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Adefovir: New Antiviral Agent for Treatment of Chronic Hepatitis B

This new agent was effective against e antigen-positive and -negative disease, and drug resistance did not develop, although nephrotoxicity may be a risk at high doses.

Despite the existence of a vaccine for hepatitis B virus (HBV), more than 350 million people worldwide have chronic HBV infection, resulting in 1 million deaths yearly from cirrhosis, hepatocellular carcinoma, and other complications. The current therapies, interferon alfa and lamivudine, have drawbacks. Interferon use is limited by its parenteral administration, adverse effects, and expense; annually, about 15% of lamivudine-treated patients experience drug resistance. A new antiviral agent is now available for chronic HBV infection: Adefovir dipivoxil (AD) is the prodrug of adefovir, a nucleoside analogue active against HBV DNA polymerase. Researchers from 2 placebo-controlled, randomized, and manufacturer-supported clinical trials at 110 sites worldwide now report positive results for AD treatment of chronic hepatitis B in patients with HBV e antigen-negative or antigen-positive hepatitis. HBV e antigen-negative disease is associated with progressive liver dysfunction, likely necessitating long-term therapy, whereas HBV e antigen-positive disease, which is treated with antiviral agents, may undergo remission, permitting cessation of drug therapy.

Hadziyannis and colleagues studied 185 patients with e antigen-negative chronic HBV disease characterized by abnormal liver biopsies, elevated serum HBV DNA levels (100,000 copies/mL), and elevated serum alanine aminotransferase levels. For 48 weeks, 123 patients received 10 mg of oral AD daily, and 62 received placebo. Of 178 patients with assessable baseline liver biopsies, 64% of AD recipients (77 of 121) demonstrated post-treatment histologic improvement, compared with 33% of placebo recipients (19 of 57; P<0.001). Post-treatment, serum HBV DNA levels were undetectable (<400 copies/mL) in 51% of AD recipients (63 of 123) and in none of 61 placebo recipients (P<0.001); 72% of AD recipients (84 of 116) and 29% of placebo recipients (17 of 59) had normal alanine aminotransferase levels (P<0.001). No drug resistance (measured by HBV polymerase gene mutations) developed. Adverse events were similar in both groups.

Marcellin and colleagues evaluated 515 patients with e antigen-positive chronic HBV disease; baseline clinical characteristics were similar to those in the Hadziyannis study, except with higher serum HBV DNA levels (1,000,000 copies/mL). For 48 weeks, 172 patients received daily 10-mg AD, 173 received daily 30-mg AD, and 170 received placebo. Baseline liver biopsies were assessable in 494 patients. Post-treatment histologic improvement was found in 53% of 10-mg recipients (89 of 168), 59% of 30-mg recipients (98 of 165), and 25% of placebo recipients (41 of 161; P<0.001 for each AD group vs. placebo). After treatment, 21% of 10-mg AD recipients (36 of 171) had undetectable serum HBV levels, as did 39% of 30-mg recipients (67 of 173); none of 167 placebo recipients achieved undetectable levels (P<0.001 for each AD group vs. placebo). Alanine aminotransferase levels remained normal in about half of patients in both AD groups and in 16% of placebo recipients (P<0.001 for each AD group vs. placebo). No drug resistance developed. Adverse events were similar in the 10-mg AD and placebo groups, but 8% of 30-mg AD recipients had reversible increases in serum creatinine levels.

Comment: These results clearly establish that AD is an important new antiviral agent for the treatment of chronic HBV infection with histologic liver abnormalities. These researchers did not compare AD directly with lamivudine, which was not yet licensed when the studies began. AD's clinical efficacy parallels that of lamivudine for patients with e antigen-positive disease, but no resistance to AD had developed after 48 weeks of therapy. Whether resistance to AD will develop during longer treatment will be determined by a 5-year follow-up study now underway. AD's efficacy against chronic HBV infection may be enhanced if it is combined with other antiviral agents, a potential subject for future studies. The FDA licensed AD for use in September 2002.

— Neil R. Blacklow, MD

Published in Journal Watch Infectious Diseases March 21, 2003

Citation(s):

Hadziyannis SJ et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003 Feb 27; 348:800-7.

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Marcellin P et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003 Feb 27; 348:808-16.

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Mailliard ME and Gollan JL. Suppressing hepatitis B without resistance -- So far, so good. N Engl J Med 2003 Feb 27; 348:848-50.

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