Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.
Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.
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DOI：
10.1371/journal.pmed.0050203
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发表时间：
2008-10-21
期刊：
影响因子：
15.8
通讯作者：
INSIGHT SMART Study Group
中科院分区：
文献类型：
--
作者：
Kuller LH;Tracy R;Belloso W;De Wit S;Drummond F;Lane HC;Ledergerber B;Lundgren J;Neuhaus J;Nixon D;Paton NI;Neaton JD;INSIGHT SMART Study Group
在抗逆转录病毒治疗管理策略试验中，随机接受间歇性、cd4引导的抗逆转录病毒治疗（ART）（药物保护[DC]）的参与者的全因死亡率高于连续接受抗逆转录病毒治疗（病毒抑制[VS]）的参与者。我们假设抗逆转录病毒治疗中断后HIV-RNA水平升高诱导了组织因子通路的激活、血栓形成和纤维蛋白溶解。储存的样品用于测量六种生物标志物：高敏c反应蛋白（hsCRP）、白介素-6 （IL-6）、淀粉样蛋白A、淀粉样蛋白P、d -二聚体和凝血酶原片段1+2。进行了两项研究：(1)巢式病例对照研究，研究生物标志物与死亡率的关联；(2)研究比较DC和VS参与者的生物标志物变化。对于(1)，在研究开始时和死亡前（最新水平）确定85例死亡和两个对照（n = 170）的标记物，这些对照与国家、年龄、性别和随机化日期相匹配。采用logistic回归估计优势比（ORs）。对于每种生物标志物，将三个上四分位数中的每一个与最低四分位数进行比较。对于(2)，在研究开始时和随机分组后1个月，对249名DC和250名VS参与者的生物标志物进行了评估。研究开始时较高水平的hsCRP、IL-6和d -二聚体与全因死亡风险增加显著相关。未调整的or（最高与最低四分位数）分别为2.0（95%可信区间[CI]， 1.0-4.1; p = 0.05）、8.3 （95% CI, 3.3-20.8; p < 0.0001）和12.4 （95% CI, 4.2-37.0; p < 0.0001）。当分别分析DC组和VS组以及评估最新水平时，调整后的关联是显著的。IL-6和d -二聚体在1个月时DC组增加30%和16%，VS组增加0%和5%（两种生物标志物的治疗差异p < 0.0001）；DC组的升高与1个月时HIV-RNA水平相关（p < 0.0001）。在扩展的病例-对照分析中（每个病例4个对照），调整最新IL-6和d -二聚体水平后，死亡率的OR （DC/VS）分别从1.8 （95% CI, 1.1-3.1; p = 0.02）降至1.5 （95% CI, 0.8-2.8）和1.4 （95% CI, 0.8-2.5）。IL-6和d -二聚体与全因死亡率密切相关。中断抗逆转录病毒治疗可能通过提高IL-6和d -二聚体水平进一步增加死亡风险。减少对HIV的炎症反应和降低IL-6和d -二聚体水平的疗法可能值得研究。试验注册：ClinicalTrials.gov （NCT00027352）。James Neaton和他的同事分析了之前的一项随机对照试验（SMART试验）中持续与中断HIV治疗的参与者的生物标志物数据，发现死亡率与IL-6和纤维蛋白d二聚体有关。全球有3 000多万人感染了人类免疫缺陷病毒（艾滋病毒），这种病毒会导致获得性免疫缺陷综合症（艾滋病）。HIV感染并破坏免疫系统细胞（包括CD4细胞，一种淋巴细胞）。艾滋病毒感染的第一阶段可能会出现短暂的流感样疾病，但在第二阶段，可能会持续多年，艾滋病毒在淋巴腺（全身的小免疫系统器官）中复制而不会引起任何症状。然而，最终，免疫系统变得如此受损，以至于艾滋病毒感染者开始屈从于“机会性”感染（例如细菌性肺炎）和癌症（特别是卡波西肉瘤），这些是免疫系统通常可以预防的。艾滋病本身的特点是一种或多种严重的机会性感染或癌症（所谓的艾滋病相关疾病）和血液CD4细胞计数低。艾滋病毒感染无法治愈，但抗逆转录病毒疗法（ART）——强效抗逆转录病毒药物的组合——可以控制住这种感染，因此许多艾滋病毒阳性患者的预期寿命现在大大延长了。不幸的是，抗逆转录病毒治疗的效果有时会随着时间的推移而减弱，而长期的抗逆转录病毒治疗可能会导致令人不快的副作用。因此，替代抗逆转录病毒治疗方案在临床试验中不断得到检验。例如，在抗逆转录病毒治疗管理策略（SMART）试验中，hiv阳性患者要么接受持续抗逆转录病毒治疗（病毒抑制组或VS组），要么仅在其CD4细胞计数低于250个细胞/mm3时接受抗逆转录病毒治疗（药物保护组或DC组；正常成人CD4细胞计数约为1000个细胞/mm3）。出乎意料的是，DC组比VS组死于非艾滋病疾病（包括心脏和循环系统问题）的人数更多，这一结果导致试验提前停止。对这些超额死亡的一个可能解释是，抗逆转录病毒治疗中断后艾滋病毒水平升高可能引起炎症反应（感染或损伤时发生的非特异性免疫反应）和/或高凝状态（在未受损的血管内形成血块的情况），这些变化增加了非艾滋病疾病死亡的风险。在这项研究中，研究人员检验了这一假设。研究人员测量了85名在SMART试验期间死亡的人（分别为55名和30名接受DC和VS的参与者）和170名作为比较（对照）参与者的血液样本中表明存在炎症或凝血增加的蛋白质（生物标志物）的水平。(两名对照参与者与每名已经死亡的参与者“匹配”。在这项“病例对照”研究中，研究开始时炎症生物标志物高敏感性c反应蛋白（hsCRP）和白细胞介素6 （IL-6）以及凝血生物标志物d -二聚体的水平升高与死亡风险增加有关。hsCRP值在测量值的最高四分之一的人的死亡风险是hsCRP值在最低四分之一的人的两倍（以比值比为2表示）。对于IL-6和d -二聚体，等效比值比分别为8.3和12.4。此外，研究开始后hsCRP、IL-6和d -二聚体的增加与死亡风险增加有关。研究人员还从两个治疗组中随机选择了250名患者，测量了相同生物标志物的血液水平。在试验的第一个月，DC组的IL-6水平增加了30%，而VS组的IL-6水平没有变化。在同一时期，DC组和VS组的d -二聚体水平分别增加了16%和5%。一个月后，DC组中这两种标记物的增加与HIV RNA水平有关。综上所述，这些发现表明，hiv诱导的炎症和凝血激活增加了hiv阳性患者的死亡风险，而中断ART进一步增加了这种风险，可能是通过增加IL-6和d -二聚体的水平。由于在本研究中只有少数人死亡，这些生物标志物与接受治疗和未接受治疗的hiv阳性个体的死亡和疾病之间的关系需要在进一步的研究中得到证实。然而，这些发现表明，减少HIV复制对炎症和血液凝固的影响，或降低IL-6和d -二聚体水平的治疗方法的发展，可能会延长HIV阳性患者的预期寿命。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0050203访问这些网站。有关SMART试验的信息可从美国国家过敏和传染病研究所获得，该研究所提供有关HIV/AIDS各方面的全面信息，也可从国际艾滋病慈善机构Avert获得有关HIV/AIDS的信息。有关SMART试验的更多信息可在ClinicalTrials.gov上获得，这是一个由美国国家卫生研究院维护的临床试验数据库
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]). We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case–control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0–4.1; p = 0.05), 8.3 (95% CI, 3.3–20.8; p < 0.0001), and 12.4 (95% CI, 4.2–37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case–control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1–3.1; p = 0.02) to 1.5 (95% CI, 0.8–2.8) and 1.4 (95% CI, 0.8–2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. Trial Registration: ClinicalTrials.gov (NCT00027352). Analyzing biomarker data from participants in a previous randomized controlled trial of continuous versus interrupted HIV treatment (the SMART trial), James Neaton and colleagues find that mortality was related to IL-6 and fibrin D-dimers. Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). HIV infects and destroys immune system cells (including CD4 cells, a type of lymphocyte). The first stage of HIV infection can involve a short flu-like illness but in the second stage, which can last many years, HIV replicates in the lymph glands (small immune system organs throughout the body) without causing any symptoms. Eventually, however, the immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections (for example, bacterial pneumonia) and cancers (in particular, Karposi sarcoma) that the immune system would normally prevent. AIDS itself is characterized by one or more severe opportunistic infections or cancers (so-called AIDS-related diseases) and by a low blood CD4 cell count. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV-positive people now have substantially improved life expectancy. Unfortunately, the effectiveness of ART sometimes wanes over time and prolonged ART can cause unpleasant side effects. Consequently, alternative ART regimens are continually being tested in clinical trials. In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, for example, HIV-positive patients received either continuous ART (the viral suppression or VS arm), or ART only when their CD4 cell counts were below 250 cells/mm3 (the drug conservation or DC arm; the normal adult CD4 cell count is about 1,000 cells/mm3). Unexpectedly, more people died in the DC arm than in the VS arm from non-AIDS diseases (including heart and circulation problems), a result that led to the trial being stopped early. One possible explanation for these excess deaths is that increased HIV levels following ART interruption might have induced an inflammatory response (a non-specific immune response that occurs with infection or wounding) and/or a hypercoagulable state (a condition in which blood clots form inside undamaged blood vessels) and that these changes increased the risk of death from non-AIDS diseases. In this study, the researchers test this hypothesis. The researchers measured the levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) in stored blood samples from the 85 people who died during the SMART trial (55 and 30 of the participants assigned to receive DC and VS, respectively) and from 170 survivors who served as comparison (control) participants. (Two control participants were “matched” to each participant who had died (cases). In this “case-control” study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter (this is expressed as an odds ratio of 2). For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Furthermore, increases in hsCRP, IL-6 and D-dimer after study entry were associated with an increased risk of death. The researchers also measured blood levels of the same biomarkers in 250 randomly chosen patients from each of the two treatment arms. IL-6 levels increased by 30% over the first month of the trial in the DC arm but were unchanged in the VS arm. Over the same period, D-dimer levels increased by 16% and 5% in the DC and VS arms, respectively. Increases in both markers in the DC arm were related to HIV RNA levels after one month. Taken together, these findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. Because only a small number of people died in this study, the relationship between these biomarkers and death and illness among treated and untreated HIV-positive individuals needs to be confirmed in further studies. However, these findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050203. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and about the SMART trial HIV InSite has comprehensive information on all aspects of HIV/AIDS Information is also available from Avert, an international AIDS charity, on HIV/AIDS More information about the SMART trial is available on ClinicalTrials.gov, a database of clinical trials maintained by the US National Institutes of Health
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影响因子：
8.8
作者：
Derhaschnig, U;Bergmair, D;Jilma, B
通讯作者：
Jilma, B
影响因子：
5.9
作者：
Harris, TB;Ferrucci, L;Wallace, R
通讯作者：
Wallace, R
影响因子：
5
作者：
Kuller, LH;Tracy, RP;Meilahn, EN
通讯作者：
Meilahn, EN
影响因子：
5.9
作者：
Cohen, HJ;Harris, T;Pieper, CF
通讯作者：
Pieper, CF
DOI：
10.1055/s-2005-922485
发表时间：
2005-11-01
期刊：
Seminars in vascular medicine
影响因子：
--
作者：
Lowe, Gordon D O
通讯作者：
Lowe, Gordon D O