Emory University School of Medicine, Atlanta, Georgia, USA.
Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
Clin Infect Dis. 2022 Jan 7;74(1):95-104. doi: 10.1093/cid/ciab212.
Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART).
AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir.
Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (P = .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; P = .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]).
In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART.
NCT02475655.
炎症与人类免疫缺陷病毒（HIV）感染者的终末器官疾病和死亡率有关。鲁索利替尼是一种 Jak1/2 抑制剂，可降低无 HIV 和 HIV 储存标志物的个体的全身炎症，在体外。该试验的目的是确定鲁索利替尼在接受抗逆转录病毒治疗（ART）的 HIV 感染者中的安全性和疗效。
艾滋病临床试验组（ACTG）A5336 是一项开放标签、多地点、随机对照试验（RCT）。参与者使用集中式软件随机分配（2:1）接受鲁索利替尼（每天两次，10 毫克）加稳定的 ART 治疗 5 周，或单独接受 ART，分层为依非韦伦的使用。符合条件的参与者在接受 ART 治疗≥2 年后，无合并症，且 CD4+T 细胞>350/µL。主要终点是提前停药、安全事件和血浆白细胞介素 6（IL-6）变化。次要终点包括其他炎症/免疫激活和 HIV 储存标志物的测量。
2016 年 5 月 16 日至 2018 年 1 月 10 日期间，共招募了 60 名参与者。鲁索利替尼的主要安全性事件发生率为 2.5%（1 例），对照组为 0%（P=0.67）。3 名参与者（7.5%）提前停止使用鲁索利替尼。第 5 周时，鲁索利替尼组的 IL-6（平均折叠变化[FC]，0.93 对 1.10；P=0.18）和可溶性 CD14（平均 FC，0.96 对 1.08；相对 FC，0.96[90%置信区间{CI}，0.90-1.02]）水平较对照组有差异。鲁索利替尼降低了表达 HLA-DR/CD38 的 CD4+T 细胞（平均差异，-0.34%[90%CI，-0.66%至-0.12%]）和 Bcl-2（平均差异，-3.30%[90%CI，-0.47%至-0.13%]）。
在这项接受 ART 的健康、病毒抑制 HIV 感染者的 RCT 中，鲁索利替尼耐受性良好。基线 IL-6 水平正常，无显著降低。鲁索利替尼显著降低了免疫激活和细胞存活标志物。针对 Jak 抑制剂的未来研究应针对尽管接受抑制性 ART 但仍有炎症残留的 HIV 感染者。
NCT02475655。
