Pharmacology Update

Adefovir (Hepsera) for the Treatment of Chronic Hepatitis B Infection

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has recently approved adefovir dipivoxil for the treatment of chronic hepatitis B in adults. This prodrug of adefovir is a nucleotide analog that was originally developed for the treatment of HIV infections but has also been found to be active against the hepatitis B virus. Adefovir dipivoxil is marketed as Hepsera by Gilead Sciences.

Indications

Adefovir is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevation of serum aminotransferases (ALT or AST) or histological active disease.1

Dosage

The recommended dose is 10 mg once daily. It may be taken without regard to meals.

Dosage reduction is recommended in patients with renal impairment and it is dosed based on creatinine clearance.1 The dose should be 10 mg every 2 days for patients with a creatinine clearance of 20-49 mL/min, 10 mg every 3 days for creatinine clearance 10-19 mL/min, and 10 mg every 7 days for patients on hemodialysis.1

Potential Advantages

Adefovir appears to be effective in treating lamivudine-resistant strains and wild type of hepatitis B virus.1,2 A mean reduction in serum hepatitis B virus (HBV) DNA of 3.11 ± 0.94 log10 copies/mL were reported in 59 patients with clinical evidence of lamivudine-resistant HBV compared to no decrease in patients who remained on lamivudine alone.1 Adefovir appears to have a low potential to be involved in drug interactions involving cytochrome P450 isoenzymes.1

Potential Disadvantages

Adefovir is potentially nephrotoxic. The effect appears to be dose-related and is more likely in patients who are at risk for renal dysfunction, are currently renal impaired, or are taking concomitant nephrotoxic drugs. All patients on adefovir should be monitored for changes in renal function.1

Exacerbations of hepatitis have been reported in up to 25% of patients who discontinue adefovir. This usually occurs within 12 weeks after discontinuation.1 The dose of adefovir for HBV is subtherapeutic for HIV. Patients should be offered HIV antibody testing to avoid emergence of resistant HIV due to unrecognized or untreated HIV infection.1 Lactic acidosis has been reported with the use of nucleoside analogs. Obesity, prolonged use, and female sex appear to be risk factors.1

Comments

The approval of adefovir for the treatment of HBV infections was based on the results of 2 double-blind, randomized, placebo-controlled studies in 507 adults. The indications were based on histological, virological, biochemical, and serological response in HbeAg positive and negative patients as well as lamivudine-resistant hepatitis B patients with either compensated or decompensated liver function.1 In one study, 329 subjects had HBeAg-positive chronic HBV, a median total Knodell Histology Activity Index (HAI) of 10, median serum HBV of 8.38 log10 copies/mL, a median ALT level of 2.3 time upper limits of normal (ULN), and 24% had previous interferon alpha therapy. Histological response with adefovir was 53% at week 48 compared to 25% for placebo. Histological improvement was defined as 2 or more points decrease in the Knodell necro-inflammatory score with no worsening of the Knodell fibrosis score. Adefovir resulted in a mean reduction in HBV DNA of 3.57 ± 1.64 copies/mL compared to 0.98 ± 1.32 for placebo. ALT normalization was 48% vs 16%, and HBeAg conversion was 12% vs 6%. The second study included 184 patients with HBeAg negative/HV DNA positive chronic HBV infection with a median total Knodell Histology Activity Index (HAI) of 10, median serum HBV of 7.08 log10 copies/mL, a median ALT level of 2.3 ´ ULN, and 41% had prior interferon alpha therapy. Histological improvement was 64% vs 35%, and mean reduction in serum HBV DNA was 3.65 ± 1.14 copies/mL compared to 1.32 ± 1.25 for placebo. ALT normalization was 72% vs 29%. Open-label studies suggest that adefovir is effective in pre- and post-liver transplant patients and those with clinical evidence of lamivudine-resistant HBV. Limited data suggest that treatment with adefovir may not lead to emergence of resistant virus after up to 60 weeks of therapy.3 The primary limitations of adefovir therapy are nephrotoxicity and exacerbation of hepatitis upon discontinuation of therapy. Patients should be monitored periodically after discontinuation of therapy. The wholesale cost for 30 days of therapy is $440.

Clinical Implications

Chronic hepatitis B infection can be a life-long disease that can lead to cirrhosis, liver cancer, liver failure and ultimately death. The CDC estimates that about 1.25 million Americans have chronic HBV infections. Long-term control of viral replication is problematic. Current therapy includes interferon alpha-2b and lamivudine. Interferon is limited by side effects, need for parenteral administration, and toxicity in decompensated patients.4 While lamivudine is given orally, is generally well tolerated, and can be used with hepatic decompensation, emergence of resistant strains is a major drawback—occurring in 15-32% of patients by 6 months.4-6 Adefovir provides an oral alternative for the treatment of chronic hepatitis B infections, even if they are lamivudine-resistant.

Dr. Elliott is Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.

References

1. Hepsera Product Information. Gilead Sciences. September 2002.

2. Xiong X, et al. Hepatology. 1998;28:1669-1673.

3. Yang H, et al. Hepatology. 2002;36(2):464-1673.

4. Pessoa MG, Wright TL. J Gastroenterol Hepatol. 1999;14(suppl):S6-11.

5. Papatheodoriis GV, et al. Am J Gastroenterol. 2002;97(7):1618-1628.

6. Benhamou Y, et al. Lancet. 2001;358(9283):718-723.