Background

Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor.

Methods

In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort.

Results

A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log₁₀ copies per milliliter in the fostemsavir group and 0.17 log₁₀ copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure.

Conclusions

In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.)

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Fostemsavir, a Novel Treatment for HIV-1
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中文翻译：

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成人多药耐药HIV-1感染的Fostemsavir

背景

在一些经历过多次抗逆转录病毒疗法且治疗选择有限的人类免疫缺陷病毒1型（HIV-1）感染的患者中，需要具有新型作用机制的新型抗逆转录病毒药物。Fostemsavir是temsavir的前药，temsavir是第一个研究性的HIV-1附着抑制剂。

方法

在这项正在23个国家/地区进行的正在进行的3期试验中，我们根据患者的剩余治疗选择将其纳入了对多药耐药HIV-1感染的患者分为两个队列。在第一个队列中，我们分配了（以3：1的比例）可以选择使用至少一种但不超过两种抗逆转录病毒药物的至少一种完全有效的，已批准的抗逆转录病毒药物的患者，以加入任一福斯特沙韦（一定剂量）每日两次，每次600 mg）或安慰剂治疗失败的治疗方案，持续8天，然后进行开放标签的fostemsavir加优化的背景治疗（随机分组）。在第二个队列中，没有残留抗逆转录病毒选择的患者从第1天开始接受开放标签的fostemsavir加优化的背景治疗（非随机队列）。

结果

总共治疗了371名患者，其中包括272名随机队列患者和99名非随机队列患者。在第8天，fostemsavir组的HIV-1 RNA水平平均下降为0.79 log ₁₀拷贝/毫升和0.17 log ₁₀在安慰剂组中复制（P <0.001）。在第48周时，随机队列中54％的患者和非随机队列中38％的患者发生了病毒学应答（HIV-1 RNA水平，<40拷贝/毫升）。CD4 + T细胞计数的平均增加分别为每立方毫米139个细胞和每立方毫米64个细胞。不良事件导致7％的患者停用fostemsavir。在随机队列中，在47名病毒学衰竭患者中有20名（43％）发现了糖蛋白120（gp120）替代。

结论

在具有有限治疗选择的具有多重耐药性HIV-1感染的患者中，接受fostemsavir的患者在前8天中的HIV-1 RNA水平明显低于接受安慰剂的患者。疗效持续了48周。（由Bristol-Myers Squibb和GSK / ViiV Healthcare资助; BRIGHTE ClinicalTrials.gov编号，NCT02362503。）

快速视频摘要
Fostemsavir，一种治疗HIV-1的新型疗法
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