Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation
Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation
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DOI：
10.1016/s0140-6736(96)02266-0
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发表时间：
1997-01-04
期刊：
影响因子：
168.9
通讯作者：
Brown, NA
中科院分区：
文献类型：
--
作者：
Bartholomew, MM;Jansen, RW;Brown, NA
研究背景终末期乙型肝炎病毒（HBV）感染的原位肝移植术后常并发HBV复发，拉米夫定（一种胞嘧啶核苷类似物）已被证明能抑制HBV感染。我们报告的耐药性拉米夫定在三例接受移植的终末期肝病继发于B型肝炎。方法两例患者接受拉米夫定移植后复发HBV感染，而第三例患者开始治疗移植前1个月，试图防止移植后HBV复发。这三名患者最初对治疗反应良好，但所有患者在治疗9-10个月后病毒复发。从血清中扩增HBV DNA，并通过保守的聚合酶结构域-酪氨酸，甲硫氨酸，天冬氨酸，天冬氨酸（YMDD）位点进行测序。我们评估了HBV对拉米夫定的敏感性，通过感染原代人肝细胞，在治疗开始前和不同浓度的lamivudine.Findings复发后取血清，DNA测序显示在所有拉米夫定治疗期间HBV聚合酶基因的YMDD位点内的一个共同的突变。在用预处理血清感染的肝细胞中，通过加入低至0.03 μ mol/L的拉米夫定，HBV DNA浓度降低至对照培养物的6%以下。相比之下，在复发后血清治疗的培养物中，HBV DNA浓度没有下降到对照值的20%以下，即使拉米夫定在30 μ mol/L。解释拉米夫定耐药已在HIV患者的聚合酶基因的YMDD位点突变的报告。我们的研究结果表明，拉米夫定耐药的共同机制，涉及在病毒聚合酶的同源结构域相似的点突变的HIV和HBV。
Background Orthotopic liver transplantation for end-stage hepatitis-B-virus (HBV) infection is commonly complicated by recurrence of HBV, Lamivudine, a cytosine nucleoside analogue, has been shown to suppress HBV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver disease secondary to hepatitis B.Methods Two of the patients received lamivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an attempt to prevent HBV recurrence after transplantation. The three patients initially responded well to treatment, but viral recurrence occurred after 9-10 months of treatment in all patients. HBV DNA was amplified from serum and sequenced through a conserved polymerase domain-the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed the susceptibility of HBV to lamivudine by infecting primary human hepatocytes with serum taken before the start of treatment and after recurrence in varying concentrations of lamivudine.Findings DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all during lamivudine treatment. In hepatocyte infected with pretreatment serum, HBV DNA concentrations were reduced to less than 6% of those in control cultures by addition of lamivudine in concentrations as low as 0.03 mu mol/L. By contrast, in cultures treated with serum taken after recurrence, HBV DNA concentrations did not fall below 20% of control values, even with lamivudine at 30 mu mol/L.Interpretation Resistance to lamivudine has been reported in HIV patients with mutations in the YMDD locus of the polymerase gene. Our findings indicate a common mechanism of lamivudine resistance for HIV and HBV that involves similar point mutations in homologous domains of the viral polymerases.