Acute exacerbation and hepatitis B virus clearance after emergence of YMDDmotif mutation during lamivudine therapy

Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication, bu t its long-term use may be associated with HBV tyrosine-methionine-aspartat e-aspartate (YMDD) motif mutation. To examine the clinical features and cou rse after emergence of YMDD mutants, SS patients who received lamivudine th erapy over 104 weeks at our unit were assayed for YMDD mutation(s), Thirty- two of them were found to have the YMDD mutation. They continued lamivudine therapy and were followed up weekly or biweekly if clinically indicated, T hirty (93.7%) of them showed elevation of alanine transaminase (ALT), and 1 3 (40.6%) experienced acute exacerbation at 4 to 94 weeks (median, 24 weeks ) after emergence of the YMDD mutant. The incidence of exacerbation is much higher than 4.3% in patients without the YMDD mutation (P = .003). Compare d with patients without exacerbation, patients with exacerbation had a sign ificantly higher serum HBV-DNA level after emergence of the YMDD mutant (P <.003). Before exacerbation, serum HBV-DNA level was rising to its peak, fo llowed by the peaking of ALT (247-2,010 U/L) 1 to 4 weeks later. Three pati ents developed hepatic decompensation, but then in association with hepatit is B e antigen (HBeAg) seroconversion, recovered. Of the 12 evaluable patie nts, 8 (75%) showed HBeAg seroconversion, and 3 showed mutant clearance wit hin 1 to 5 months after exacerbation, In contrast, none of the patients wit hout exacerbation showed HBeAg seroconversion (P <.001). These results indi cate that acute exacerbations may occur after emergence of the YMDD mutatio n. The incidence, clinicopathological features, and subsequent course, and possibly the underlying immune mechanisms, are similar to those of wild-typ e HBV chronic infection. Because severe hepatitis may occur, patients shoul d be followed carefully once the YMDD mutant emerges.