HBV野生株和YMDD变异HBV病毒复制的比较...

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[B]Comparison of Viral Replication Fitness of Wild-Type and Epivir-HBV (lamivudine)-resistant HBV in Patients[/B]

Epivir-HBV (lamivudine)-resistant HBV has been described as replication
defective based on early clinical observations and in vitro data for single
mutations of M204V or M204I in the YMDD motif of HBV polymerase. However,
recent data suggests that compensatory mutations also emerge and patients with
long-term lamivudine resistance undergo disease progression.

The objectives of the current study were to compare levels of serum HBV DNA
and ALT in patients with lamivudine-resistant and wild-type HBV and to
determine the prevalence of compensatory mutations in YMDD-mutants and their
contributions to replication fitness.

Patients analyzed were enrolled in trials of adefovir dipivoxil for the
treatment of wild-type (2 trials, n=695) or lamivudine-resistant HBV (3
trials, n=203). Patients were required to have serum HBV DNA levels 5 log10
copies/mL at entry. Serum HBV DNA was measured by Roche Amplicor PCR. DNA
sequencing was used to identify resistance mutations at baseline.

At baseline, patients with lamivudine-resistant HBV had similar serum HBV DNA
(medians 7.7, 8.1, and 8.8 log10 copies/mL) compared to patients with
wild-type HBV (medians 7.1 and 8.4 log10 copies/mL); median ALT levels were
79-82 IU/L in lamivudine-resistant and 94-98 IU/L in wild-type patients.

Compensatory mutations (V173L, L180M) that enhance the replication of
YMDD-mutant HBV in vitro were found in the majority (88%) of
lamivudine-resistant patients. At baseline, four major mutational patterns
were identified in patients with lamivudine-resistant HBV (L180M+M204V [58%],
V173L+L180M+M204V [17%], M204I [12%], L180M+M204I [11%]); serum HBV DNA did
not vary significantly across the different mutational patterns.

Conclusions: Lamivudine-resistant HBV is capable of replicating to levels
comparable to wild-type HBV and causing abnormally high ALT. Exclusion of
patients with lower serum HBV DNA levels from eligibility preclude an
assessment across a greater spectrum of viral load. The four patterns of
lamivudine resistance mutations all had similar levels of serum HBV DNA.

05/21/03

Reference
W Delaney Iv and others. Comparison of Viral Replication Fitness of Wild-Type
and Lamivudine-Resistant HBV in Patients. Abstract 339 (topic forum).
Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.