A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with ac tivity against retroviruses and herpesviruses, and in vitro activity agains t hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patie nts (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study, Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) posi tive for greater than or equal to 6 months, with elevated hepatic transamin ases and serum HBV DNA greater than or equal to 50 pg ml(-1), were randomiz ed to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, da ily, oral dose for 28 days. Antiviral activity was assessed by changes in s erum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log(10) in al l active drug recipients (median fall 1.8 log(10) pg ml(-1)) but increased by 0.01 log(10) pg ml(-1) in controls (P = 0.002). Reductions were sustaine d during treatment. HBV DNA returned to baseline over 1-6 weeks following d iscontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb oc curred 12 weeks after treatment ended, Liver transaminase elevations > 300 U l(-1) were observed in three patients during therapy (leading to protocol -specified treatment discontinuation or dose reduction) and in four patient s during follow-up. On-treatment transaminase elevations were associated wi th HIV status, occurring in three of six HIV-uninfected patients compared w ith none of nine who were HIV infected, In addition, a slower return to bas eline of serum HBV DNA levels was observed in the non-HIV-infected patients . Treatment for chronic hepatitis B as a once-daily oral dose was well tole rated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment, Furth er studies are warranted to investigate the safety and optimum dose and dur ation, of adefovir dipivoxil treatment for chronic hepatitis B.