Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
Department of Research and Development, Gilead Sciences, Inc, Foster City, California.
Clin Gastroenterol Hepatol. 2014 Dec;12(12):2106-12.e1. doi: 10.1016/j.cgh.2014.05.024. Epub 2014 Jun 11.
BACKGROUND & AIMS: A recent study compared the efficacy of tenofovir disoproxil fumarate (TDF) vs the combination of emtricitabine and TDF (FTC/TDF) in patients with lamivudine-resistant chronic hepatitis B who were treated for as long as 96 weeks. We report findings from resistance analyses conducted for this study.
Two hundred eighty patients with chronic hepatitis B virus (HBV) infection and lamivudine resistance (confirmed by INNO-LiPA Multi-DR) were randomly assigned (1:1) to groups treated with TDF or FTC/TDF. The HBV reverse transcriptase domain from the polymerase gene from all patients was sequenced at baseline and from 18 viremic patients at week 96 or early discontinuation.
At screening for the efficacy study, 99% of patients were found to have lamivudine resistance. Prior exposure to entecavir or entecavir resistance was observed in 12% of patients, and 22% of patients had been previously exposed to adefovir; 1.8% were resistant to adefovir. Only 18 patients (6.4%) qualified for sequence analysis, including 1 patient who experienced virologic breakthrough and 17 with persistent viremia. Six of these patients did not have any sequence changes from baseline in HBV reverse transcriptase (33%), and sequence analysis could not be performed for 5 patients (28%). In 2 patients who qualified for phenotypic analysis (1 given TDF and 1 given FTC/TDF), no resistance to TDF was observed. Neither previous treatment exposure nor resistance to entecavir or adefovir affected viral kinetics. However, the mean baseline level of HBV DNA was significantly higher in viremic patients than in patients with viral suppression by week 96 (7.28 log10 IU/mL vs 5.62 log10 IU/mL; P = .0003).
No resistance to TDF was detected through 96 weeks of treatment in patients with lamivudine-resistant chronic hepatitis B. Prior treatment or resistance to entecavir or adefovir did not affect viral kinetics through 96 weeks. No additional benefit was observed with the addition of emtricitabine vs TDF monotherapy. ClinicalTrial.gov number: NCT00737568.
最近的一项研究比较了替诺福韦酯（TDF）与恩曲他滨和 TDF（FTC/TDF）联合治疗拉米夫定耐药慢性乙型肝炎患者的疗效，这些患者最长接受了 96 周的治疗。我们报告了这项研究中进行的耐药性分析结果。
280 例慢性乙型肝炎病毒（HBV）感染且对拉米夫定耐药（通过 INNO-LiPA Multi-DR 确认）的患者被随机（1:1）分配至 TDF 或 FTC/TDF 治疗组。所有患者在基线时和 96 周或提前停药时的 18 例病毒血症患者中对 HBV 聚合酶基因的逆转录酶区域进行了测序。
在疗效研究的筛查时，99%的患者发现存在拉米夫定耐药。12%的患者先前接触过恩替卡韦或恩替卡韦耐药，22%的患者先前接触过阿德福韦；1.8%的患者对阿德福韦耐药。仅有 18 例患者（6.4%）符合测序分析条件，包括 1 例发生病毒学突破和 17 例持续病毒血症的患者。这些患者中有 6 例（33%）HBV 逆转录酶没有任何基线序列改变，5 例（28%）无法进行序列分析。在符合表型分析的 2 例患者中（1 例给予 TDF，1 例给予 FTC/TDF），未观察到对 TDF 的耐药性。先前的治疗暴露或恩替卡韦或阿德福韦耐药均未影响病毒动力学。然而，与第 96 周时病毒抑制的患者相比，病毒血症患者的基线 HBV DNA 水平显著更高（7.28 log10 IU/mL 比 5.62 log10 IU/mL；P =.0003）。
在拉米夫定耐药的慢性乙型肝炎患者中，经过 96 周的治疗未检测到对 TDF 的耐药性。在第 96 周时，先前的治疗或恩替卡韦或阿德福韦耐药未影响病毒动力学。与 TDF 单药治疗相比，添加恩曲他滨没有观察到额外的益处。临床试验注册号：NCT00737568。
