Long-Term Safety of Lamivudine Treatment in Patients With Chronic Hepatitis B

ANNA S. F. LOK, CHING-LUNG LAI, NANCY LEUNG, GUANG-BI YAO,_ ZHEN-YU CUI,EUGENE R. SCHIFF, JULES L. DIENSTAG, E. JENNY HEATHCOTE, NANCY R. LITTLE, DOROTHEA A. GRIFFITHS, STEPHEN D. GARDNER, and MARY CASTIGLIA

Abstract  University of Michigan Medical Center, Ann Arbor, Michigan; University of Hong Kong and Queen Mary Hospital, Hong Kong, China; §Prince of Wales Hospital, Hong Kong, China; Shanghai Jingan-Qu Central Hospital, Shanghai, China; Beijing Ditan Hospital, Beijing, China; University of Miami School of Medicine, Miami, Florida; Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts; University Health Network, University of Toronto, Toronto, Canada; GlaxoSmithKline, Research Triangle Park, North Carolina

BACKGROUND & AIMS: Data on the long-term safety of lamivudine are limited. The aim of this analysis was to determine the incidence of hepatitis flares, hepatic decompensation, and liver-disease-related (LDR) serious adverse events (SAE) during long-term lamivudine treatment. METHODS: We reviewed data on 998 patients with HBeAg-positive compensated chronic hepatitis B who received lamivudine for up to 6 years (median, 4 years) and 200 patients who received placebo for 1 year. RESULTS: Hepatitis flares occurred in 10% of the lamivudine-treated patients in year 1 and in 18%-21% in years 2-5. A temporal association between hepatitis flares and lamivudine-resistant mutations increased from 43% in year 1 to >80% in year 3. Ten hepatic decompensation events occurred in 8 (<1%) lamivudine-treated patients. Fifty-three (5%) lamivudine-treated patients experienced a total of 60 LDR SAEs. Four patients died, 2 from liver-related causes. The proportion of patients with a documented lamivudine-resistant mutation increased from 23% in year 1 to 65% in year 5. During each year of the study, patients with lamivudine-resistant mutations experienced significantly more hepatitis flares than patients without lamivudine-resistant mutations (P < 0.005). The occurrence of hepatic decompensation (0%-2%) and LDR SAEs (1%-10%) among patients with lamivudine resistance remained stable during the first 4 years with mutations and increased afterward to 6% (P = 0.03) and 20% (P = 0.009), respectively. CONCLUSIONS: This study demonstrated that lamivudine treatment for up to 6 years has an excellent safety profile in patients with HBeAg-positive compensated liver disease, but patients with long-standing lamivudine-resistant mutations may experience worsening liver disease.

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