在慢性乙型肝炎患者中通过96周治疗未检测到对替诺福韦阿拉

StephenW

Antimicrob Agents Chemother. 2018 Jul 23. pii: AAC.01064-18. doi: 10.1128/AAC.01064-18. [Epub ahead of print]
No Resistance to Tenofovir Alafenamide Detected Through 96 Weeks of Treatment in Patients with Chronic Hepatitis B.
Cathcart AL1, Chan HL2, Bhardwaj N3, Liu Y3, Marcellin P4, Pan CQ5, Shalimar6, Buti M7, Cox S3, Parhy B3, Zhou E3, Martin R3, Chang S3, Lin L3, Flaherty JF3, Kitrinos KM3, Gaggar A3, Izumi N8, Lim YS9.
Author information

1
    Gilead Sciences, Foster City, CA, United States [email protected].
2
    Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
3
    Gilead Sciences, Foster City, CA, United States.
4
    Service d'Hépatologie, Hôpital Beaujon, Clichy, France.
5
    Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Medical Center, NYU School of Medicine, New York, NY.
6
    Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
7
    Hospital Universitari Vall d'Hebron, Barcelona, Spain.
8
    Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
9
    Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Abstract

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In 2 clinical trials, 1298 HBeAg-positive and HBeAg-negative patients with CHB were randomized 2:1 and treated with TAF (n=866) or TDF (n=432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (pol/RT) were assessed using INNO-LiPA Multi DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥69IU/mL) by HBV pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to study drug. At baseline, the majority of patients harbored virus with wild type pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF 11.1%, TDF 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF: 2.8%, TDF: 3.2%) that was often associated with drug nonadherence (TAF: 30%, TDF: 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96 with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro. After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA <69 IU/mL) was similar across treatment groups and no substitutions associated with resistance to TAF or TDF were detected.

PMID:
    30038044
DOI:
    10.1128/AAC.01064-18

StephenW

抗微生物剂Chemother。 2018年7月23日.pii：AAC.01064-18。 doi：10.1128 / AAC.01064-18。 [提前打印]
在慢性乙型肝炎患者中通过96周治疗未检测到对替诺福韦阿拉芬胺的耐药性
Cathcart AL1，Chan HL2，Bhardwaj N3，Liu Y3，Marcellin P4，Pan CQ5，Shalimar6，Buti M7，Cox S3，Parhy B3，Zhou E3，Martin R3，Chang S3，Lin L3，Flaherty JF3，Kitrinos KM3，Gaggar A3， Izumi N8，Lim YS9。
作者信息

1
    Gilead Sciences，Foster City，CA，美国[email protected]。
2
    香港中文大学消化病研究所医学与治疗学系消化疾病国家重点实验室。
3
    吉利德科学，福斯特城，加利福尼亚州，美国。
4
    Service d'Hépatologie，HôpitalBeaujon，Clichy，France。
五
    纽约大学朗格医学中心医学系消化内科和肝脏病学系，纽约大学医学院，纽约，纽约。
6
    印度新德里全印度医学科学院消化内科。
7
    医院Universitari Vall d'Hebron，巴塞罗那，西班牙。
8
    日本东京武藏野红十字医院消化内科和肝病科。
9
    韩国首尔蔚山大学医学院牙山医学系消化内科。

抽象

与替诺福韦地索普西富马酸盐（TDF）相比，替诺福韦艾拉酚胺（TAF）显示出与慢性乙型肝炎（CHB）患者相当的疗效和改善的安全性。但是，有限的数据可用于其电阻曲线。在2项临床试验中，1298例HBeAg阳性和HBeAg阴性的CHB患者按2：1随机分组，并用TAF（n = 866）或TDF（n = 432）治疗。使用INNO-LiPA Multi DR v2 / v3评估HBV聚合酶/逆转录酶（pol / RT）中的基线核苷（t）ide类似物抗性取代。在第96周或停药时，通过HBV pol / RT测序对病毒血症（HBVDNA≥69IU/ mL）患者进行耐药性监测。对具有保守位点置换或病毒学突破的患者进行体外表型分析，同时粘附于研究药物。在基线时，大多数患者携带野生型pol / RT病毒（89.2％），其中10.8％具有抗性相关突变。在第96周，TAF或TDF组中相似百分比的患者符合序列分析（TAF 11.1％，TDF 10.9％）。其中，一小部分患者经历了病毒学突破（TAF：2.8％，TDF：3.2％），这通常与药物不依从性相关（TAF：30％，TDF：50％）。在整个治疗组中，132名患者在第96周时有资格进行序列分析，其中近一半患者与基线无序列变化（43.2％）。大多数序列变化发生在多态性位置，并且没有分离物显示体外易感性降低。 96周后，实现病毒抑制的患者比例（HBV DNA <69 IU / mL）在治疗组中相似，未检测到与TAF或TDF抗性相关的替代。

结论：
    30038044
DOI：
    10.1128 / AAC.01064-18