Paik Yong-Han, Han Kwang-Hyub, Hong Sun Pyo, Lee Hyun Woong, Lee Kwan Sik, Kim Soo-Ok, Shin Ji Eun, Ahn Sang Hoon, Chon Chae Yoon, Moon Young Myoung
Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Antivir Ther. 2006;11(4):447-55.
The early emergence of lamivudine (3TC)-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutants has been reported during 3TC therapy in patients with chronic hepatitis B (CHB) in hepatitis B virus (HBV)-endemic areas; however, its clinical impact during long-term 3TC therapy is unknown. This study was performed to investigate the impact of the early emergence of YMDD mutants 3 months after the initiation of treatment on the outcomes of long-term 3TC therapy in HBV e antigen (HBeAg)-positive CHB. We analysed YMDD genotypes in consecutive samples from 30 patients with HBeAg positive CHB throughout 3TC treatment using both restriction fragment length polymorphism and mass spectrometric assays. Long-term outcome was compared between patients who had YMDD mutations detected at 3 months and those who had no mutations. YMDD mutation was detected in 16 (53.3%) out of 30 patients at 3 months and only the rtM2041 mutation was found. Cumulative HBeAg loss rates at 3 years was 12.5% and 57.4% in patients who had the rtM2041 mutant and wild-type virus at 3 months, respectively (P=0.010). Cumulative viral breakthrough rates at 3 years was 75.0% and 14.3% in patients who had the rtM204I mutant and wild-type virus at 3 months, respectively (P=0.002). Logistic regression revealed that YMDD mutation at 3 months was significantly related to viral breakthrough within 24 months (P=0.003). In conclusion, early detection for HBV YMDD mutation at 3 months may be useful to predict the long-term outcomes of 3TC therapy in patients with HBeAg-positive CHB in HBV-endemic areas.
在乙型肝炎病毒（HBV）流行地区，慢性乙型肝炎（CHB）患者接受拉米夫定（3TC）治疗期间，已报告出现对3TC耐药的酪氨酸-甲硫氨酸-天冬氨酸-天冬氨酸（YMDD）突变体；然而，其在长期3TC治疗中的临床影响尚不清楚。本研究旨在调查治疗开始3个月后YMDD突变体的早期出现对HBeAg阳性CHB患者长期3TC治疗结局的影响。我们使用限制性片段长度多态性和质谱分析法，分析了30例HBeAg阳性CHB患者在整个3TC治疗过程中的连续样本中的YMDD基因型。比较了3个月时检测到YMDD突变的患者和未发生突变的患者的长期结局。30例患者中有16例（53.3%）在3个月时检测到YMDD突变，且仅发现rtM204I突变。3个月时具有rtM204I突变体和野生型病毒的患者，3年时累积HBeAg转阴率分别为12.5%和57.4%（P=0.010）。3个月时具有rtM204I突变体和野生型病毒的患者，3年时累积病毒突破率分别为75.0%和14.3%（P=0.002）。逻辑回归显示，3个月时的YMDD突变与24个月内的病毒突破显著相关（P=0.003）。总之，在3个月时早期检测HBV YMDD突变，可能有助于预测HBV流行地区HBeAg阳性CHB患者3TC治疗的长期结局。
