Drugs for Hepatitis B and C

Introduction / Overview

Brief Introduction to the Topic

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent significant global health burdens, with chronic disease states contributing to liver cirrhosis, hepatocellular carcinoma, and extra‑hepatic manifestations. Pharmacologic intervention has evolved from interferon‑based regimens to highly potent nucleos(t)ide analogues and direct‑acting antiviral agents, resulting in unprecedented rates of viral suppression and sustained virologic response. The therapeutic landscape is dynamic, with emerging agents targeting viral replication, host factors, and immune modulation.

Clinical Relevance and Importance

Effective pharmacologic control of HBV and HCV is essential for reducing morbidity and mortality, preventing transmission, and improving quality of life. In addition, the economic impact of chronic liver disease underscores the need for cost‑effective treatments. The integration of pharmacology with clinical hepatology informs patient‑centered care and guides health‑policy decisions.

Learning Objectives

• Describe the classification and chemical structure of antiviral agents used for HBV and HCV.
• Explain the pharmacodynamic mechanisms underlying viral inhibition and host immune modulation.
• Summarize pharmacokinetic profiles, including absorption, distribution, metabolism, and excretion, and their clinical implications.
• Identify approved therapeutic indications and common off‑label applications of antiviral drugs for hepatitis B and C.
• Recognize adverse effect profiles, drug interactions, and special population considerations to optimize therapeutic outcomes.

Classification

Drug Classes and Categories

Antiviral agents for HBV and HCV are grouped according to their mechanism of action and chemical composition. For HBV, the primary classes include nucleos(t)ide analogues (NA) and interferon‑α preparations. For HCV, the current therapeutic arsenal comprises direct‑acting antiviral (DAA) classes: protease inhibitors, NS5A inhibitors, polymerase inhibitors, and ribavirin, an adenosine analogue used as a nucleoside broad‑spectrum agent.

Chemical Classification

• Nucleos(t)ide Analogues (NA): 5‑hydroxyl or 3′‑deoxy analogues of natural nucleosides; include lamivudine, adefovir dipivoxil, entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF).
• Protease Inhibitors: Macrocyclic lactones or peptidomimetics targeting HCV NS3/4A protease; examples are glecaprevir, paritaprevir, and boceprevir.
• NS5A Inhibitors: Highly potent inhibitors of the HCV replication complex; include ledipasvir, daclatasvir, and velpatasvir.
• RNA Polymerase Inhibitors: Nucleoside analogues that inhibit HCV NS5B RNA polymerase; sofosbuvir and dasabuvir fall within this category.
• Interferon‑α: Recombinant cytokines that activate antiviral gene expression; administered subcutaneously or intravenously.
• Ribavirin: A guanosine analogue with broad antiviral activity; used in combination therapy for HCV and occasionally for HBV.

Mechanism of Action

Detailed Pharmacodynamics

• HBV Nucleos(t)ide Analogues:
  • Incorporated into viral reverse‑transcriptase‑mediated DNA synthesis; cause chain termination or lethal mutagenesis.
  • Lamivudine and entecavir exhibit high viral selectivity, reducing off‑target effects.
  • Tenofovir disoproxil fumarate and tenofovir alafenamide are phosphorylated intracellularly to the active diphosphate form, which competes with natural deoxyadenosine triphosphate.
• Interferon‑α:
  • Binds to type‑I interferon receptors (IFNAR1/2) on hepatocytes and immune cells.
  • Activates the JAK‑STAT pathway, leading to transcription of interferon‑stimulated genes (ISGs) such as 2′‑5′‑oligoadenylate synthetase, MxA, and PKR, which inhibit viral replication and enhance antigen presentation.
• HCV Direct‑Acting Antivirals:
  • Protease Inhibitors block the NS3/4A serine protease essential for processing the HCV polyprotein, thereby halting formation of functional viral proteins.
  • NS5A Inhibitors disrupt the assembly of the replication complex; they prevent interaction of NS5A with host lipid droplets and viral RNA.
  • NS5B Polymerase Inhibitors (sofosbuvir) act as chain terminators during RNA synthesis; dasabuvir inhibits the RNA‑dependent RNA polymerase by non‑nucleoside binding allosteric inhibition.
  • Ribavirin is incorporated into viral RNA, causing lethal mutagenesis; it also enhances innate immune responses via activation of the protein kinase R pathway.

Receptor Interactions

While direct antiviral agents do not typically engage host cell receptors, interferon‑α exerts its effects through engagement of the IFNAR heterodimeric receptor complex. Nucleos(t)ide analogues and ribavirin are predominantly intracellularly activated, circumventing extracellular receptor pathways.

Molecular/Cellular Mechanisms

At the cellular level, HBV nucleos(t)ide analogues accumulate in the mitochondria of hepatocytes, leading to inhibition of mitochondrial DNA polymerase γ; this underlies some of the mitochondrial toxicity observed with certain agents. Protease inhibitors and NS5A inhibitors disrupt the membranous web architecture of HCV replication, a structure derived from host lipid metabolism. The combination of multiple DAAs targeting distinct viral proteins reduces the likelihood of resistance emergence, a principle supported by the multiplicity of mechanisms of action.

Pharmacokinetics

Absorption

• HBV Nucleos(t)ide Analogues:
  • Lamivudine: Oral bioavailability ≈ 80 %; absorption enhanced by food.
  • Adefovir dipivoxil: Oral absorption 38 %; limited by renal excretion.
  • Entecavir: Oral bioavailability ≈ 60 %; not significantly affected by food.
  • Tenofovir disoproxil fumarate: Poor oral bioavailability (≈ 25 %); absorption improved with food.
  • Tenofovir alafenamide: Significantly higher bioavailability (≈ 60 %); minimal impact of food.
• Interferon‑α:
  • Administered parenterally; subcutaneous formulations exhibit peak plasma concentrations within 2–4 h.
• DAAs:
  • Glecaprevir: Oral bioavailability 30 %; absorption enhanced with food.
  • Paritaprevir: Oral bioavailability 15 %; requires co‑administration with ritonavir for pharmacokinetic boosting.
  • Ledipasvir: Oral bioavailability 10 %; absorption markedly increased with food.
  • Sofosbuvir: Oral bioavailability 80 %; absorption not significantly affected by food.
  • Dasabuvir: Oral bioavailability 20 %; absorption enhanced by food.

Distribution

• Wide distribution in the central nervous system is limited due to the blood‑brain barrier; however, hepatocyte uptake is efficient for both NA and DAAs.
• Plasma protein binding ranges from low (e.g., sofosbuvir, 30 %) to high (e.g., ledipasvir, 99 %).
• Drug sequestration into hepatic tissue is critical for antiviral activity; this is achieved via hepatic transporters such as OATP1B1/3 and MATE1/2K.

Metabolism

• HBV Nucleos(t)ide Analogues:
  • Lamivudine: Primarily metabolized via glucuronidation; minimal hepatic metabolism.
  • Adefovir dipivoxil: Hydrolyzed to adefovir in plasma; negligible hepatic biotransformation.
  • Entecavir: Metabolized by glucuronidation and deamination; excreted unchanged in urine.
  • Tenofovir disoproxil fumarate: Converted to tenofovir via esterase activity; tenofovir is excreted unchanged.
  • Tenofovir alafenamide: Hydrolyzed intracellularly to tenofovir; minimal systemic metabolism.
• DAAs:
  • Glecaprevir: Metabolized via CYP3A4; ritonavir co‑administration inhibits CYP3A4, increasing plasma concentrations.
  • Paritaprevir: Similar CYP3A4 metabolism; boosted by ritonavir.
  • Ledipasvir: Minimal metabolism; excreted unchanged via feces.
  • Sofosbuvir: Prodrug metabolized by hepatic esterases to the active triphosphate; further metabolized to inactive GS‑331007.
  • Dasabuvir: Metabolized by CYP3A4 and CYP2C8; excreted primarily via biliary excretion.

Excretion

• HBV Nucleos(t)ide Analogues: Renal excretion predominates; adefovir dipivoxil and tenofovir disoproxil fumarate are eliminated unchanged in urine; tenofovir alafenamide’s active metabolite is cleared via renal pathways.
• Interferon‑α: Metabolized by proteolytic degradation; excreted in urine and bile.
• DAAs: Glecaprevir and paritaprevir undergo hepatobiliary excretion; ledipasvir is primarily fecal; sofosbuvir metabolites are excreted renally; dasabuvir is largely excreted via feces.

Half‑Life and Dosing Considerations

• Lamivudine: Half‑life ≈ 5 h; dosing 100 mg twice daily.
• Adefovir dipivoxil: Half‑life ≈ 12 h; dosing 10–20 mg daily.
• Entecavir: Half‑life ≈ 25 h; dosing 0.5–1.0 mg daily.
• Tenofovir disoproxil fumarate: Half‑life ≈ 17 h; dosing 300 mg daily.
• Tenofovir alafenamide: Half‑life ≈ 17 h; dosing 25 mg daily.
• Interferon‑α: Half‑life ≈ 4–6 h; dosing 3 × 10^6 IU subcutaneously weekly.
• Protease Inhibitors: Glecaprevir half‑life ≈ 12 h; paritaprevir half‑life ≈ 9 h; dosing in combination with ritonavir 150 mg/100 mg twice daily.
• NS5A Inhibitors: Ledipasvir half‑life ≈ 50 h; dosing 90 mg daily.
• Polymerase Inhibitors: Sofosbuvir half‑life ≈ 27 h; dosing 400 mg daily.
• Dasabuvir half‑life ≈ 46 h; dosing 150 mg twice daily.

Therapeutic Uses / Clinical Applications

Approved Indications

• HBV:
  • Chronic hepatitis B infection; treatment of cirrhosis and prevention of disease progression.
  • HBV reactivation prophylaxis in immunosuppressed patients.
  • HBV infection in patients undergoing organ transplantation.
• HCV:
  • Acute and chronic HCV infection across genotypes 1–6.
  • Combination therapy with DAAs yielding sustained virologic response (SVR) rates ≥95 % in most patient populations.
  • HCV treatment in co‑infections with HIV, HBV, or hepatitis D virus (HDV) when appropriate.

Off‑Label Uses

• Lamivudine and ribavirin have been used in HBV–HCV co‑infected patients to achieve viral suppression when DAAs are contraindicated.
• Interferon‑α has been applied in difficult‑to‑treat HCV genotypes (e.g., genotype 3) as part of extended regimens.
• Tenofovir disoproxil fumarate has demonstrated activity against HIV‑associated hepatitis B in HIV‑HBV co‑infection.
• Use of DAAs in patients with decompensated cirrhosis or organ transplant recipients, although data are emerging.

Adverse Effects

Common Side Effects

• HBV Nucleos(t)ide Analogues:
  • Lamivudine: Peripheral neuropathy, anemia, fatigue.
  • Adefovir dipivoxil: Renal tubular dysfunction, osteomalacia.
  • Entecavir: Headache, dizziness, nausea.
  • Tenofovir disoproxil fumarate: Renal dysfunction, bone mineral density loss.
  • Tenofovir alafenamide: Generally better renal and bone safety profile; mild gastrointestinal upset.
• Interferon‑α:
  • Flu‑like symptoms, depression, leukopenia, thrombocytopenia.
  • Autoimmune manifestations such as thyroiditis or alopecia.
• DAAs:
  • Glecaprevir / Paritaprevir: Pruritus, rash, elevated liver enzymes.
  • Ledipasvir: Diarrhea, fatigue, headache.
  • Sofosbuvir: Nausea, headache, anemia (when combined with ribavirin).
  • Dasabuvir: Headache, fatigue, mild hepatotoxicity.
  • Ribavirin: Hemolytic anemia, teratogenicity, respiratory depression.

Serious / Rare Adverse Reactions

• Adefovir dipivoxil: Acute tubular necrosis, nephrotoxicity.
• Tenofovir disoproxil fumarate: Fanconi syndrome, osteonecrosis of the femoral head.
• Interferon‑α: Severe depression, psychosis, exacerbation of underlying psychiatric disorders.
• DAAs: Drug‑induced liver injury, especially in patients with advanced fibrosis; hypersensitivity reactions.
• Ribavirin: Teratogenic effects leading to spontaneous abortion or fetal malformations; thus contraindicated in pregnancy.

Black Box Warnings

Tenofovir disoproxil fumarate carries a black box warning regarding renal impairment and bone mineral density loss. Ribavirin is contraindicated in pregnancy due to teratogenicity. Interferon‑α is associated with a warning for the risk of depression and suicidality. Patients should be monitored accordingly.

Drug Interactions

Major Drug‑Drug Interactions

• Tenofovir disoproxil fumarate:
  • Co‑administration with certain antitubercular agents (e.g., rifampin) reduces plasma concentrations.
  • Drugs that are substrates of P‑glycoprotein (P‑gp) may alter tenofovir exposure.
• Tenofovir alafenamide:
  • Less interaction with P‑gp substrates; still caution with strong CYP3A inhibitors/inducers due to prodrug activation.
• Interferon‑α:
  • Concurrent use with immunosuppressants (e.g., corticosteroids) may blunt antiviral response.
  • Beta‑blockers may mask bradycardia induced by interferon‑α.
• DAAs:
  • Glecaprevir / Paritaprevir: Ritonavir boosts plasma concentrations but can increase CYP3A metabolism of other agents, reducing efficacy.
  • Ledipasvir: Interacts with proton‑pump inhibitors, reducing absorption; co‑administration with high‑dose PPIs is discouraged.
  • Sofosbuvir: Minimal CYP interactions; however, concomitant use with ribavirin can increase anemia risk.
  • Dasabuvir: CYP3A inhibitors/inducers alter drug levels; caution with ketoconazole, rifampin, or carbamazepine.
• Ribavirin:
  • Concomitant use with erythropoietin may reduce hemoglobin drop.
  • Interaction with antineoplastic agents can enhance hematologic toxicity.

Contraindications

• Tenofovir disoproxil fumarate: Severe renal impairment (eGFR <30 mL/min/1.73 m²).
• Tenofovir alafenamide: Severe hepatic dysfunction (Child‑Pugh C).
• Interferon‑α: History of severe depression, uncontrolled psychiatric disease.
• DAAs: Certain HCV genotypes may be resistant; genotype 3 may require extended therapy.
• Ribavirin: Pregnancy, lactation, uncontrolled anemia.

Special Considerations

Use in Pregnancy / Lactation

• Tenofovir alafenamide and entecavir are considered relatively safe during pregnancy; tenofovir disoproxil fumarate is also acceptable but with caution regarding bone health.
• Lamivudine and adefovir dipivoxil have limited data but are generally regarded as category C; use if benefits outweigh risks.
• Interferon‑α is contraindicated in pregnancy due to teratogenicity and potential fetal harm.
• Ribavirin is contraindicated in pregnancy and lactation because of teratogenicity.
• DAAs: Sofosbuvir and ledipasvir are category B; however, data are limited; use is generally avoided unless benefits are compelling.

Paediatric / Geriatric Considerations

• In paediatric populations, dosing is weight‑based; tenofovir alafenamide has been approved for children >2 years of age. Ribavirin is not typically used in children due to toxicity.
• Geriatric patients may exhibit altered pharmacokinetics; dose adjustments for renal impairment are essential.
• Immunosenescence may affect interferon‑α response; monitoring for depression is crucial.

Renal / Hepatic Impairment

• Tenofovir disoproxil fumarate: Dose reduction to 200 mg daily in patients with eGFR 30–50 mL/min/1.73 m²; avoid if eGFR <30 mL/min/1.73 m².
• Tenofovir alafenamide: No dose adjustment required for mild‑moderate hepatic impairment; caution in severe hepatic disease.
• Lamivudine: Minimal dose adjustment required; monitor for nephrotoxicity.
• Interferon‑α: Dose reduction or discontinuation may be necessary in hepatic decompensation; careful monitoring of liver enzymes.
• DAAs: Sofosbuvir is safe in mild‑moderate hepatic impairment; dose adjustment required in severe hepatic dysfunction (Child‑Pugh C).

Summary / Key Points

• Nucleos(t)ide analogues remain the cornerstone of HBV therapy, offering high potency with acceptable safety profiles when monitored properly.
• Interferon‑α, though less frequently used due to adverse effects, can be effective in selected patient populations, particularly those refusing or intolerant of oral agents.
• DAA regimens have transformed HCV management, achieving SVR rates >95 % across all genotypes with short treatment durations.
• Drug–drug interactions, especially involving CYP3A4 and P‑gp pathways, necessitate careful medication reconciliation and monitoring.
• Special populations—including pregnant women, children, and patients with renal/hepatic impairment—require individualized dosing strategies and vigilant surveillance for toxicity.
• Emerging therapeutic agents, such as capsid assembly modulators and therapeutic vaccines, hold promise but require further clinical validation.

References

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