General Information

Hepsera (adefovir dipivoxil) is a nucleotide analogue.

Hepsera is specifically indicated for the treatment of chronic hepatitis B in patients 12 years of age and older.

Hepsera is supplied as tablets for oral administration. The recommended dose of Hepsera in chronic hepatitis B patients for patients 12 years of age and older with adequate renal function is 10 mg, once daily, taken orally, without regard to food. The optimal duration of treatment is unknown.

Mechanism of Action

Adefovir dipivoxil is a diester prodrug of adefovir, which is an acyclic nucleotide analog of adenosine monophosphate. Adefovir is phosphorylated to the active metabolite, adefovir diphosphate, by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. 

Side Effects

The most common adverse events reported during clinical studies were:

• asthenia (weakness)
• headache
• abdominal pain
• nausea
• flatulence
• diarrhea
• dyspepsia

In addition, adverse events reported in pre- and post-liver transplant patients included, but were not limited to:

• fever
• vomiting
• hepatic failure
• increases in serum creatinine
• renal failure
• renal insufficiency
• increases in ALT and AST levels
• abnormal liver function

The Hepsera drug label comes with the following Black Box Warning: Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Hepsera. In patients at risk of or having underlying renal dysfunction, chronic administration of Hepsera may result in nephrotoxicity. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.

Clinical Trial Results

Clinical trials data suggested that treatment with adefovir dipivoxil was associated with suppression of hepatitis B virus (HBV) DNA to undetectable levels in 80% of subjects who received 12 to 15 months of treatment. These results complement previous data characterizing adefovir dipivoxil as a compound that remains active against all clinically relevant strains of HBV tested to date. The open-label study involved 23 subjects with chronic HBV infection who had failed treatment with the antiviral agent lamivudine (3TC).

Interim phase III data evaluating adefovir dipivoxil showed that the trial met its primary endpoint of improvement in liver histology at week 48 compared to baseline. The two-year, randomized, double-blind, placebo-controlled trial enrolled 515 subjects with chronic HBV infection. Two doses of adefovir dipivoxil were evaluated, including the 10 mg dose that was approved and an exploratory 30 mg dose. Improvement in liver histology was observed in 53% of subjects treated with adefovir dipivoxil 10 mg, compared to 25% of placebo-treated subjects, as measured by liver biopsies. Similar efficacy results were obtained for adefovir dipivoxil 10 and 30 mg in terms of liver histology, seroconversion and reduction in HBV DNA.

Preliminary phase III trial results indicated that treatment with adefovir dipivoxil 10 mg once daily for 48 weeks was associated with improvements in liver histology in 64% of drug-treated subjects compared to 33% of subjects who received placebo. The ongoing, multicenter, double-blind, placebo-controlled trial (Study 438) included 185 subjects with precore mutant chronic hepatitis B virus and compensated liver function. In addition to the primary endpoint, the trial met secondary efficacy endpoints including change in HBV viral load.