美国ViiV医疗保健公司Max Lataillade, D.O.小组近期取得一项新成果。他们发现Fostemsavir治疗多重耐药性HIV-1感染患者有效。该研究成果发表在2020年3月26日出版的《新英格兰医学杂志》上。

对于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）感染患者，需要新作用机制的新型抗逆转录病毒药物。Fostemsavir是temsavir的前药，temsavir是研究中的第一类HIV-1附着抑制剂。

研究组在23个国家/地区进行了一项3期临床试验，招募了371名多重耐药性HIV-1感染患者，根据剩余的治疗选择将这些患者纳入两个队列。随机队列272名患者，至少对一种抗逆转录病毒疗法有效，在此基础上，按3：1随机分组，分别接受Fostemsavir或安慰剂进行治疗，8天后，接受开放标签的Fostemsavir+优化的基础治疗。非随机队列99名，对所有抗逆转病毒疗法均无效，直接进入开放标签的Fostemsavir治疗。

治疗第8天，Fostemsavir组的HIV-1 RNA水平中位下降了0.79 log10拷贝/毫升，显著大于安慰剂组（0.17 log10拷贝/毫升）。在第48周时，随机队列中54%的患者和非随机队列中38%的患者发生病毒学应答，CD4+ T细胞计数每立方毫米分别中位增加了139个细胞和64个细胞。Fostemsavir组中有7%的患者因不良事件而停药。随机队列的47名病毒学失败患者中有20名（43%）采用糖蛋白120替代。

总之，对于选择有限的多重耐药性HIV-1感染患者，接受Fostemsavir治疗的前8天内，HIV-1 RNA的下降幅度明显大于安慰剂，且疗效持续了48周。

附：英文原文

Title: Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection

Author: Michael Kozal, M.D., Judith Aberg, M.D., Gilles Pialoux, M.D., Pedro Cahn, M.D., Melanie Thompson, M.D., Jean-Michel Molina, M.D., Beatriz Grinsztejn, M.D., Ricardo Diaz, M.D., Antonella Castagna, M.D., Princy Kumar, M.D., Gulam Latiff, M.D., Edwin DeJesus, M.D., Mark Gummel, M.S., Margaret Gartland, M.Sc., Amy Pierce, B.S., Peter Ackerman, M.D., Cyril Llamoso, M.D., and Max Lataillade, D.O. for the BRIGHTE Trial Team

Abstract:

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.

DOI: 10.1056/NEJMoa1902493

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1902493