Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière - Charles Foix, Laboratoire de Virologie, F75013 Paris, France.
Université de Paris, IAME, UMR1137, INSERM, Laboratoire de Virologie, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
J Antimicrob Chemother. 2020 Jun 1;75(6):1588-1590. doi: 10.1093/jac/dkaa060.
GS-6207 is a first-in-class HIV capsid inhibitor, targeting several functions of the HIV capsid in the viral cycle, including viral particle assembly, capsid formation and nuclear entry. GS-6207 has demonstrated picomolar potency in vitro, activity confirmed by high potency in a Phase 1 clinical study, with a long-acting antiretroviral profile with potential dosing every 6 months. In vitro resistance selections previously conducted with increasing doses of GS-6207 have identified capsid variants with reduced susceptibility to GS-6207.
To study the prevalence of capsid mutations associated with in vitro resistance to GS-6207 in people living with HIV (PLWH).
Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N.
Among the samples from the 1500 patients studied, none of the seven GS-6207 resistance mutations identified during in vitro selection experiments was detected, regardless of HIV subtype or PLWH treatment history.
Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations.
GS-6207 是一种首创的 HIV 衣壳抑制剂，针对 HIV 衣壳在病毒周期中的多个功能，包括病毒颗粒组装、衣壳形成和核内进入。GS-6207 在体外具有皮摩尔效力，在一项 1 期临床研究中得到了高活性的证实，具有长效抗逆转录病毒特性，潜在的给药间隔为每 6 个月一次。先前进行的递增剂量 GS-6207 体外耐药选择确定了对 GS-6207 敏感性降低的衣壳变异体。
研究与 HIV 感染者（PLWH）对 GS-6207 体外耐药相关的衣壳突变的流行情况。
对来自未经 ART 治疗或经 ART 治疗的 PLWH（包括 PI 经验者）的血浆样本进行测序，并分析在体外耐药选择过程中发现的衣壳变异体的存在：L56I、M66I、Q67H、K70N、N74D、N74S 和 T107N。
在所研究的 1500 名患者的样本中，无论 HIV 亚型或 PLWH 治疗史如何，均未检测到在体外选择实验中确定的七种 GS-6207 耐药突变。
在体外选择并表现出对 GS-6207 表型耐药的七种 HIV 衣壳取代物中，在这个大型数据集内，未观察到这七种突变中的任何一种，这表明无论是先前 PI 治疗失败的 PLWH 还是出现 PI 耐药突变的 PLWH，都预计不会影响这些不同 HIV 感染人群中 GS-6207 的活性。
