A protease inhibitors 
      • NS5A inhibitors
      • NS5B RNA polymerase inhibitors 
    • Direct-acting antivirals are typically given as a combination therapy. 
      • > 90% success rate 
      • No significant side effects

IFN-α

Chemistry

Interferons are a type of signaling protein belonging to the cytokines family.

Mechanism of action

IFN-α works through several mechanisms:

  • Induces intracellular signals responsible for inhibition of viral:
    • Entry into a cell
    • Protein processing
    • Replication
  • Modulates the immune system:
    • ↑ Expression of MHC molecules
    • ↑ Phagocytic activity
    • ↑ Survival, proliferation, and activity of cytotoxic CD8+ T cells and natural killer cells → lysis of infected cells

Pharmacokinetics

  • Absorption: 
    • Available in IV, IM, and SC forms
    • Poor oral bioavailability 
    • Absorption is slow.
  • Metabolism: undergoes proteolysis by endogenous proteases 
  • Excretion: renal and biliary

Indications

  • Hepatitis:
    • Chronic hepatitis B 
    • Hepatitis C
      • Acute
      • Chronic (in combination with ribavirin)
    • Chronic hepatitis D
    • Chronic hepatitis E
  • Malignancies, such as:
    • Non-Hodgkin lymphoma (NHL)
    • Malignant melanoma
    • Hairy cell leukemia (HCL)
    • Kaposi sarcoma 
    • Multiple myeloma (MM)
  • Other hematologic conditions:
    • Polycythemia vera (PCV)
    • Thrombotic thrombocytopenic purpura (TTP)

Adverse effects

  • Flu-like syndrome
    • Headache
    • Fever and chills
    • Myalgia
    • Malaise
  • Transient ↑ in liver enzymes after 8–10 weeks of therapy
  • On prolonged therapy:
    • CNS effects
      • Mood disorders
      • Seizures
      • Confusion
      • Suicidal thoughts 
    • Bone marrow suppression
      • Neutropenia
      • Thrombocytopenia
    • Induction of autoantibodies and autoimmune disease

Contraindications

  • Decompensated liver disease
  • Autoimmune diseases
  • Prior history of cardiac arrhythmia
  • Uncontrolled seizure disorder
  • Pregnancy

Drug interactions

  • ↑ Serum levels of:
    • Methadone
    • Theophylline
  • ↑ Risk of liver failure → didanosine 
  • ↑ Risk of myelosuppression with:
    • Zidovudine
    • Clozapine

Ribavirin

Chemistry

  • Guanosine analogue
  • Prodrug → metabolized into active form within cells

Mechanism of action

  • Resembles guanosine → interferes with the synthesis of guanosine triphosphate (GTP) 
  • Inhibits viral RNA-dependent polymerase of some viruses
  • Results in inhibition of:
    • Viral replication (DNA and RNA)
    • Viral protein synthesis

Pharmacokinetics

  • Absorption:
    • Rapidly absorbed
    • Bioavailability:
      • ↑ With high-fat meals
      • ↓ With antacids
  • Distribution:
    • Large volume of distribution
    • Not protein bound
  • Metabolism: phosphorylated intracellularly to active metabolites
  • Excretion: 
    • Urine (primary)
    • Feces

Indications

  • Viral hepatitis:
    • Chronic hepatitis C (in combination with IFN)
    • Chronic hepatitis E 
  • Respiratory syncytial virus (RSV) infection 
  • Specific viral hemorrhagic fevers (such as Lassa fever)

Adverse effects

  • Pruritis
  • GI upset
  • Depression
  • Hemolytic anemia (HA) (dose dependent)

Contraindications

  • Anemia
  • Significant cardiovascular disease (potential severe anemia → myocardial ischemia)
  • Severe renal impairment
  • Pregnancy (teratogenic)

Drug interactions

  • ↑ Risk of mitochondrial toxicity: didanosine
  • Myelosuppression
    • Azathioprine
    • Zidovudine (particularly anemia)

NS3A/4A Protease Inhibitors

Medications in this class

  • Simeprevir
  • Glecaprevir
  • Grazoprevir
  • Paritaprevir
  • Voxilaprevir

Mechanism of action

NS3A/4A protease inhibitors is a drug class that inhibits NS3/4A serine protease, which is necessary for HCV replication.

Pharmacokinetics

  • Distribution: protein-bound
  • Metabolized: cytochrome P450 (CYP) enzymes (mainly CYP3A)
  • Excretion: mainly in feces

Indications

NS3A/4A protease inhibitors are used (usually in combination therapy with another DAV) to treat chronic hepatitis C.

Adverse effects

  • Nausea
  • Headache
  • Fatigue
  • Diarrhea
  • Rashes and photosensitivity

Drug interactions

  • Can enhance hypoglycemic effect of antidiabetic medications
  • ↑ Serum concentrations of some statins
  • CYP3A4 inducers and inhibitors → alter levels of NS3A/4A protease inhibitors

NS5A Inhibitors

Medications in this class

  • Daclatasvir
  • Ledipasvir
  • Velpatasvir
  • Elbasvir
  • Ombitasvir
  • Pibrentasvir

Mechanism of action

  • The exact mechanism is unclear.
  • Bind to NS5A → inhibit viral replication

Pharmacokinetics

  • Absorption: generally well absorbed
  • Distribution: protein bound
  • Metabolism: Most are metabolized by the CYP system (often CYP3A4).
  • Elimination: mainly in feces

Indications

These medications are used (usually in combination therapy with another DAV) for the treatment of chronic hepatitis C.

Adverse effects

  • Headache
  • Fatigue 
  • Nausea

Drug interactions

  • Can enhance hypoglycemic effect of antidiabetic medications
  • ↑ Serum concentrations of some statins
  • CYP3A4 inducers and inhibitors → alter levels of NS5A inhibitors

NS5B RNA-Dependent RNA Polymerase Inhibitors

Classification

  • Nucleoside/nucleotide polymerase inhibitors (NPIs): sofosbuvir
  • Non-nucleoside polymerase inhibitors (NNPIs): dasabuvir

Mechanism of action

NS5B RNA-dependent RNA polymerase inhibitors target NS5B (an RNA-dependent RNA polymerase).

  • NPIs are activated in hepatocytes → compete with nucleotides and incorporated into viral RNA → new nucleotides cannot be added → viral replication halts
  • NNPIs allosterically bind to NS5B → ↓ polymerase function → inhibit viral replication

Pharmacokinetics

  • Distribution: protein bound
  • Metabolism: 
    • NPIs phosphorylated in hepatocytes → active form
    • Dasabuvir: CYP2C8 and CYP3A
  • Excretion:
    • Sofosbuvir: primarily urine
    • Dasabuvir: primarily feces

Indications

NS5B RNA-dependent RNA polymerase inhibitors are used (usually in combination therapy with another DAV) for the treatment of chronic hepatitis C.

Adverse effects

  • Fatigue
  • Headache
  • Insomnia
  • Nausea
  • May reactivate hepatitis B

Drug interactions

  • Can enhance hypoglycemic effect of antidiabetic medications
  • ↑ Serum concentrations of some statins
  • Amiodarone → ↑ bradycardia (with sofosbuvir)

References

  1. Miller, K. (n.d.) Hepatitis C treatments. WebMD, https://www.webmd.com/hepatitis/understanding-hepatitis-c-treatment
  2. Centers for Disease Control and Prevention. (n.d). Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. CDC. Retrieved February 10, 2021, from https://www.cdc.gov/hepatitis/hcv/management.htm
  3. Hepatitis C Online. (n.d.) HCV medications. https://www.hepatitisc.uw.edu/page/treatment/drugs
  4. Chopra, S, & Pockros, P. (2020). Overview of the management of chronic hepatitis C virus infection. UpToDate. Retrieved January 28, 2021, from https://www.uptodate.com/contents/overview-of-the-management-of-chronic-hepatitis-c-virus-infection
  5. Pockros, PJ. (2021). Direct-acting antivirals for the treatment of hepatitis C virus infection. In Bloom, A. (Ed.), UpToDate. Retrieved August 5, 2021, from https://www.uptodate.com/contents/direct-acting-antivirals-for-the-treatment-of-hepatitis-c-virus-infection#H1225365836
  6. Ahmed, A, & Daniel JF. Mechanisms of hepatitis C viral resistance to direct-acting antivirals. Viruses, Vol. 7, No. 12, Dec. 2015, pp. 6716–29.
  7. HCV Guidelines. (n.d.) Simplified HCV treatment* for treatment-naive adults without cirrhosis. HCV Guidelines. https://www.hcvguidelines.org/treatment-naive/simplified-treatment
  8. Thomas, H, Foster, G, & Platis, D. (2003). Mechanisms of action of interferon and nucleoside analogues. Journal of Hepatology. 39:S93-S98. https://www.journal-of-hepatology.eu/article/S0168-8278(03)00207-1/pdf
  9. Safrin, S. (2012). Antiviral agents. In Katzung, BG, Masters, SB, & Trevor, AJ. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 861–890). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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