Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Hepsera (Gilead Sciences)
10 mg tablets
Approved indication: hepatitis B
Australian Medicines Handbook section 5.3
Although Australian children are now immunised against hepatitis B, infection still occurs in adults and is endemic in Aboriginal and Torres Strait Islander communities. Some people who are infected develop chronic hepatitis B which may lead to cirrhosis and liver failure. Patients with chronic hepatitis B can be treated with injections of interferon. Lamivudine, a nucleoside analogue, can be used as an oral treatment.
Adefovir is a nucleotide analogue of adenosine monophosphate. Cells convert adefovir to adefovir diphosphate which competes with the normal substrate of the viral DNA polymerase. The concentration of adefovir diphosphate needed to inhibit the enzyme in hepatitis B virus is lower than the concentration which inhibits human DNA polymerase. When adefovir diphosphate gets incorporated into viral DNA, it inhibits replication by preventing elongation of the nucleic acid chain.
As adefovir is not well absorbed it is given as a prodrug. Adefovir dipivoxil is taken once a day and is converted to adefovir (bioavailability 59%) by hydrolysis. Most of this adefovir is later excreted unchanged in the urine.
Patients who do not have detectable hepatitis B e antigen1 (HBeAg) may have an increased risk of progressive liver damage. A multi centre study randomised 123 of these patients to take adefovir dipivoxil and 61 to take a placebo for 48 weeks. Concentrations of viral DNA reduced significantly in 51% of the adefovir group but not in any of the patients given a placebo. Although 33% of the placebo group had improved liver histology, this was significantly less than the 64% who improved with adefovir dipivoxil.2
Another study of 515 patients who did have detectable HBeAg produced similar results. While viral DNA concentrations were not reduced by placebo, they were undetectable in 39% of patients taking adefovir dipivoxil 30 mg and in 21% of those taking 10 mg. Liver biopsies after 48 weeks of treatment showed improvement in 59% (30 mg) and 53% (10 mg) of the adefovir group and 25% of the placebo group.3 As adverse effects are more frequent at higher doses the recommended daily dose of adefovir dipivoxil is 10 mg.
In the clinical trials adverse events occurred with a similar frequency in patients taking adefovir dipivoxil or placebo. Common adverse events include asthenia, headache, abdominal pain and diarrhoea. Adefovir dipivoxil can be prescribed for patients with hepatic impairment, but the dose requires adjustment in patients with renal impairment. Nephrotoxicity may occur during long-term therapy so renal function should be monitored particularly if the patient takes other treatments, such as non-steroidal anti-inflammatory drugs, which affect the kidney.
The effectiveness of lamivudine in chronic hepatitis B is reduced because the virus becomes resistant to the drug. So far, the virus has not developed significant resistance to adefovir. A small study in patients with HIV infection who also had lamivudine-resistant hepatitis B found that adefovir dipivoxil significantly reduced the concentrations of viral DNA.4
The available drugs for hepatitis B have not yet been compared directly so it is difficult to know which will produce the best outcomes for patients. While liver histology improved in the patients who responded to adefovir dipivoxil, we do not know if this will reduce the long-term complications of chronic hepatitis B. The optimum duration of treatment is uncertain, and up to 25% of patients will develop an exacerbation of their hepatitis after they stop taking adefovir dipivoxil.
- Siebert D, Locarnini S. Hepatitis B: issues in laboratory diagnosis and vaccination. Aust Prescr 1998;21:72-5.
- Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800-7.
- Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-16.
- BenhamouY, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001;358:718-23.