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Increasing Hepatitis B Treatment With Adefovir and Entecavir Drive Resistance Patterns in the United States: Presented at AASLD

By Maria Bishop

BOSTON, MA -- November 6, 2007 -- Increasing use of the drugs adefovir and entecavir in the treatment of patients with hepatitis B virus (HBV) has been accompanied by increasing resistance mutations in the treated population, researchers reported here at the 58th Annual Scientific Meeting of the American Association for the Study of Liver Disease (AASLD).

Ron Kagan, PhD, Associate Director, Bioinformatics, Department of Infectious Diseases, Quest Diagnostics Nichols Institute, San Juan Capistrano, California, United States, led an evaluation team in examining a clinical database of 13,394 HBV polymerase gene sequences obtained between June 2002 and September 2007 to assess changes in the prevalence of resistance-associated mutations for lamivudine, adefovir and entecavir. Antiviral drug prescriptions were obtained from Verispan (a provider of de-identified patient-centric, longitudinal data).

Evaluations showed that predicted lamivudine resistance in clinical samples declined from 18.2% in 2003 to 9.8% in 2007.

Adefovir resistance increased from <.5% in 2002 to 2003 to 3.6% in the first 9 months of 2007. This increase closely tracked the increased utilisation of adefovir from 2003 to 2007. Adefovir-associated mutations A181V/T and N236T were found in 2.8% and 1.5% of samples submitted in 2007, respectively, compared with 2002 to 2003 frequencies of only.4% (P =.001) and 0% (P =.0067), respectively.

Following approval of entecavir in 2005, predicted resistance was 0%,.5%, and.7% respectively for 2005-2007. The increase in samples with predicted resistance (3 before 2005 vs 56 in 2006 to 2007) was significant (P <.0001) following the increasing use of entecavir. The frequency of two entecavir resistance mutations -- S202G/I and T184A/G/I/L/S -- increased significantly in 2006 to 2007 as compared with 2004 to 2005 (0 vs 45 and 2 vs 44, respectively).

The distribution of resistance mutations differed by genotype. Lamivudine resistance mutations were more common in genotype A, while adefovir mutations appeared more frequently in genotype C. Ethnic and geographic differences in HBV genotype distribution may potentially contribute to treatment differences, noted Dr. Kagan, which may account for resistance-mutation differences between genotypes.

In 2007, 7.4% of sequences with lamivudine-associated mutations also had entecavir-associated mutations, consistent with data showing a 9% rebound rate after 2 years in lamivudine-refractory, entecavir-treated patients.

Dr. Kagan concluded that continued surveillance of HBV mutation patterns in large clinical databases such as this one may aid in the detection of emerging mutational patterns to HBV antivirals and combination therapies.

All authors in this study are employed by Quest Diagnostics Nichols Institute.


[Presentation title: Increasing Adefovir and Entecavir Utilization Drive Hepatitis B Resistance Patterns in a US National Reference Laboratory Database. Abstract 954]

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