HBV with Epivir-HBV (lamivudine) Resistance

aloha

May Be Less Fit and Less Pathogenic


By Brian Boyle, MD
Hepatitis B virus (HBV) is a significant cause of morbidity and mortality worldwide. In order to replicate and cause damage, HBV requires the activity of a DNA polymerase, and this enzyme is the target of the nucleoside analogues, including Epivir (lamivudine) used in the treatment of HBV.

Treatment with the Epivir selects for HBV variants with amino acid changes in the YMDD motif (tyrosine [Y], methionine [M], aspartate [D], and aspartate [D] amino acid residues at position 552 of the HBV DNA polymerase) of the polymerase protein and this mutation results in high-grade resistance to HBV. This resistance comes at a cost, however, and this cost is a reduced affinity for nucleotide substrates and some functional impairment that results in lower levels of HBV DNA and potentially less capacity for causing disease.

In a study published in Clinical Infectious Diseases, YMDD variants were studied in 794 patients enrolled in 4 multicenter, controlled studies of Epivir therapy (100mg once daily). Of the patients studied, 469 had been treated with Epivir, some for up to 4 years. YMDD variants were detected in 24%, 42%, 53% and 70% of the patients treated with Epivir for 1, 2, 3 and 4 years, respectively.

However, while the patients treated with Epivir who did not develop the YMDD variant did best (of course), patients treated with Epivir who developed the YMDD variant continued to have lower median serum HBV DNA levels, serum alanine transaminase (ALT) levels and improved liver histologic findings relative to those patients who had received placebo. The emergence of the YMDD variant was associated with male sex, and a higher baseline body mass index or HBV DNA level.

The authors conclude, 搃n compensated chronic hepatitis B, YMDD variants increased with the duration of lamivudine treatment. Despite the emergence of variants, many patients maintained improvements in markers of HBV infection and liver injury, although there was not necessarily histologic benefit, after several years of YMDD-variant HBV infection.?/span>

03/21/03

Reference
C Lai and others. Prevalence and Clinical Correlates of YMDD Variants during Lamivudine Therapy for Patients with Chronic Hepatitis B. Clinical Infectious Diseases 2003; 36:687?6.
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