Baker Jason V, Sharma Shweta, Grund Birgit, Rupert Adam, Metcalf Julia A, Schechter Mauro, Munderi Paula, Aho Inka, Emery Sean, Babiker Abdel, Phillips Andrew, Lundgren Jens D, Neaton James D, Lane H Clifford
Department of Medicine University of Minnesota, Minneapolis, Minnesota.
Division of Biostatistics School of Statistics, University of Minnesota, Minneapolis, Minnesota.
Open Forum Infect Dis. 2017 Nov 28;4(4):ofx262. doi: 10.1093/ofid/ofx262. eCollection 2017 Fall.
The Strategic Timing of AntiRetroviral Treatment (START) trial demonstrated that immediate (at CD4+ >500 cells/µL) vs deferred (to CD4+ <350 cells/µL or AIDS) antiretroviral therapy (ART) initiation reduced risk for AIDS and serious non-AIDS (SNA). We investigated associations of inflammation, coagulation, and vascular injury biomarkers with AIDS, SNA or death, and the effect of immediate ART initiation.
Biomarkers were measured from stored plasma prior to randomization and at month 8. Associations of baseline biomarkers with event risk were estimated with Cox regression, pooled across groups, adjusted for age, gender, and treatment group, and stratified by region. Mean changes over 8 months were estimated and compared between the immediate and deferred ART arms using analysis of covariance models, adjusted for levels at entry.
Baseline biomarker levels were available for 4299 START participants (92%). Mean follow-up was 3.2 years. Higher levels of IL-6 and D-dimer were the only biomarkers associated with risk for AIDS, SNA or death, as well as the individual components of SNA and AIDS events (HRs ranged 1.37-1.41 per 2-fold higher level), even after adjustment for baseline CD4+ count, HIV RNA level, and other biomarkers. At month 8, biomarker levels were lower in the immediate arm by 12%-21%.
These data, combined with evidence from prior biomarker studies, demonstrate that IL-6 and D-dimer consistently predict clinical risk across a broad spectrum of CD4 counts for those both ART-naïve and treated. Research is needed to identify disease-modifying treatments that target inflammation beyond the effects of ART.
抗逆转录病毒治疗（ART）启动的战略时机（START）试验表明，立即（CD4+>500个细胞/µL时）与延迟（至CD4+<350个细胞/µL或艾滋病时）开始抗逆转录病毒治疗可降低患艾滋病和严重非艾滋病（SNA）的风险。我们研究了炎症、凝血和血管损伤生物标志物与艾滋病、SNA或死亡之间的关联，以及立即启动ART的效果。
在随机分组前和第8个月时从储存的血浆中测量生物标志物。通过Cox回归估计基线生物标志物与事件风险之间的关联，合并各研究组的数据，校正年龄、性别和治疗组，并按地区分层。使用协方差分析模型估计8个月内的平均变化，并在立即启动ART组和延迟启动ART组之间进行比较，校正入组时的水平。
4299名START参与者（92%）有基线生物标志物水平数据。平均随访时间为3.2年。即使校正了基线CD4+计数、HIV RNA水平和其他生物标志物后，较高水平的白细胞介素-6（IL-6）和D-二聚体仍是与艾滋病、SNA或死亡风险以及SNA和艾滋病事件的各个组成部分相关的唯一生物标志物（每升高2倍水平，风险比范围为1.37-1.41）。在第8个月时，立即启动ART组的生物标志物水平低12%-21%。
这些数据与先前生物标志物研究的证据相结合，表明IL-6和D-二聚体始终能预测初治和已治疗人群在广泛CD4计数范围内的临床风险。需要开展研究以确定针对炎症的疾病改善治疗方法，这些方法的作用超出ART的效果。
