No Resistance to Tenofovir Disoproxil Fumarate Detected After up to 144 Weeks of Therapy in Patients Monoinfected With Chronic Hepatitis B Virus
No Resistance to Tenofovir Disoproxil Fumarate Detected After up to 144 Weeks of Therapy in Patients Monoinfected With Chronic Hepatitis B Virus
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DOI：
10.1002/hep.24078
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发表时间：
2011-03-01
期刊：
影响因子：
13.5
通讯作者：
Borroto-Esoda, Katyna
中科院分区：
文献类型：
--
作者：
Snow-Lampart, Andrea;Chappell, Brandi;Borroto-Esoda, Katyna
富马酸替诺福韦酯（TDF）是一种核苷酸类似物，具有有效的抗人类免疫缺陷病毒1型和B肝炎病毒（HBV）活性。迄今为止，尚未证实HBV对TDF临床耐药的报告。在两项3期研究（GS-US-174-0102和GS-US-174-0103）中，375例B肝炎e抗原阴性（HBeAg-）患者和266例HBeAg+慢性B肝炎患者（一些核苷类药物初治，一些拉米夫定治疗）以2：1的比例随机接受TDF（n = 426）或阿德福韦酯（ADV; n = 215）治疗48周。第48周后，合格患者接受开放标签TDF，无中断。研究持续至第384周/第8年;第144周数据见此处。根据方案，病毒血症患者（HBV DNA水平>= 400拷贝/mL或69 IU/mL）可以选择在第72周或之后添加恩曲他滨（FTC）。HBV聚合酶/逆转录酶（pol/RT）耐药分析基于群体双脱氧测序。在具有源自患者血清的重组HBV的HepG 2细胞中进行表型分析。在两项研究中，大多数患者维持TDF单药治疗（607/641，95%）。在基线时对所有患者、第144周或接受TDF单药治疗的最后一次病毒血症患者（34例接受TDF治疗，19例接受ADV-TDF治疗）以及在添加FTC后仍保持病毒血症的患者（7/20例接受TDF治疗，5/14例接受ADV-TDF治疗）进行HBV pol/RT耐药分析。没有患者发生与TDF耐药相关的氨基酸置换。在144周内，TDF单药治疗的病毒学突破并不常见（13/426，3%），大多数病例（11/13，85%）归因于记录的不依从性。持续到第144周的病毒血症（>= 400拷贝/mL）是罕见的（5/641，0.8%），并且通过群体或克隆分析与对TDF的病毒学耐药性无关。结论：在暴露于TDF单药治疗长达144周后，核苷初治或核苷经验丰富的患者均未发生与TDF耐药相关的HBV pol/RT突变。（肝脏学2011;53：763-773）
Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with potent activity against human immunodeficiency virus type 1 and hepatitis B virus (HBV). To date, no reports of HBV clinical resistance to TDF have been confirmed. In two phase 3 studies (GS-US-174-0102 and GS-US-174-0103), 375 hepatitis B e antigen-negative (HBeAg-) patients and 266 HBeAg+ patients with chronic hepatitis B (some nucleoside-naive and some lamivudine-experienced) were randomized 2:1 to receive TDF (n = 426) or adefovir dipivoxil (ADV; n = 215) for 48 weeks. After week 48, eligible patients received open-label TDF with no interruption. The studies are being continued through week 384/year 8; week 144 data are presented here. Per protocol, viremic patients (HBV DNA level >= 400 copies/mL or 69 IU/mL) had the option of adding emtricitabine (FTC) at or after week 72. Resistance analyses of HBV polymerase/reverse transcriptase (pol/RT) were based on population dideoxy sequencing. Phenotypic analyses were conducted in HepG2 cells with recombinant HBV derived from patient serum. Most patients maintained TDF monotherapy treatment across both studies (607/641, 95%). A resistance analysis of HBV pol/RT was performed at the baseline for all patients, for viremic patients at week 144 or at the last time when they were on TDF monotherapy (34 on TDF and 19 on ADV-TDF), and for patients who remained viremic after the addition of FTC (7/20 on TDF and 5/14 on ADV-TDF). No patient developed amino acid substitutions associated with resistance to TDF. Virological breakthrough on TDF monotherapy was infrequent over 144 weeks (13/426, 3%) and was attributed to documented nonadherence in most cases (11/13, 85%). Persistent viremia (>= 400 copies/mL) through week 144 was rare (5/641, 0.8%) and was not associated with virological resistance to TDF by population or clonal analyses. Conclusion: No nucleoside-naive or nucleoside-experienced patient developed HBV pol/RT mutations associated with TDF resistance after up to 144 weeks of exposure to TDF monotherapy. (HEPATOLOGY 2011;53:763-773)