Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA.
Clinical Research, Gilead Sciences, Inc., Foster City, CA, USA.
Antivir Ther. 2023 Dec;28(6):13596535231220754. doi: 10.1177/13596535231220754.
Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people with HIV (PWH) harbouring multidrug resistance in combination with an optimized background regimen (OBR). Here, we describe in vitro analysis of the interplay between entry inhibitors (EI; enfuvirtide, fostemsavir, ibalizumab, and maraviroc) susceptibility and LEN susceptibility in samples from 72 participants in the phase 2/3 CAPELLA study, as well as the emergence of resistance in CAPELLA through 52 weeks.
The phenotypic susceptibility to EIs of screening samples from participants was analysed using entry assays, and susceptibility to LEN was generated. Genotypic and phenotypic resistance to LEN was evaluated for subjects with virological failure through Week 52.
Overall, viruses with resistance to EIs showed no cross-resistance to LEN, with a mean fold change from wild type close to 1.0. Of the 22 participants analysed for resistance through Week 52, 9 participants (13%) had emergence of capsid resistance mutation(s) while the remaining 13 participants (18%) had no change in the capsid sequence.
The sequence from EI-resistant isolates did not affect LEN susceptibility. The lack of cross-resistance to LEN across ARV-resistant isolates supports the use of LEN in PWH regardless of their treatment history. During the second half-year period of the CAPELLA Study, development of LEN resistance was rare and was overall associated with functional LEN monotherapy due to either nonadherence or resistance-driven non-susceptibility to OBR.
Lenacapavir（LEN）是一种新型的人类免疫缺陷病毒 1 型（HIV-1）衣壳功能抑制剂，用于治疗携带多种耐药性且接受过大量治疗的 HIV 感染者（PWH），与优化背景治疗方案（OBR）联合使用。在此，我们描述了 72 名 CAPELLA 研究 2/3 期参与者样本中，进入抑制剂（EI；恩夫韦肽、福斯特玛韦、ibalizumab 和马拉维若）敏感性与 LEN 敏感性之间的体外分析，以及 CAPELLA 研究中通过 52 周出现的耐药性情况。
使用进入测定法分析来自参与者筛选样本的 EI 表型敏感性，并生成 LEN 敏感性。通过第 52 周，对病毒学失败的受试者进行 LEN 基因型和表型耐药性评估。
总体而言，对 EI 耐药的病毒对 LEN 无交叉耐药性，与野生型的平均倍数变化接近 1.0。在第 52 周进行耐药性分析的 22 名参与者中，9 名（13%）出现了衣壳耐药突变，而其余 13 名（18%）衣壳序列未发生变化。
来自 EI 耐药分离株的序列并未影响 LEN 的敏感性。对 LEN 的耐药性无交叉耐药性支持在无论其治疗史如何的情况下，都可以在 PWH 中使用 LEN。在 CAPELLA 研究的下半年期间，LEN 耐药性的发展很少见，总体上与 LEN 单药治疗耐药或不依从导致的 OBR 非敏感性有关。
