HBV Resistance to Adefovir Dipivoxil are Low

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HBV Resistance to Adefovir Dipivoxil Appears Low After One Year of Therapy



By Brian Boyle, MD



Hepatitis B virus (HBV) resistance to antiviral agents can present a significant obstacle to successful treatment. Several studies presented at the 52nd annual meeting of the American Association for the Study of Liver Disease found that a significant number of patients treated with Epivir-HBV (lamivudine) will develop resistance to that agent, and that the likelihood of resistance increases with the duration of therapy.



The likelihood of HBV developing resistance to an emerging therapy for chronic HBV, adefovir dipivoxil (ADV), is less well established. To this point, no specific HBV mutations associated with resistance to ADV have been identified.



To further explore HBV resistance to ADV, patients enrolled in a phase III study of ADV for the treatment of chronic HBV were evaluated. The 515 patients enrolled were HBeAg+ and received either ADV 10 mg, ADV 30 mg or placebo once daily for 48 weeks. These patients were monitored for the emergence of potential ADV resistance mutations following the first year of the study.



A prospective, blinded genotypic analysis was performed on serum HBV isolates from all patient samples with detectable HBV DNA at baseline and at week 48, or the last available on-therapy visit. The baseline and post-treatment sequences were compared for each patient to identify any mutations that emerged. Mutations observed at conserved sites of HBV polymerase were further characterized in vitro in a cell culture model of drug susceptibility.



Paired baseline and post-treatment HBV DNA sequences were obtained from 370 (72%) patients. Of these patients, 76 (21%) developed a total of 135 amino acid substitutions. Most of these changes (93%) were considered natural HBV polymorphisms and unlikely to be associated with resistance. There were 6 novel substitutions (R366K, S467A, H481L, V562A, E566K, K589R) observed once each at conserved sites in HBV polymerase; however, in vitro cell culture assays showed that HBV mutants with most of these mutations remained fully susceptible to adefovir and the analysis for the H481L mutation is ongoing.



The authors conclude, "Following 1 year of ADV or placebo therapy the majority of substitutions observed were at natural polymorphic sites in HBV polymerase and the rare substitutions that were seen at conserved sites were not associated with decreased susceptibility to adefovir in vitro. This blinded genotypic analysis suggests the frequency of resistance after 1 year ADV therapy is very low."



11/26/01



Reference

C Westland and others. Week 48 resistance surveillance in chronic hepatitis B patients enrolled in a phase III clinical study of adefovir dipivoxil. Abstract 1099. Program and Abstracts Book of the American Association for the Study of Liver Diseases 52nd Annual Meeting (52nd AASLD). November 9-13, 2001. Dallas, Texas.