Clinical and virological features of non-breakthrough and severe exacerbation due to lamivudine-resistant hepatitis B virus mutants
Clinical and virological features of non-breakthrough and severe exacerbation due to lamivudine-resistant hepatitis B virus mutants
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DOI：
10.1002/jmv.20546
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发表时间：
2006-03-01
影响因子：
12.7
通讯作者：
Kumada, H
中科院分区：
文献类型：
--
作者：
Suzuki, F;Akuta, N;Kumada, H
在拉米夫定治疗B型肝炎病毒（HBV）感染期间发生YMDD突变的患者表现出不同的临床病程。一些患者显示正常的ALT水平，而另一些患者由于YMDD突变体而发生重度肝炎加重（SHE）。我们研究了362例接受拉米夫定治疗的日本成年患者中的136例YMDD突变患者。对出现YMDD变异后无HBV DNA升高的患者（无升高组）进行临床和病毒学特征研究。此外，还对YMDD突变体所致SHE患者进行了病毒学分析。非升高组患者的特征是治疗前HBeAg阴性，治疗期间HBeAg丢失，从开始治疗到出现YMDD突变体的持续时间较长，没有混合型YMDD突变体。SHE患者在恶化时聚合酶基因内的逆转录酶（rt）区域的置换比没有SHE的患者多，尽管没有发现特异性置换。HBV全基因组序列分析显示SHE患者的X、rt和表面蛋白发生了更多的替换。总之，在非升高组中，治疗开始时或YMDD变异体出现前HBeAg阴性是一个重要因素。RT区及其他蛋白质的多处替换可能与拉米夫定耐药病毒引起的重型肝炎的发生有关。
Patients who develop YMDD mutant during lamivudine therapy for hepatitis B virus (HBV) infection exhibit various clinical courses. Some patients show normal ALT levels, whereas others develop severe hepatitis exacerbations (SHEs) due to YMDD mutants. We studied 136 patients with YMDD mutant among 362 Japanese adult patients on lamivudine therapy. Clinical and virological features of patients without elevated HBV DNA after emergence of YMDD mutant (non-elevated group) were investigated. Moreover, virological analysis was also performed in patients with SHE due to YMDD mutants. Patients in the non-elevated group were characterized by HBeAg-negative pretreatment, HBeAg loss during therapy, a longer duration from commencement of therapy until emergence of YMDD mutant, and no mixed-type YMDD mutants. Patients with SHE had more substitutions in the reverse transcriptase (rt) region within the polymerase gene at the time of exacerbation than those without SHE, although no specific substitutions were noted. Sequence analysis of full-length HBV genome showed more substitutions in X, rt, and surface proteins in patients with SHE than in those without elevated HBV DNA level. In conclusion, negativity for HBeAg at commencement of therapy or before emergence of YMDD mutant was an important factor among non-elevated group. More substitutions in the rt region and the other proteins may be related to the emergence of severe hepatitis caused by lamivudine-resistant virus.