背景:HIV感染者(PWH)合并症的风险增加,血浆IL-6水平是这些结果的最可靠预测因子之一。Tocilizumab(TCZ)阻断IL-6的受体,抑制该细胞因子的功能。
方法:这是一个40周的安慰剂对照,交叉试验(NCT02049437),在该试验中,采用稳定抗逆转录病毒治疗(ART)的PWH被随机分配接受3个月剂量的TCZ或匹配的安慰剂静脉注射.经过10周的治疗期和12周的冲洗,参与者被切换到相反的治疗。主要终点是安全性和治疗后C反应蛋白(CRP)和CD4T细胞周期水平。次要终点包括炎症指数和脂质水平的变化。
结果:在TCZ给药期间有9个2级或更高的治疗相关毒性(主要是中性粒细胞减少症),在安慰剂给药期间有2个。34名参与者中有31名完成了研究,并纳入了修改后的意向治疗分析。TCZ降低CRP水平(中位数降低1819.9ng/ml,p<0.0001;效应大小0.87)和PWH中炎症标志物减少,包括D-二聚体,可溶性CD14和肿瘤坏死因子受体。TCZ给药后,所有成熟亚群的T细胞周期趋于减少,但仅在幼稚CD4T细胞中显著。脂质水平,包括与CVD风险相关的脂质类别,在TCZ治疗期间增加。
结论:TCZ是安全的,可减少PWH的炎症,确定IL-6是预测ART治疗的PWH发病率和死亡率的炎症环境的关键驱动因素。TCZ治疗期间血脂升高的临床意义需要进一步研究。
People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine.
This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels.
There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment.
TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.