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标题: CROI2015:替诺福韦Alafenamide有效,但更安全的肾脏和骨骼比TDF [打印本页]

作者: newchinabok    时间: 2015-3-14 09:48     标题: CROI2015:替诺福韦Alafenamide有效,但更安全的肾脏和骨骼比TDF

CROI 2015: Tenofovir Alafenamide as Effective but Safer for Kidneys and Bones than TDF
Print         Email Details Category: Experimental HIV Drugs         Published on Friday, 27 February 2015 00:00         Written by Liz Highleyman
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Paul Sax (Photo: Liz Highleyman)
Tenofovir alafenamide (TAF), a new formulation that has lower concentrations in the blood but reaches higher levels in cells, is as effective as the older version, tenofovir disoproxil fumarate (TDF), according to a report at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle. A second study showed that TAF has less detrimental effects on the kidneys and bones compared with TDF. TAF has been submitted for approval in the U.S. and Europe.

Gilead Sciences' tenofovir disoproxil fumarate (Viread) is one of the most widely used antiretroviral drugs. It is a component of the Truvada coformulation -- used for both HIV treatment and pre-exposure prophylaxis (PrEP) -- and of the single-tablet regimens Atripla, Compera, and Stribild. TDF is highly potent and generally safe and well-tolerated, but it can cause kidney and bone toxicity in some patients.

TAF is a new pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells infected with HIV. TAF produces adequate intracellular levels with lower doses, which means lower concentrations in the blood plasma and less drug exposure for the kidneys, bones and other organs and tissues. A Phase 2 clinical trial previously showed that a regimen of TAF plus emtricitabine, elvitegravir, and cobicistat was comparable to TDF/emtricitabine/elvitegravir/cobicistat (Stribild) but caused less kidney impairment and bone loss.

David Wohl from the University of North Carolina presented combined primary results from 2 Phase 3 studies (GS-US-292-0104 and GS-US-292-0111) looking at the antiviral activity and overall safety of TAF in a new single-tablet regimen. Paul Sax from Brigham and Women's Hospital in Boston followed the next day with data on TAF's effects on kidneys, bones, and lipids.

Study 104 and Study 111 were randomized controlled trials conducted in Europe (both), North America (both), Latin America (Study 111), and Asia (Study 104). Together they included 1733 previously untreated participants with similar characteristics in both trials.

Most (85%) were men, one-quarter were black, 19% were Hispanic/Latino, and the median age was 34 years. They had well-controlled HIV disease with a median viral load of 4.58 log copies/mL and a median CD4 cell counts of approximately 400 cells/mm3. They had normal kidney function at baseline with a median estimated glomerular filtration rate (eGFR) of approximately 115 mL/min.

Participants were randomly assigned to receive a once-daily single-tablet regimen containing emtricitabine, elvitegravir, and cobicistat with either 10 mg TAF or 300 mg TDF. The primary analysis was done at week 48 of treatment.

Efficacy and Overall Safety Results

The 2 regimens had similar high efficacy, showing that the TAF coformulation is non-inferior to the TDF coformulation.
At 48 weeks, 92% of people in the TAF arm and 90% in the TDF arm achieved viral suppression (HIV RNA <50 copies/mL) in the combined analysis (93% vs 92% in Study 104; 92% vs 89% in Study 111).
CD4 cell gains were also similar, at 211 cells/mm3 in the TAF arm and 181 cells/mm3 in the TDF arm.
Viral suppression rates for the TAF and TDF regimens were similar regardless of whether participants had high or low baseline viral load, CD4 counts above or below 200 cells/mm3, male or female sex, black or non-black race/ethnicity, and age over or under 50 years.
In both studies, 4% of participants experienced virological failure; among the small number (about 2%) who met the criteria for resistance testing, very few in either arm showed evidence of any primary resistance mutations (0.8% with TAF, 0.6% with TDF).
Treatment was generally safe and well-tolerated and overall drug safety profiles were similar in both arms.
45 patients (5%) in the TAF arm and 71 (8%) in the TDF arm discontinued treatment early, including 8 and 13 people, respectively, who did so due to adverse events.
About 40% of participants overall experienced drug-related adverse events, mostly mild-to-moderate.
The most common side effects were diarrhea (18%), nausea (16%), and headache, all occurring with similar frequency in both groups.
In both the TAF and TDF arms there were few serious adverse events (8% vs 7%) or drug discontinuation for this reason (0.9% vs 1.5%); 20% experienced grade 3 or 4 laboratory abnormalities in both groups.
"Nothing stood out" in terms of adverse events association with TAF that have not already been seen with TDF, Wohl said.

Kidney, Bone, and Lipid Results

In a separate report, Sax described kidney, bone, and lipid-related adverse events and toxicities.

A pharmacokinetic analysis confirmed that TAF produced lower plasma levels of tenofovir than TDF, but intracellular levels were 4 times higher with TAF; the steady-state tenofovir concentration was 91% lower with TAF compared to TDF.

Looking at kidney-related side-effects, eGFR decreased -- indicating worsening function -- by -6.6% in the TAF arm and by -11.2% in the TDF arm by week 48. The change occurred during the first few weeks of treatment and then stabilized.

In the TAF arm there were no kidney-related adverse events leading to treatment discontinuation. 3 people had hypophosphataemia and 2 had protein in their urine. In the TDF arm, there were 4 kidney-related discontinuations: 2 cases of kidney failure, 1 person with decreased eGFR, and 1 with nephropathy. In addition, 1 patient had subclinical tubulopathy, 4 had hypophosphataemia, and 2 each had glucose and protein in their urine. No one in either arm, however, had overt tubulopathy or Fanconi syndrome.

Turning to bone effects, DEXA measurements were done at baseline and at weeks 24 and 48. People taking TAF experienced smaller average decreases in bone mineral density at 48 weeks than people taking TDF at both the spine (-1.30 vs -2.86) and the hip (-0.66 vs -2.95). Spinal bone loss started soon after starting treatment, reaching a plateau at 24 weeks. Hip bone mineral density continued to fall through week 48, but much more steeply in the TDF arm.

However, not everyone experienced bone loss. In the TAF group, 26% had spine bone loss and 17% had hip bone loss of at least 3%. Bone loss occurred more often in the TDF arm, with 45% and 50% having at least a 3% decrease at the spine and hip, respectively. A small proportion of participants actually gained bone density: 7% at both the spine and hip in the TAF arm, and 3% at both sites in the TDF arm.

Finally, researchers looked at blood lipid levels, which are known to play a role in cardiovascular disease. Levels of total, LDL ("bad") and HDL ("good") cholesterol, as well as triglycerides, rose by small amounts across the board, but more so in the TAF arm; total-to-HDL cholesterol ratio stayed about the same.

Sax suggested that the lipid differences might be occurring because tenofovir reduces lipid levels, but the lower concentration produced by TAF does so less compared with TDF.

Conclusions

Wohl’s team concluded that the TAF and TDF coformulations led to "high and similar response rates, irrespective of age, sex, race, HIV-1 RNA, and CD4 cell count," with "low rates of virological failure, with resistance <1% in both arms."

"Efficacy was very comparable and clearly TAF held its own against TDF," Wohl said at a CROI press conference. "This is very reassuring data as we think about TAF as a component of antiretroviral therapy."

Sax’s team concluded that "detailed protocol-specified renal [kidney] and bone endpoints confirmed the favorable safety and tolerability profile of TAF." Compared with TDF, TAF demonstrated no discontinuations due to renal adverse events; significantly smaller decreases in eGFR; significantly less proteinuria, albuminuria, and tubular proteinuria; significantly less impact on spine and hip bone mineral density; and greater increases in fasting lipids.

Sax explained at the press conference that while the long-term clinical effects are not yet known, this analysis "strongly suggests [TAF] will be safer in the long run for the kidneys and bones than TDF."

Based on these favorable findings, Gilead has submitted the TAF coformulation for regulatory review in the U.S. Europe. The U.S. Food and Drug Administration (FDA) is expected to make a decision by November 2015.

Stand-alone TAF is also being developed as a treatment for hepatitis B virus (HBV) infection. In addition, the company is developing a dual coformulation of TAF and emtricitabine, which will be the successor to Truvada.

Asked about the role of TAF as PrEP for HIV prevention, Marshall Fordyce from Gilead said at the press conference that the company is collaborating with the U.S. Centers for Disease Control and Prevention (CDC) on a study of emtricitabine and TAF for PrEP in macaque monkeys. Fordyce noted that the TAF combination "will have the same development pathway" as TDF for PrEP, presumably suggesting that Gilead will not conduct PrEP trials itself. "To reproduce iPrEx [with the new formulation] would be a large undertaking," he
作者: newchinabok    时间: 2015-3-14 09:49

CROI 2015:替诺福韦Alafenamide有效,但更安全的肾脏和骨骼比TDF
打印Email详细资料分类:实验HIV药物上周五公布,2015年2月27日00:00撰稿利兹Highleyman
ALT
保罗·萨克斯(图片:利兹Highleyman)
替诺福韦alafenamide(TAF),一个新的提法,在血液中浓度较低,但在细胞中达到更高的水平,是有效的旧版本,富马酸替诺福韦酯(TDF),根据在2015年会议上逆转录病毒和机会的报告感染(CROI)本周在西雅图。另一项研究表明,TAF对与TDF相比,肾脏和骨骼少的不利影响。 TAF已经报批,在美国和欧洲。

吉利德科学'富马酸替诺福韦酯(Viread的)是使用最广泛的抗逆转录病毒药物之一。它是特鲁瓦达coformulation的组分 - 同时用于艾滋病治疗和暴露前预防(PREP) - 和单片剂的服法ATRIPLA,Compera和Stribild。 TDF是高度有效的和一般是安全且耐受性良好,但它可以引起肾和骨毒性在一些患者。

TAF是一个新的前体药物,提供活性剂,替诺福韦二磷酸,更有效地细胞感染了艾滋病毒。 TAF产生足够的细胞内水平与较低剂量,这意味着血浆和更少的药物暴露于肾脏,骨头和其他器官和组织中的浓度较低。第2阶段的临床试验以前表明,TAF加恩曲他滨,elvitegravir,和cobicistat的一个方案是可比的TDF /恩曲他滨/ elvitegravir / cobicistat(Stribild),但​​引起较少肾损伤和骨质流失。

来自北卡罗莱纳大学的戴维·沃尔介绍,从2 3期研究(GS-US-292-0104和GS-US-292-0111)看着TAF的抗病毒活性和整体安全性的新单片联合初步结果养生之道。保罗·萨克斯来自布莱根妇女医院在波士顿跟随第二天上肾脏,骨骼和血脂TAF的效果数据。

研究104和111研究在欧洲(两者),北美(两者),拉丁美洲(研究111)进行的随机对照试验,和亚洲(104研究)。他们一起列入1733以前未经治疗的参与者在两个试验相似的特点。

大多数(85%)为男性,四分之一是黑人,19%是西班牙裔美国人/拉丁美洲,中位年龄为34岁。他们良好控制HIV病的4.58日志拷贝/ mL的平均病毒载量和大约400个/ mm3的中位数CD4细胞计数。它们具有正常的肾功能基线的中值估计的肾小球滤过率的约115毫升/分钟(EGFR)。

参与者被随机分配接受每日一次的含单片方案恩曲他滨,elvitegravir和cobicistat带为10毫克TAF或300毫克TDF。初步分析已完成在治疗48周。

功效和整体安全性结果

2方案也有类似的高效力,表明TAF coformulation是非劣于TDF coformulation。
在48周,人在TAF臂和90%,在TDF臂92%实现了抑制病毒(HIV RNA <50拷贝/毫升)的组合分析(93%比92%的研究104; 92%和89%的在研究111)。
CD4细胞涨幅也相似,在TAF手臂211个/ mm3和TDF手臂181个/ mm3。
病毒抑制率的TAF和TDF方案相似,无论参与者高或低基线病毒载量,CD4计数高于或低于200个/ mm3,男性或女性,黑色或不黑种族/族裔和年龄超过或根据50年。
在两项研究中,参与者的4%经历了病毒学失败;在小数量(约2%)谁见了标准电阻测试,很少在任何手臂显示任何原发性耐药突变的证据(0.8%TAF,0.6%与TDF)。
治疗一般是安全和耐受性良好及整体用药安全配置文件是在这两个武器类似。
45例(5%),在TAF手臂和71(8%)在TDF手臂停产早期治疗,包括8和13人,分别谁这样做,由于不良事件。
约40%的参与者整体经历药物相关的不良事件,多为轻至中度。
最常见的副作用是腹泻(18%),恶心(16%),头痛,全部采用两组相似的频率出现。
在TAF和TDF手臂均很少有严重不良事件(8%和7%),或者因为这个原因(0.9%对1.5%),停药; 20%经验丰富的3级或4实验室异常两组。
不良事件的关联与TAF还没有已经看到的TDF方面“没什么一枝独秀”,Wohl说。

肾,骨和脂质结果

在另一份报告中,萨克斯描述肾脏,骨骼和脂肪有关的不良事件和不良反应。

药代动力学分析证实,TAF生产替诺福韦TDF比降低血浆浓度,但细胞内水平高4倍与TAF;稳态诺福韦浓度降低91%的TAF相比TDF。

纵观肾脏相关的副作用,EGFR下降 - 这表明不断恶化的功能 - 由-6.6%,在TAF的手臂和-11.2%,在TDF手臂由48周期间的头几个星期的治疗发生了变化,那么稳定。

在TAF手臂没有肾相关的不良事件导致治疗中断。 3人有低磷酸盐血症,2例蛋白在他们的尿液。在TDF手臂,有4肾相关的停药2例肾功能衰竭,1人以降低EGFR,1例肾病。此外,1例有亚临床型肾小管病,4例低磷酸盐血症和2各有葡萄糖和蛋白质在他们的尿液。没有人在任何手臂,然而,有明显的肾小管病或Fanconi综合征。

谈到骨效应,DEXA测量完成在基线和24周和48人正在经历TAF骨矿物质密度较小的平均跌幅在48周的人比服用TDF在两个脊椎(-1.30 VS -2.86)和臀部(-0.66 VS -2.95)。脊柱骨质流失很快就开始在开始治疗后,在24周时达到平台。髋部骨密度继续下降至48周,但更陡峭的TDF手臂。

然而,不是每个人都经历了骨量丢失。在TAF组,26%的患者脊柱的骨损失和17%的患者髋骨的骨损失中的至少3%。骨损失在TDF臂更经常发生,用45%,并具有至少3%的下降,在脊柱和髋部,分别为50%。与会者小部分实际上已经获得骨密度:7%的无论是在TAF臂脊柱和髋部,以及3%的TDF手臂两个站点。

最后,研究人员观察血脂水平,这是众所周知的发挥在心血管疾病的作用。总共,低密度脂蛋白水平(“坏”)和高密度脂蛋白(“好”)胆固醇,以及甘油三酯,上升全线少量的,但更多的是在该TAF臂;总对HDL胆固醇的比例停留差不多。

萨克斯表明脂质差异可能发生的,因为减少了替诺福韦脂质水平,但是由TAF产生的低浓度并因此较少与TDF比较。

结论

沃尔的研究小组得出的结论是,TAF和TDF共配导致了“高,类似的反应率,不论年龄,性别,种族,HIV-1 RNA和CD4细胞计数,”与“病毒学失败率很低,电阻<1%双臂“。

“功效很是可比的,明确TAF举行了自己对TDF,”沃尔在CROI新闻发布会上说。 “这是非常令人欣慰的数据,我们认为有关TAF作为抗逆转录病毒治疗的一个组成部分。”

萨克斯的研究小组得出结论认为,“详细的协议规定的肾[肾]和骨终点证实TAF的良好的安全性和耐受性。”与TDF相比,TAF证明因肾功能不良事件没有停药;显著较小的跌幅表皮生长因子受体;显著少蛋白尿,蛋白尿和肾小管性蛋白尿;对脊柱和髋部的骨密度显著的影响较小;和更大的增加空腹血脂。

萨克斯在新闻发布会上说,虽然尚不清楚长期的临床效果,这种分析解释“强烈暗示[TAF]将是更安全的,从长远来看对肾脏和骨骼比TDF。”

基于这些有利的结果,Gilead公司已经提交了TAF coformulation在美国欧洲的监管审查。美国食品和药物管理局(FDA),预计到2015年11月作出决定。

单机TAF也被开发作为对乙型肝炎病毒(HBV)感染的疗法。此外,该公司正在开发TAF和恩曲他滨的双coformulation,这将是继任者特鲁瓦达。

当被问及TAF的作用PrEP的艾滋病预防,马歇尔福代基列在新闻发布会上表示,该公司正在与美国疾病控制和预防中心(CDC)的对恩曲他滨和TAF一项研究猕猴的合作的PrEP 。福代斯指出,TAF组合“将具有相同的发展道路”为TDF的准备,想必这表明Gilead公司将不进行PrEP试验本身。 “要重现iPrEx [新配方]将是一个巨大的工程,”他
作者: newchinabok    时间: 2015-3-14 09:50

TAF已经报批,在美国和欧洲。
作者: newchinabok    时间: 2015-3-14 09:51

本帖最后由 newchinabok 于 2015-3-14 09:51 编辑

与TDF相比,TAF证明没有因肾功能不良事件停药
作者: 重韧    时间: 2015-3-14 10:12

本帖最后由 重韧 于 2015-3-14 10:12 编辑

现在在美国应该也还没有TAF 吧。只是报批。
作者: 682256    时间: 2015-6-5 21:04

是说替诺和恩替有相同抗病毒疗效,但对肾脏和骨骼的副作用比恩替更安全
作者: 9病成医    时间: 2015-6-5 22:20

回复 682256 的帖子

不是替诺跟恩替比较,而是两种替诺比较,一是富马酸替诺福韦酯(TDF),就是目前使用的替诺,二是替诺福韦alafenamide(TAF),即将上市的替诺。
作者: 9病成医    时间: 2015-6-5 22:22

替诺福韦alafenamide(TAF)——替诺福韦艾拉酚胺
作者: 682256    时间: 2015-6-5 22:31

本帖最后由 682256 于 2015-6-5 22:33 编辑

词汇不够大意,下次可得好好查生词了,谢谢楼上
作者: yelanglms    时间: 2015-6-6 08:58

TDF有了多年使用经验,但TAF没有,这是两者差异。
作者: 肝肠欲断    时间: 2015-6-7 20:32

回复 yelanglms 的帖子

有道理




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