ICAAC 2013 ：新泰诺福韦配方肾脏和骨骼的影响较小

StephenW

                                                                ICAAC 2013: New Tenofovir Formulation Has Less Effect on Kidneys and Bones                                                                Published on Friday, 13 September 2013 00:00                                                        Written by Liz Highleyman               
                                                                                               

Paul Sax (Photo: Liz Highleyman)

                                       
               
               
                Tenofovir alafenamide (TAF), a new formulation that reaches higher levels in cells but allows for lower dosing, was as effective as the current tenofovir disoproxil fumarate (TDF) formulation but had less impact on markers of kidney function and bone turnover, researchers reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) this week in Denver.

        Tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) is among the most widely used antiretroviral drugs, as it is highly effective and generally regarded as safe and well-tolerated. However, it can cause kidney toxicity in susceptible individuals and is associated with bone loss that begins soon after starting treatment. The long-term consequences of these side effects are a growing concern in light of guidelines recommending earlier treatment and expanding use of Truvada for pre-exposure prophylaxis (PrEP).
        Gilead Sciences' new TAF formulation produces 5-fold higher concentrations of active tenofovir diphosphate in the cells that harbor HIV, but drug levels in the blood remain much lower compared with TDF. This enables reduced dosing that is expected to have less detrimental effects on the kidneys and bones.
        Paul Sax from Brigham and Women's Hospital in Boston presented late-breaking results from a Phase 2 study (GS-US-292-0102) comparing TAF at 10 mg versus TDF at 300 mg, both as part of a single-tablet regimen that also includes the integrase inhibitor elvitegravir, cobicistat (a pharmacoenhancer or "booster"), and emtricitabine. The TDF-containing coformulation is marketed as Stribild; the TAF version is not yet approved. Given the apparent advantages of TAF, advocates have asked Gilead to request approval for the single agent as well as the new coformulation.
        This double-blind, placebo-controlled trial included 170 previously untreated people with HIV who were randomly assigned (2:1) to receive the TAF or TDF coformulations once-daily for 48 weeks.
        Almost all participants were men, more than two-thirds were white, nearly one-third were black, and the median age was about 35 years. The median baseline CD4 T-cell count was about 390 cells/mm3 (though about 15% had less than 200 cells/mm3) and the median viral load was approximately 40,000 copies/mL. At study entry they had normal kidney function with a median estimated glomerular filtration rate (eGFR) of 115 mL/min. People with hepatitis B or C coinfection were excluded.
        Results

•                 At this year's Retrovirus conference, Andrew Zolopa reported 24-week interim data showing that 88% of people taking the TAF coformulation achieved HIV RNA < 50 copies/mL compared with 90% of those taking Stribild.
•                 48-week data showed little change: 88.4% of people in the TAF arm and 87.9% in the TDF arm achieved undetectable viral load in an intent-to-treat "snapshot' analysis" (90.2% vs 89.7% in a missing=failure analysis).
•                 CD4 cell gains at 48 weeks were 177 and 204 cells/mm3, respectively, not a statistically significant difference.
•                 Virological non-response was a bit less common in the TAF group (6.3%) than in the TDF group (10.3%); more Stribild recipients discontinued due to lack of efficacy (3.4% vs none), but more TAF recipients stopped early due to adverse events (3.6% vs none) or had missing 48-week data (5.4% vs 1.7%).
•                 6 participants -- 3 in each arm -- who experienced virological failure underwent resistance testing, which indicated that no one in the TAF arm developed resistance but 2 people taking Stribild showed double resistance mutations (M184V/K70E and M184V/E92Q).
•                 26 patients participated in a pharmacokinetic substudy, which showed:
  

        o   The TAF coformulation produced trough (minimum) and total (area under the curve) tenofovir plasma concentrations of 11 ng/mL and 326 ng*hr/mL, respectively, compared with 83 ng/mL and 3,795 ng*hr/mL with the TDF coformulation.

        o   Overall plasma exposure was 91% lower with TAF.

        o   Conversely, tenofovir diphosphate exposure in peripheral blood mononuclear cells was 5.3-fold higher with TAF than TDF

•                 The TAF and TDF coformulations were both generally safe and well-tolerated, with most side-effects being mild or moderate.
•                 Most adverse events occurred at similar rates in both groups, but nausea was nearly twice as common in the TAF arm (21% vs 12%).
•                 There were no treatment-related serious adverse events in either arm.
•                 Laboratory abnormalities were also generally comparable in the 2 treatment arms.
•                 However, more people in the TAF arm had abnormally high low-density lipoprotein (LDL or "bad cholesterol"); Sax explained that tenofovir has a lipid-lowering effect in the blood, but this didn't happen to the same extent with TAF because its plasma concentration is so much lower.
•                 Turning to kidney function, there was less change in eGFR over time in the TAF coformulation arm compared with the Stribild arm (-5.5 and -10.0, respectively).
•                 Other indicators of kidney function including protein in the urine (2.7% vs 5.2%), changes in serum creatinine (0.9% vs 3.4%), and 2 exploratory urine markers of proximal renal tubulopathy (retinol binding protein/creatinine ratio and beta-2 microglobulin/creatinine ratio) also favored the TAF coformulation.
•                 No cases of renal tubulopathy were seen in either arm, and no one discontinued therapy due to kidney-related side effects.
•                 Looking at bone loss, bone mineral density -- as measured by DEXA scans taken at 24 and 48 weeks -- decreased less in the TAF arm than in the TDF arm both at the spine (-1.00 vs -3.37) and at the hip (-0.62 vs -2.39).
•                 One-third of participants taking the TAF coformulation experienced no change in hip bone density, compared with just 7% in the Stribild arm.
•                 Biomarkers of bone resorption and bone formation favored TAF over TDF (procollagen type 1 N-terminal propeptide: 109% vs 169%; C-terminal telopeptide: 119% vs 178%). No fragility fractures occurred in either arm.
•                 A related poster presentation showed that TAF did not lead to unexpectedly high concentrations of tenofovir in bone-forming cells known as primary osteoblasts and did not have a cytotoxic effect on these cells at clinically relevant concentrations in a laboratory study.
  

        Treatment-naive patients taking the TAF coformulation had high levels of viral suppression over 48 weeks, comparable to those seen with Stribild, the researchers summarized. However, patients taking the TAF coformulation had a smaller decrease in eGFR and significantly smaller decreases in bone mineral density of the hip and spine.
        Kidney biomarker changes have been attributed to cobicistat inhibiting renal tubule secretion, Sax noted. But it not clear why this effect is smaller with TAF than with TDF, since the dose of cobicistat in the coformulations is the same.
        Sax added that Phase 3 studies are underway and researchers are making an "aggressive attempt" to enroll more women.
        9/13/13
        References
        P Sax, I Brar, R Elion, et al. 48-week study of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF), each in a single tablet regimen (STR) with elvitegravir, cobicistat, and emtricitabine [E/C/F/TAF vs. E/C/F/TDF] for initial HIV treatment. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H1464d.
        Y Liu, K Kitrinos, D Babusis et al. Lack of tenofovir alafenamide (TAF) effect on primary osteoblasts in vitro at clinically relevant drug concentrations
. Abstract H-664. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013). Denver, September 10-13, 2013. Abstract H-664.
        Other Source

StephenW

泰诺福韦alafenamide的（ TAF ） ，达到更高水平的细胞，但允许低剂量新配方，是作为当前富马酸替诺福韦（ TDF ）制定有效的，但有肾功能及骨代谢标志物的影响较小，研究人员在第53届跨领域研讨会抗微生物制剂和化疗（ ICAAC 2013 ）本周在丹佛。

替诺福韦（ Viread的，也Truvada的， Atripla的， Complera ， Stribild coformulations的）是其中最广泛使用的抗逆转录病毒药物，因为它是非常有效的，并且普遍认为的安全性和耐受性良好。但是，它可以导致肾毒性易感个体，并伴有骨质流失，尽快开始治疗后开始。这些副作用的长期后果是光的指引，建议早期治疗和扩大使用Truvada的暴露前预防（PrEP ）的日益关注。

吉利德科学公司的新的TAF制定产生5倍的高浓度的主动替诺福韦二磷酸在细胞海港艾滋病毒，但药物在血液中水平仍远低于与TDF 。这可减少剂量，预计将有较少的不利影响，对肾脏和骨骼。

布里格姆和妇女医院在波士顿的保罗·萨克斯提出的最新结果，从第2阶段研究（ GS - US - 292 - 0102 ）比较TAF与TDF 10毫克300毫克，无论是作为一个单一片剂的方案的一部分，也包括整合酶抑制剂elvitegravir的， cobicistat （ pharmacoenhancer或“助力器” ） ，恩曲他滨。含TDF coformulation的是市场Stribild TAF版本尚未得到批准。鉴于TAF优势明显，倡导者们要求吉利德请求批准为单剂以及新coformulation的。

这项双盲，安慰剂对照试验，包括170以前未经治疗的艾滋病病毒感染者被随机分配（2:1）收到的TAF或TDF coformulations的每日一次，共48周。

几乎所有的参与者是男性，超过三分之二为白色，近三分之一是黑人，平均年龄为35岁左右。中位数基线CD4 T细胞计数约390 cells/mm3 （约15％ ，虽然低于200 cells/mm3 ）和病毒载量的中位数约40,000拷贝/ ml 。进入研究时，他们不得不与中位数的估计肾小球滤过率（eGFR ）为115毫升/分钟，肾功能正常。与乙型或丙型肝炎合并感染的人被排除在外。

结果

    在今年的逆转录病毒会议上，安德鲁Zolopa报道为期24周的中期数据显示， 88 ％的人服用TAF coformulation的实现艾滋病毒的RNA < 50拷贝/毫升， Stribild者相比，有90％的。
    48周的数据显示，变化不大： 88.4％的人在TDF臂TAF手臂和87.9％ ，实现了病毒载量检测不到意向性治疗“快照”分析“ （90.2 ％比89.7 ％ ，在一个缺少=失败分析）。
    在48周的CD4细胞收益分别为177和204 cell/mm3之，不具有统计学显着性差异。
    病毒学非的反应是少了几分在TAF组（6.3％）比在TDF组（10.3％） ; Stribild收件人停产，由于缺乏疗效（ 3.4 ％比没有），但更多的TAF收件人早期由于停止不良事件（ 3.6 ％比无）或已经丢失48周的数据（5.4 ％比1.7 ％ ） 。
    6参与者 - 3 - 谁在每个手臂经历病毒学失败进行电阻测试，这表明，在TAF臂产生抗药性，但2人服用Stribild ，没有人表现出双的阻力的突变（ M184V/K70E M184V/E92Q ） 。
    26名患者参加的药代动力学的亚组，这表明：

Ø TAF coformulation的生产槽（最小）和替诺福韦的血浆浓度计（曲线下面积） 11毫微克/毫升和326纳克小时/毫升，分别比83毫微克/毫升和3,795纳克* HR /毫升TDF coformulation 。

Ø总体血浆暴露了TAF低91％ 。

Ø相反，替诺福韦二磷酸暴露在外周血单核细胞高5.3倍，比TDF与TAF

    TAF和TDF coformulations的普遍安全和耐受性良好，大多数副作用是轻度或中度。
    大多数不良事件发生率相似，在这两个群体，但恶心了近两倍，在的TAF手臂（ 21％比12％） 。
    目前还没有治疗相关的严重不良事件，无论是手臂。
    实验室检查异常也普遍在2治疗武器相媲美。
    然而，更多的人在TAF臂有异常高的低密度脂蛋白（ LDL或“坏胆固醇” ） ;萨克斯解释说，替诺福韦在血液中具有降脂作用，但是这并没有发生相同的程度与TAF因为其血药浓度低得多。
    至于肾功能，有EGFR在在TAF coformulation手臂随着时间的推移变化较小比与的Stribild组（分别为-5.5和-10.0， ） 。
    其他肾功能指标，包括尿液中的蛋白质（2.7 ％比5.2 ％ ） ，血清肌酐（ 0.9 ％比3.4％） ，和2个肾近端肾小管尿液标记的探索（视黄醇结合蛋白/肌酐比值和β- 2微球蛋白/肌酐比值）也赞成在TAF coformulation 。
    没有例肾脏肾小管看到无论是手臂，也没有人因终止治疗肾功能相关的副作用。
    在24周和48周寻找骨质流失，骨质密度 - 作为衡量DEXA扫描 - 在TAF臂下降较少比TDF手臂都在脊柱（-1.00与-3.37 ）和臀部（ -0.62和-2.39 ） 。
    有三分之一的参与者服用TAF coformulation的经历没有改变，髋部骨密度， Stribild臂相比，仅有7 ％ 。
    骨吸收和骨形成的生物标志物的青睐TAF超过TDF （ Ⅲ型前胶原N-末端肽： 109％和169％ ; C-末端肽： 119％与178 ％ ） 。无论是手臂没有发生脆性骨折。
    一个相关的海报演示表明， TAF并不会导致至意外高浓度的替诺福韦被称为成骨细胞的成骨细胞，并在临床相关浓度在实验室研究并没有对这些细胞有细胞毒作用。

治疗初治患者服用TAF coformulation的有高水平的病毒抑制，超过48周， Stribild看到，研究人员总结。但是，患者在服用TAF coformulation的跌幅收窄eGFR和髋部和脊柱骨密度显着跌幅较小。

萨克斯指出，肾脏的生物标志物的变化已被归因于cobicistat抑制肾小管分泌。但是，尚不清楚为什么这种影响是小了TAF在coformulations cobicistat的剂量是相同的，因为比与TDF 。

萨克斯说，第3阶段研究正在进行中，研究人员正在“积极尝试”更多的妇女参加。

13年9月13日

参考文献

P萨克斯，我布拉尔， R埃利恩，等。 48周替诺福韦alafenamide的研究（ TAF）与富马酸替诺福韦（ TDF ） ，在一个单一的平板电脑方案（ STR ） ， cobicistat elvitegravir的，和恩曲他滨[ E / C / F / TAF与E / C / F / TDF ]最初艾滋病毒治疗。第53届抗微生物制剂和化疗（ ICAAC 2013）跨学科会议。丹佛， 2013年9月10-13日。摘要H1464d 。

Ÿ刘，K ，D Babusis Kitrinos等。缺乏的替诺福韦alafenamide （ TAF ）影响成骨细胞在体外临床相关的药物浓度
。摘要H - 664 。第53届抗微生物制剂和化疗（ ICAAC 2013 ）跨学科会议。丹佛， 2013年9月10-13日。摘要H - 664 。

StephenW

请注意：以上有关艾滋病毒，需要证实HBV结果.

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