DDW2019[405]效果和安全性结果从 TDF切换至 TAF

StephenW

405
EFFICACY AND SAFETY RESULTS 48 WEEKS AFTER SWITCHING FROMTENOFOVIR DISOPROXIL FUMARATE (TDF) TO TENOFOVIRALAFENAMIDE (TAF) VS CONTINUED TDF TREATMENT INVIROLOGICALLY-SUPPRESSED PATIENTS WITH CHRONIC HEPATITIS B(CHB)Pietro Lampertico, Maria Buti, Scott Fung, Sang Hoon Ahn, Wan-Long Chuang, WonYoung Tak, Alnoor Ramji, Chi-Yi Chen, Edward Tam, Ho Bae, Xiaoli Ma, John F. Flaherty,Anuj Gaggar, Audrey H. Lau, Becket Feierbach, George Wu, Vithika Suri, ManiSubramanian, Huy N. Trinh, Seung-Kew Yoon, Kosh Agarwal, Young-Suk Lim, Henry L.ChanBackground and Aims:TAF, a novel prodrug of tenofovir (TFV), was recently approved for treatment of CHB. TAF has greater plasma stability, more targeted delivery of TFV to the liver, and reduced circulating levels of TFV compared to TDF at approved doses. TAF has  shown efficacy non-inferior to  TDF with improved renal and bone safety in viremic CHB patients at Weeks  48  and  96.  We evaluated efficacy and safety in stable,  virally-suppressed patients who were switched from TDF to TAF vs. continued TDF for an additional year.Method:In this Phase 3 study (NCT02979613), CHB patients on TDF for≥48 weeks with HBV DNA<LLOQ (local laboratory) for≥12 weeks and<20 IU/mL at screening were randomized (1:1) to TAF 25 mg QD or TDF 300 mg QD, each with matching placebo, and treated for 48 weeks. After this, all patients received open-label TAF for an additional 48weeks. The primary efficacy analysis was the proportion of patients with HBV  DNA≥20IU/mL at Week 48 based on the modified US FDA-defined Snapshot algorithm; the study was powered to show non-inferiority in efficacy of TAF compared to TDF, with a 4% margin.Key prespecified secondary safety endpoints were assessed sequentially: changes in hip and spine bone mineral density (BMD), and changes in estimated creatinine clearance by Cock-croft-Gault  (eGFRCG).  Markers of bone turnover and renal tubular function were serially assessed. Viral resistance was evaluated by population sequencing those patients who experienced virologic breakthrough or viremia at the time of discontinuation.Results:488 patients were randomized and treated at 42 sites in 8 countries. At baseline the groups were similar:median age 52 y (22%≥60 y), 71% male, 82% Asian, 68% HBeAg-negative, and medianALT 23 U/L. Median eGFRCGwas 90.5 mL/min; 45% and 50% had low BMD by T scores at hip and spine, respectively. Median (Q1, Q3) duration of prior TDF was 222 (145, 305)weeks.  Key efficacy/safety results are summarized in the  Table.  TAF  demonstrated  non-inferior efficacy to TDF with a similar rate (0.4%) having HBV DNA≥20 IU/mL at Week48, (difference in proportions: 0.0%, 95% CI, -1.9% to 2.0%). TAF treatment resulted in increases in hip/spine BMD with less impact on bone turnover makers; switching from TDF to  TAF  also resulted in increased eGFRCG and decreases in markers of tubular function. Rates  of ≥Grade  2 adverse events (AEs) and serious AEs  were low and similar  between groups. No viral resistance was observed in the 3/243 (1.2%) and 2/245 (0.8%) TAF andTDF patients, respectively, who qualified for testing.Conclusion: Virologically-suppressed CHB patients  who were switched  to TAF  demonstrated non inferior efficacy  to continued TDF with improved bone and renal safety

StephenW

405
效果和安全性结果从TENOFOVIR DISOPROXIL FMAARATE（TDF）切换至TENOFOVIRALAFENAMIDE（TAF）后继续使用TDF治疗慢性乙型肝炎患者（CHB）Pietro Lampertico，Maria Buti，Scott Fung，Sang Hoon Ahn，Wan-Long Chuang，WonYoung Tak，Alnoor Ramji，Chi-Yi Chen，Edward Tam，Ho Bae，Xiaoli Ma，John F. Flaherty，Anuj Gaggar，Audrey H. Lau，Becket Feierbach，George Wu，Vithika Suri，ManiSubramanian，Huy N. Trinh ，Seung-Kew Yoon，Kosh Agarwal，Young-Suk Lim，Henry L.ChanBackground和Aims：TAF，一种新型的替诺福韦（TFV）前药，最近被批准用于治疗CHB。与批准剂量的TDF相比，TAF具有更高的血浆稳定性，更有针对性地将TFV递送至肝脏，并且降低了TFV的循环水平。在第48周和第96周，TAF显示效果不低于TDF，改善了viremicCHB患者的肾脏和骨骼安全性。我们评估了稳定的，病毒抑制的患者的疗效和安全性，这些患者从TDF转为TAF而不是继续使用TDF 。方法：在这项3期研究（NCT02979613）中，在HBF DNA <LLOQ（当地实验室）≥12周且≥10周且在筛查时<20 IU / mL的TDF患者≥30周的CHB患者随机（1：1）至TAF 25 mg QD或TDF 300 mg QD，每种都配有匹配的安慰剂，并治疗48周。在此之后，所有患者接受开放标签TAF再持续48周。主要疗效分析是基于修改后的美国FDA定义的快照算法，第48周HBVDNA≥20IU/ mL的患者比例;该研究显示，与TDF相比，TAF的疗效非劣效，保证金为4％。按顺序评估关键的预期次要安全性终点：髋骨和脊柱骨密度（BMD）的变化，以及Cock估计肌酐清除率的变化-croft-Gault（eGFRCG）。连续评估骨转换和肾小管功能的标志物。通过对在停药时经历病毒学突破或病毒血症的患者进行人群测序来评估病毒抗性。结果：488名患者被随机分组​​并在8个国家的42个地点接受治疗。在基线时，各组相似：中位年龄52岁（22％≥60岁），71％男性，82％亚洲人，68％HBeAg阴性，中位数为23 U / L.中位数eGFRCG为90.5 mL / min; 45％和50％的髋部和脊柱T分数均低于BMD。先前TDF的中位数（Q1，Q3）持续时间为222（145,305）周。关键功效/安全性结果总结在表中。 TAF表现出对TDF的非劣效性，在第48周具有相似的HBVDNA≥20IU/ mL的比率（0.4％）（比例差异：0.0％，95％CI，-1.9％至2.0％）。 TAF治疗导致髋/脊柱BMD增加，对骨转换制造者的影响较小;从TDF转换为TAF也导致eGFRCG增加和管状功能标志物减少。 ≥Grade2不良事件（AEs）和严重AE的发生率较低且组间相似。在符合检测条件的3/243（1.2％）和2/245（0.8％）TAF和TDF患者中均未观察到病毒耐药。结论：病毒学抑制的转为TAF的CHB患者对继续使用TFF表现出非劣效性。改善骨骼和肾脏安全性

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