Adefovir dipivoxil, a nucleotide analogue, has shown significant antiviral activity in patients with chronic hepatitis B, in phase 1 and 2 clinical trials.
In this double-blind study, a team of international researchers assessed 185 patients with chronic hepatitis B, who were negative for hepatitis B e antigen (HBeAg).
The team randomized patients to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks.
The team considered that the primary end point to be histologic improvement.
At week 48, 64% of patients who had base-line liver-biopsy specimens available in the adefovir dipivoxil group had improvement in histologic liver abnormalities. This compared with 33% of patients in the placebo group.
The researchers found reductions in serum hepatitis B virus (HBV) DNA levels in the adefovir dipivoxil group. HBV DNA levels fell to less than 400 copies per ml in 51% of patients in the adefovir dipivoxil group, but in none of those in the placebo group.
They determined that the median decrease in log-transformed HBV DNA levels was greater in the adefovir dipivoxil group, than in the placebo (3.91 versus 1.35 log copies per ml).
In addition, the team found that alanine aminotransferase levels had normalized at week 48 in 72% of patients receiving adefovir dipivoxil, compared with 29% those receiving placebo.
No HBV polymerase mutations associated with resistance to adefovir were identified.
Furthermore, the safety profile of adefovir dipivoxil was similar to that of the placebo.
Dr Stephanos Hadziyannis's team concluded, "In patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil treatment resulted in significant histologic, virologic, and biochemical improvement, with an adverse-event profile similar to that of placebo".
"There was no evidence of the emergence of adefovir-resistant HBV polymerase mutations."
In a related study in the same publication, a second team of researchers assessed patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg).
In this study, the research team randomly assigned 515 patients to receive 10 mg of adefovir dipivoxil, 30 mg of adefovir dipivoxil, or placebo daily for 48 weeks.
The primary end point of the study was histologic improvement in the 10-mg group.
|Patients showing histologic improvement:|
- 10 mg adefovir = 53%
- 30 mg adefovir = 59%
- placebo = 25%
|New England Journal of Medicine|
After 48 weeks of treatment, more patients who received 10 mg or 30 mg of adefovir dipivoxil, than who received placebo, had histologic improvement (53%, 59%, 25%, respectively).
In addition, patients in the adefovir dipvoxil group had a reduction in serum HBV DNA levels, undetectable levels (fewer than 400 copies per ml of serum HBV DNA, normalization of alanine aminotransferase levels, and HBeAg seroconversion.
Again, no adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.
The research team determined that the safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo.
However, in the 30mg group there was a higher frequency of adverse events and renal laboratory abnormalities.
Dr Patrick Marcellin's team concluded, "In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion".
"The 10-mg dose has a favorable risk-benefit profile for long-term treatment".
"No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene".