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Adefovir for hepatitis B triggered few drug-resistant viral mutants.

NEW ORLEANS -- Longterm adefovir dipivoxil treatment of patients with chronic hepatitis B who were negative for hepatitis B e antigen was safe and effective and produced a low rate of drug-resistant mutants. The low rate of selection for drug-resistant viral mutants sets adefovir apart from lamivudine, Dr. E. Jenny Heathcote reported at the annual Digestive Disease Week.

In this study, no hepatitis B virus mutants resistant to adefovir appeared during the first 48 weeks of treatment. Resistant strains appeared in 4 of 134 patients (3%) who were treated for 98 weeks, and an additional 2 patients developed resistant mutants out of 70 patients who were treated for a total of 144 weeks (a 2.9% rate during weeks 98-144), said Dr. Heathcote, head of the division of clinical studies resource center at Toronto Western Hospital.

In contrast, treatment of chronic hepatitis B infection with lamivudine, the only other oral drug approved for this indication, has been associated with a 15%-20% rate of resistance after 1 year of treatment, 40% after 2 years, and 67% after 4 years.

Adefovir dipivoxil was approved by the Food and Drug Administration in September 2002 for treatment of hepatitis B infection at a dosage of 10 mg/day, and is marketed as Hepsera by Gilead Sciences, the sponsor of this study. Dr. Heathcote has been a consultant to Gilead.

Results from the first 48 weeks of this study were reported last year (N. Engl. J. Med. 348[9]:800-07, 2003), along with the results from a companion study that examined the efficacy of adefovir at 10 mg/day in patients with hepatitis B e antigen (HBeAg)-positive hepatitis B (N. Engl. J. Med. 348[9]:808-16, 2003). Patients with HBeAg-negative infections usually carry mutated variants of the virus. HBeAg-negative infections are highly endemic and chronic and occur throughout the world, especially in the Mediterranean region and Southeast Asia.

Viral suppression is rarely sustained in HBeAg-negative patients taking either interferonalfa or lamivudine. Patients with an HBeAg-negative infection are usually not treated if they have fewer than 100,000 copies of hepatitis B DNA per mL of serum and normal serum levels of alanine aminotransferase (ALT). All the patients enrolled in the original study had DNA and ALT levels above these thresholds.

After the first 48 weeks of adefovir treatment, serum levels of hepatitis B DNA had dropped to an undetectable level (less than 1,000 copies/mL) in 64% of patients, and ALT levels had normalized in 73% of patients.

After 96 weeks of treatment, hepatitis B DNA was undetectable in 71% of patients, and after 144 weeks the DNA was no longer detectable in 79%. ALT levels normalized in 83% of patients after 96 weeks of treatment, and in 88% after 144 weeks of treatment.

The sustained, even improving, responses in hepatitis DNA and ALT levels with continued adefovir treatment sharply contrasted with the typical responses to lamivudine.

There were a small number of serious adverse events among patients taking adefovir long term, none of which were linked to adefovir treatment.

Despite the continued response to adefovir over 144 weeks of treatment, it is not yet clear when, if ever, treatment could stop. "The ideal goal is loss of covalently closed circular DNA and loss of surface antigen" from a patient's liver cells, "but I don't think that this has been achieved in 3 years of treatment with adefovir," he said.

BY MITCHEL L. ZOLER

Philadelphia Bureau
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Title Annotation:Gastroenterology
Author:Zoler, Mitchel L.
Publication:Internal Medicine News
Geographic Code:1USA
Date:Jul 15, 2004
Words:573
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