Lok Anna S F, Lai Ching-Lung, Leung Nancy, Yao Guang-Bi, Cui Zhen-Yu, Schiff Eugene R, Dienstag Jules L, Heathcote E Jenny, Little Nancy R, Griffiths Dorothea A, Gardner Stephen D, Castiglia Mary
Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, 48109-0362, USA.
Gastroenterology. 2003 Dec;125(6):1714-22. doi: 10.1053/j.gastro.2003.09.033.
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.
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.
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.
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.
关于拉米夫定长期安全性的数据有限。本分析的目的是确定长期使用拉米夫定治疗期间肝炎发作、肝失代偿以及肝脏疾病相关（LDR）严重不良事件（SAE）的发生率。
我们回顾了998例HBeAg阳性代偿性慢性乙型肝炎患者的数据，这些患者接受拉米夫定治疗长达6年（中位数为4年），以及200例接受安慰剂治疗1年的患者的数据。
在接受拉米夫定治疗的患者中，第1年肝炎发作的发生率为10%，第2至5年为18% - 21%。肝炎发作与拉米夫定耐药突变之间的时间相关性从第1年的43%增加到第3年的>80%。8例（<1%）接受拉米夫定治疗的患者发生了10次肝失代偿事件。53例（5%）接受拉米夫定治疗的患者共经历了60次LDR SAE。4例患者死亡，2例死于肝脏相关原因。记录有拉米夫定耐药突变的患者比例从第1年的23%增加到第5年的65%。在研究的每年中，有拉米夫定耐药突变的患者比没有拉米夫定耐药突变的患者经历更多的肝炎发作（P < 0.005）。在出现突变的前4年中，拉米夫定耐药患者中肝失代偿（0% - 2%）和LDR SAE（1% - 10%）的发生率保持稳定，之后分别增加到6%（P = 0.03）和20%（P = 0.009）。
本研究表明，拉米夫定治疗长达6年对HBeAg阳性代偿性肝病患者具有良好的安全性，但长期存在拉米夫定耐药突变的患者可能会出现肝病恶化。
