Fostemsavir resistance in clinical context: a narrative review.

IF 3.8 Q2 INFECTIOUS DISEASES
Therapeutic Advances in Infectious Disease Pub Date : 2025-03-24 eCollection Date: 2025-01-01 DOI:10.1177/20499361251325103
Jonathan M Schapiro, Rolf Kaiser, Mark Krystal, Chris M Parry, Allan R Tenorio, Eugene Stewart, Bruce Gilliam, Margaret Gartland, Andrew Clark, Jose R Castillo-Mancilla
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引用次数: 0

Abstract

Fostemsavir, a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated in combination with other antiretrovirals for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE). Temsavir binds to HIV-1 gp120, close to the CD4 binding site, preventing the initial interaction of HIV-1 with CD4 on the host cell. Amino acid substitutions at four positions in gp120 have been identified as important determinants of viral susceptibility to temsavir (S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I), with a fifth position (T202E) recently described. For most currently circulating group M HIV-1 subtypes, the prevalence of these resistance-associated polymorphisms (RAPs) is low. As with many other antiretrovirals, the impact of RAPs is modified by other changes in the target molecule. Different regions of gp120 interact to modify the temsavir binding pocket, with multiple amino acids playing a role in determining susceptibility. Extensive variability of HIV-1 gp120 means the susceptibility of clinical isolates to temsavir is also highly variable. Importantly, in vitro measurement of the susceptibility of clinical isolates to temsavir does not necessarily capture the range of susceptibilities of the heterogeneous mix of viruses generally present in each isolate. Due to these factors and limited phenotypic clinical data, thus far, no relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in individuals who are HTE; therefore, pre-treatment temsavir resistance testing may be of limited benefit. In the phase III BRIGHTE study, re-suppression after virologic failure was observed in some participants despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility, and substantial CD4+ T-cell count increases occurred even among participants with HIV-1 RNA ⩾40 copies/mL at Week 240. Clinical management of people who are HTE and experience virologic failure during treatment with fostemsavir-based regimens requires an individualized approach with consideration of potential benefits beyond virologic suppression.

临床背景下的fostemsaver耐药:一篇叙述性综述。
Fostemsavir是同类首创的gp120定向附着抑制剂temsavir的前药,可与其他抗逆转录病毒药物联合用于治疗重度治疗经验(HTE)的成人多重耐药HIV-1。Temsavir与HIV-1 gp120结合,靠近CD4结合位点,阻止HIV-1与宿主细胞上CD4的初始相互作用。gp120中四个位置(S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I)的氨基酸取代已被确定为病毒对temsavir易感性的重要决定因素,最近还发现了第五个位置(T202E)。对于大多数目前流行的M组HIV-1亚型,这些耐药性相关多态性(rap)的流行率很低。与许多其他抗逆转录病毒药物一样,RAPs的作用被靶分子的其他变化所改变。gp120的不同区域相互作用修饰temsavir结合袋,多个氨基酸在决定易感性中起作用。HIV-1 gp120的广泛变异性意味着临床分离株对temsavir的易感性也是高度可变的。重要的是,临床分离株对temsavir的体外敏感性测量不一定能捕捉到每个分离株中通常存在的异质病毒混合物的敏感性范围。由于这些因素和有限的表型临床数据,到目前为止,还没有相关的表型截断或基因型算法可以可靠地预测HTE患者对基于干细胞的治疗的反应;因此,治疗前的耐药试验可能益处有限。在III期bright研究中,在一些参与者中观察到病毒学失败后的再抑制,尽管治疗出现的基因型和/或表型证据表明temsavir易感性降低,并且即使在HIV-1 RNA大于或等于40拷贝/mL的参与者中,在第240周也发生了大量CD4+ t细胞计数增加。在以fostemsavvir为基础的方案治疗期间,HTE患者经历病毒学失败的临床管理需要个性化的方法,考虑病毒学抑制之外的潜在益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.30
自引率
8.80%
发文量
64
审稿时长
9 weeks
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