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Adefovir Dipivoxil

Adefovir Dipivoxil: A Comprehensive Guide to the Antiviral Against Hepatitis B

Introduction

Chronic Hepatitis B virus (HBV) infection continues to be a major global public health burden, affecting over 296 million people worldwide. Untreated, it can progress to cirrhosis, liver failure, or hepatocellular carcinoma, making effective treatment essential. In the landscape of antiviral therapies for HBV, Adefovir Dipivoxil stands out as one of the early oral agents that significantly altered the disease trajectory. First approved by the FDA in 2002, Adefovir Dipivoxil provided an alternative to interferon therapy and addressed issues like resistance to lamivudine. Though its use has declined in recent years with the advent of more potent agents like tenofovir, Adefovir remains a key drug with unique historical and clinical importance.

Adefovir Dipivoxil:

Adefovir Dipivoxil is the oral prodrug of Adefovir, a nucleotide analog that inhibits HBV DNA polymerase. The parent compound, Adefovir, is poorly absorbed in the gastrointestinal tract. The dipivoxil ester form improves its bioavailability, allowing it to be used orally.

Chemical Profile:

  • Class: Acyclic nucleotide phosphonate analog

  • Molecular Formula: C20H32N5O8P

  • Prodrug of: Adefovir (PMEA)

  • Brand name: Hepsera®

Mechanism of Action:

Once administered, Adefovir Dipivoxil is rapidly converted to Adefovir in vivo. Adefovir is then phosphorylated intracellularly to its active diphosphate form.

Mechanism in Detail:

  1. Adefovir Dipivoxil → Adefovir (via ester hydrolysis)

  2. Adefovir → Adefovir Diphosphate (active form)

  3. Competes with natural deoxyadenosine triphosphate (dATP)

  4. Incorporates into viral DNA

  5. Terminates DNA chain elongation

  6. Inhibits HBV DNA polymerase and reverse transcriptase

This results in:

  • Reduced viral replication

  • Lower HBV DNA levels

  • Improved liver histology

Pharmacokinetics:

Property Details
Absorption ~59% oral bioavailability
Peak plasma time ~0.6 to 4 hours after oral dose
Elimination half-life ~5 to 7 hours
Excretion Primarily via kidneys (unchanged form)

Special Notes:

  • No hepatic metabolism

  • Requires renal dosing adjustments

  • Long intracellular half-life (~12–36 hours)

Indications:

✅ FDA-Approved:

  • Chronic hepatitis B in adults with evidence of:

    • Active viral replication

    • Elevated liver enzymes (ALT, AST)

    • Histological signs of liver inflammation or fibrosis

      Off-Label Uses:

  • Lamivudine-resistant HBV

  • HIV/HBV coinfection (though limited due to weak HIV activity)

  • Prevention of HBV reactivation in immunosuppressed patients

Dosing:

Standard Adult Dose:

  • 10 mg orally once daily

In Renal Impairment:

  • Dose adjustment is required when creatinine clearance <50 mL/min

  • Extended dosing intervals (every 48–96 hours) may be necessary

Efficacy in Chronic Hepatitis B:

Adefovir's antiviral effects were established in several pivotal trials.

Key Trials:

1. Phase III Studies (Marcellin et al., 2003):

  • Population: HBeAg-positive and HBeAg-negative patients

  • Result: Significant HBV DNA suppression and ALT normalization

  • Histological improvement in 53–64% of patients

2. Lamivudine-Resistant HBV Studies:

  • Effective in suppressing resistant strains

  • Used as add-on therapy in lamivudine failure

Efficacy Summary:

  • HBV DNA ↓ by 3–4 logs in 48 weeks

  • ALT normalization in ~70%

  • HBeAg seroconversion in 12–15% (modest)

Resistance Patterns:

While resistance to Adefovir is lower than lamivudine, it does occur with prolonged use, particularly after 1–2 years of monotherapy.

Resistance Mutations:

  • rtN236T

  • rtA181V/T

These mutations:

  • Reduce drug efficacy

  • May confer cross-resistance with tenofovir

Prevention:

  • Avoid monotherapy in high-risk cases

  • Use combination therapy in lamivudine-experienced patients

Combination Therapies:

To improve efficacy and prevent resistance, Adefovir is often combined with other agents:

Common Combinations:

  • Adefovir + Lamivudine

  • Adefovir + Entecavir (rare)

  • Adefovir + Interferon (historical use)

These combinations are especially useful in resistant or complicated HBV infections.

Adverse Effects:

While generally well-tolerated, Adefovir carries a risk of dose-dependent toxicity.

Common Side Effects:

  • Headache

  • Abdominal pain

  • Asthenia

  • Nausea

  • Diarrhea

Serious Risks:

  1. Nephrotoxicity

    • Most significant risk

    • Dose-dependent (≥30 mg increases risk)

    • Requires monitoring of serum creatinine and phosphorus

  2. Lactic Acidosis and Hepatomegaly

    • Rare but serious

    • Seen with many nucleotide analogs

  3. Fanconi Syndrome (rare)

    • Proximal renal tubular dysfunction

Monitoring:

  • Renal function every 3 months

  • Urinalysis for protein, glucose, and phosphorus

Use in Special Populations:

✅ Pregnancy:

  • Category C

  • Not the preferred agent (tenofovir or lamivudine preferred)

  • Limited data on teratogenicity

✅ Pediatrics:

  • Approved for children 12 years and older

  • Dose: 10 mg/day

✅ HIV Coinfection:

  • Weak activity against HIV; monotherapy not recommended

  • May select for HIV resistance mutations

  • Use only as part of a fully suppressive ART regimen

Comparison with Other HBV Antivirals:

Drug Resistance Rate Potency Nephrotoxicity Dosing
Adefovir Moderate Moderate Yes (dose-dependent) Once daily
Lamivudine High Moderate No Once daily
Entecavir Low High No Once daily
Tenofovir Very low Very high Yes (but less in newer formulations) Once daily

Conclusion: Adefovir remains useful in multi-drug regimens or specific resistance patterns but is less favored today as first-line monotherapy.

Declining Use in Clinical Practice:

With the rise of newer, more potent, and safer options like tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), Adefovir use has significantly declined.

Reasons:

  • Inferior potency compared to tenofovir

  • Higher risk of nephrotoxicity

  • Slower viral suppression

  • Poor efficacy in high viral load settings

However, it still plays a role:

  • In resource-limited settings

  • For patients with specific resistance mutations

  • Where tenofovir is not tolerated

Hepsera®: The Brand Story:

Adefovir Dipivoxil was marketed under the brand Hepsera® by Gilead Sciences. After over a decade of service in global HBV management, generic versions are now widely available, offering cost-effective options in many countries.

Research and Future Directions:

While Adefovir is no longer in the research spotlight, it laid the groundwork for future nucleotide analog development. The lessons from Adefovir therapy continue to inform:

  • Resistance monitoring strategies

  • Long-term safety surveillance (renal and bone)

  • The design of new prodrugs and targeted antivirals

Patient Education: Counseling Points:

For those still using or prescribed Adefovir:

  • Do not miss doses: Increases risk of resistance

  • Regularly monitor kidney function

  • Take with or without food

  • Use contraception during therapy if pregnant or planning

  • Report signs of muscle weakness, bone pain, or unusual fatigue

Conclusion:

Adefovir Dipivoxil played a pivotal role in the transformation of chronic hepatitis B management. Though newer antivirals have taken the spotlight, Adefovir remains a relevant and viable option in selected clinical contexts. Its contribution to the evolution of antiviral therapy is undeniable, and understanding its profile helps clinicians make better-informed treatment decisions.

References:

  1. Marcellin P, et al. “Adefovir dipivoxil for the treatment of hepatitis B e antigen–positive chronic hepatitis B.” NEJM.

  2. Hadziyannis SJ, et al. “Adefovir dipivoxil for the treatment of hepatitis B e antigen–negative chronic hepatitis B.” NEJM.

  3. Gish RG. “The safety and efficacy of adefovir dipivoxil in patients with chronic hepatitis B.” Clin Liver Dis.

  4. Lok AS, McMahon BJ. “Chronic hepatitis B: Update 2019.” AASLD Practice Guidelines.

  5. Gilead Sciences – Hepsera Product Monograph.