Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy
Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy
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DOI：
10.1002/hep.21253
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发表时间：
2006-08-01
期刊：
影响因子：
13.5
通讯作者：
Berg, Thomas
中科院分区：
文献类型：
--
作者：
van Boemmel, Florian;Zoellner, Bernhard;Berg, Thomas
在拉米夫定耐药的B型肝炎病毒（HBV）感染患者中观察到对阿德福韦酯（ADV）的不完全病毒学应答，可能与耐药和疾病进展有关。因此，我们研究了用富马酸替诺福韦酯（TDF）替代ADV是否可以提高病毒抑制的疗效。20例慢性HBV感染（18例HBeAg+）、拉米夫定治疗期间病毒突破和ADV单药治疗15个月（范围4-28个月）后持续病毒复制（> 10（4）拷贝/mL）的患者接受TDF 300 mg每日治疗，并进行回顾性分析。通过直接测序对所有患者进行HBV聚合酶基因内核苷/核苷酸类似物耐药突变筛查。在中位3.5个月内，应用TDF导致20例患者中有19例检测不到HBV DNA，表现为HBV DNA抑制低于400拷贝/mL的检测限。14例患者中有10例在随访结束时（中位12个月，范围3-24个月），最初升高的ALT水平恢复正常。4例患者在3、4、5和16个月后HBeAg消失，1例患者在TDF治疗16个月后血清转化为抗-HBs。6例患者在TDF基线时检测到拉米夫定相关突变（rtV 1731、rtIL 180 M、rtM 204 V/1），但这显然不影响疗效。未检测到ADV耐药突变。未报告副作用。总之，这些初步的观察结果强烈提示TDF可能是一种非常有效的拯救药物，用于对拉米夫定和ADV治疗反应性改变的HBV感染患者。
Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine-resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxit fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg+), viral breakthrough during lamivudine therapy, and persistent viral replication (> 10(4) Copies/mL) after 15 months of ADV monotherapy (range 4-28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow-up (median 12 months, range 3-24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti-HBs after 16 months of TDF therapy. Lamivudine-associated mutations (rtV1731, rtIL180M, rtM204V/1) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV-resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV-infected patients with altered responsiveness to treatment with lamivudine and ADV.