Adefovir Dipivoxil Treatment of Chronic Hepatitis Due to HBV Infection

Abstracts & Commentary

Synopsis: Adefovir dipivoxil, 10 mg p.o. daily, is safe and effective in the treatment of chronic hepatitis due to HBV, regardless of the presence or absence of HBeAg, and it did not select resistant mutants after 48 weeks of administration.

Sources: Marcellin P, et al. N Engl J Med. 2003;348:808-816; Hadziyannis SJ, et al. N Engl J Med. 2003;348:800-807.

Marcellin and colleagues randomized 595 patients from 78 centers in North America, Europe, Australia, and Southeast Asia with HBeAg-positive chronic hepatitis to receive adefovir dipivoxil in 1 of 2 doses (10 mg or 30 mg daily) or placebo in a double-blind trial. Histologic improvement at 48 weeks was found in 53%, 59%, and 25%, respectively, and log-transformed HBV DNA concentration per mL of plasma decreased by 3.52, 4.76, and 0.55, respectively (P < .001 for both comparisons with placebo). No HBV polymerase mutations associated with adefovir resistance were identified. While the 10-mg dose of adefovir was associated with a safety profile similar to that of placebo, the higher dose was associated with an increased risk of adverse events. Of note was a mean increase in serum creatinine of 0.2 mg/dL in the recipients of 30-mg adefovir daily.

Hadziyannis and colleagues at 32 sites in Canada, Europe, Asia, and the Middle East randomized 185 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis in a 2:1 ratio to receive either adefovir dipivoxil (10 mg q.d.) or placebo in a double-blind study. Among those with liver biopsies, improvement in hepatic histology at 48 weeks was observed in 64% of adefovir recipients and 33% of placebo recipients (P < .001). The log-transformed median decreases in plasma HBV DNA level were 3.91 and 1.35 (P < .001), respectively, while the ALT levels normalized in 72% and 29% (P < 0.001). Mutations in HBV polymerase associated with adefovir resistance were not detected. Adefovir was well tolerated.

Comment by Stan Deresinski, MD, FACP

There are now 3 FDA-approved medications for the treatment of chronic hepatitis due to HBV infection: interferon alpha, lamivudine, and adefovir. Tenofovir, approved for the treatment of HIV infection, also has significant activity against HBV. Adefovir dipivoxil is a prodrug of adefovir, a nucleotide analog of adenosine monophosphate that acts as an inhibitor of HBV DNA polymerase.

Interferon alpha is poorly tolerated and has been increasingly supplanted by lamivudine in the treatment of this infection. While lamivudine therapy has a favorable safety profile, its use is associated with selection of resistant mutants in approximately one-third of patients after a year of therapy. Adefovir was very well tolerated at the 10-mg daily dose in both these trials, but the 30-mg dose was associated with modest increases in serum creatinine and at least 1 case of a Fanconi-like syndrome, toxicities that were anticipated as the consequence of the experience with higher-dose adefovir in HIV infection. At the same time, no mutations associated with tenofovir resistance were detected in either of these studies after 48 weeks of therapy.

In these studies, adefovir therapy was associated with improvement in liver histology and an approximately 4 log10 decrease in HBV DNA in both HBeAg-positive and -negative chronic hepatitis. The efficacy, safety, and lack of emergence of resistance make adefovir an excellent choice in the treatment of chronic hepatitis due to HBV infection. The next logical step, the use of tenofovir and lamivudine in combination, is being currently evaluated.

Dr. Deresinski is Clinical Professor of Medicine, Stanford University, Palo Alto, Calif.