慢性HIV-1感染中治疗中断的代谢和免疫激活效应：对心血管风险的影响
Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk.
作者信息
Tebas Pablo, Henry William Keith, Matining Roy, Weng-Cherng Deborah, Schmitz John, Valdez Hernan, Jahed Nasreen, Myers Laurie, Powderly William G, Katzenstein David
机构信息
University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
出版信息
PLoS One. 2008 Apr 23;3(4):e2021. doi: 10.1371/journal.pone.0002021.
BACKGROUND
Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk.
METHODOLOGY
ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count >or=500 cells/microL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/microL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels.
PRINCIPAL FINDINGS
By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (-1.19, -0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (-0.36(-0.73,-0.03)mmol/L, p = 0.0007 and -0.05(-0.26,0.03), p = 0.0033, respectively) and triglycerides decreased (-0.40 (-0.84, 0.07) mmol/L, p = 0.005). However the TC/HDL ratio remained unchanged (-0.09 (-1.2, 0.5), p = 0.2). Glucose and insulin levels did not change (p = 0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (-189, 1655), p = 0.0008) coinciding with the rebound of HIV viremia.
CONCLUSIONS
Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00015704.
背景
对成本以及抗逆转录病毒疗法（ART）相关毒性的担忧促使人们考虑采用基于CD4细胞计数的策略来管理HIV感染。在SMART试验中对该方法进行了评估，该试验报告了治疗中断（TI）后心血管事件意外增加。我们的目标是评估与抗逆转录病毒疗法中断相关的空腹代谢变化，并将其与免疫激活标志物和心血管风险的变化相关联。
方法
ACTG 5102研究纳入了47名接受稳定ART治疗的HIV-1感染者，其HIV RNA拷贝数<200 /mL且CD4细胞计数≥500个/μL。受试者被随机分配为继续接受18周的ART治疗，其中部分接受或不接受3个周期的白细胞介素-2（IL-2）治疗（周期=每8周皮下注射450万IU，每日两次，共5天）。18周后，所有受试者停止ART治疗，直至CD4细胞计数降至350个/μL以下。最初每8周评估一次血糖和血脂参数，在TI后的第2、4、8周以及之后每8周评估一次。通过流式细胞术和可溶性TNFR2水平评估免疫激活情况。
主要发现
在TI的第8周时，总胆固醇（TC）水平（中位数（Q1，Q3）（-0.73（-1.19，-0.18）mmol/L，p<0.0001）、低密度脂蛋白（LDL）、高密度脂蛋白胆固醇（-0.36（-0.73，-0.03）mmol/L，p = 0.0007和-0.05（-0.26，0.03），p = 0.0033）以及甘油三酯水平均下降（-0.40（-0.84，0.07）mmol/L，p = 0.005）。然而，TC/HDL比值保持不变（-0.09（-1.2，0.5），p = 0.2）。血糖和胰岛素水平未发生变化（分别为p = 0.6和0.8）。TI后免疫激活显著增加（CD8 + / HLA-DR + / CD38 +细胞，34%（13，43），p<0.0001），可溶性TNFR2水平升高（1089 ng/L（-189，1655），p = 0.0008），同时伴有HIV病毒血症的反弹。
结论
我们的数据表明，中断抗逆转录病毒疗法并不会降低心血管疾病（CVD）风险，因为血脂参数的改善较为有限，且HDL水平降低使其优势被抵消。与HIV病毒血症复发相关的免疫细胞激活增加和全身炎症反应可能为与治疗中断及HIV感染相关的心血管风险增加提供了更有说服力的解释。
试验注册
ClinicalTrials.gov NCT00015704。
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