By Liz Highleyman

Several nucleoside/nucleotide analogs have potent activity against wild-type hepatitis B virus (HBV), but their long-term effectiveness is limited by the emergence of drug resistance mutations, especially when used as monotherapy.

Entecavir (Baraclude), one of the newer anti-HBV agents, has a higher barrier to resistance than an older standard first-line treatment, lamivudine (3TC; Epivir-HBV). Entecavir resistance has previously not been reported in nucleoside-naive patients, and resistance is low in those who have experienced treatment failure on lamivudine.

However, in the August 2008 European Journal of Gastroenterology and Hepatology, Dutch researchers reported on the emergence of an entecavir-resistant HBV mutation despite prolonged HBV viral load suppression in a patient with pre-existing lamivudine resistance.

This individual, a 43-year-old man, was initially treated with lamivudine for hepatitis B "e" antigen (HBeAg) positive chronic hepatitis B. Viral breakthrough due to a lamivudine resistance mutation was observed, and entecavir (1 mg daily) was added to his regimen.

After the man's HBV viral load had been near the limit of detection on a PCR assay for 30 weeks, lamivudine was discontinued. His HBV DNA level remained low for nearly a year, but a second viral breakthrough occurred after 45 weeks of entecavir monotherapy.

At this point, his treatment was switched from entecavir to tenofovir (Viread), an anti-HIV drug that just this month was approved for hepatitis B treatment. After the change, the man's HBV DNA again fell below 1000 copies/mL.

Genetic sequence analysis revealed the presence of the rtL180M and rtM204V lamivudine resistance-associated mutations at the start of entecavir treatment. During entecavir therapy, the rtS202G mutation was also selected. A retrospective analysis revealed that while taking lamivudine, 3 other mutations had been selected as well: rtE1D, rtV207L, and rtI220L.

According to the authors, this is the "first case of entecavir resistance in a lamivudine-resistant patient with good initial suppression of viral replication for 70 weeks."

"On the basis of the data from cross-resistance and sensitivity testing in vitro and treatment outcomes," they added, "tenofovir proves to be a good treatment option for entecavir-resistant patients."

8/26/08

Reference
WF Leemans, HG Niesters, AA van der Eijk, and others. Selection of an entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: successful rescue therapy with tenofovir. European Journal of Gastroenterology and Hepatology 20(8): 773-777. August 2008.
(Abstract)