Treatment to reduce inflammation and improve immune recovery among older HIV pts

描述：接受治疗的艾滋病毒阳性患者患心血管疾病(CVD)、癌症和其他与艾滋病毒相关的非艾滋病疾病的风险增加。尽管使用抗逆转录病毒疗法(ART)进行了有效的治疗，但持续的免疫激活增加了患心血管疾病和非艾滋病疾病的风险，但也导致淋巴组织纤维化，限制了免疫恢复，从而进一步增加了非艾滋病疾病的风险。生物老龄化还导致全身炎症和免疫功能减弱，因此，随着艾滋病毒人口的老龄化，非艾滋病情况和多发性发病率将继续增加。确定针对这种病理的安全治疗代表着老年艾滋病毒阳性患者的一个主要未得到满足的需求。我们提出了一项随机的安慰剂对照试验，氯沙坦(每天100毫克)在接受抗逆转录病毒治疗的50岁HIV阳性患者中接受有效的ART，但检测不到HIV RNA水平。我们将研究氯沙坦对6个月内IL-6水平变化和12个月内外周血CD4计数变化的治疗效果。我们假设，氯沙坦治疗将：a)通过减少外周血中单核细胞的激活来减少全身炎症，以及b)通过下调免疫激活和转化生长因子-β介导的淋巴组织纤维化，改善T细胞动态平衡和初始T细胞的存活率，从而导致免疫恢复，如血液CD_4计数所反映的那样。我们的研究团队帮助确定了炎症在非艾滋病风险中的作用，并开发了将淋巴纤维化与T细胞稳态受损联系起来的模型。这项工作直接指导了我们对结果的选择，这既测试了基本的艾滋病毒发病机制问题，也将确定氯沙坦是否在可能与临床相关的程度上改善了免疫激活和免疫恢复。我们的方法和假设是创新的，我们的干预措施在HIV感染的背景下是新颖的，我们的方法提供了基本的随机数据来告知并证明后续临床结果试验的费用是合理的。总而言之，这项转化性试验解决了高度优先的艾滋病毒研究议程，以确定针对老年患者中非艾滋病情况的疾病修改策略。

DESCRIPTION: Treated HIV positive patients are at increased risk for cardiovascular disease (CVD), cancer, and other HIV- associated non-AIDS conditions. Ongoing immune activation, despite effective treatment with antiretroviral therapy (ART), increases risk for CVD and non-AIDS conditions, but also contributes to lymphatic tissue fibrosis, limiting immune recovery that further increases risk for non-AIDS conditions. Biologic aging also leads to systemic inflammation and waning immune function, and, thus, non-AIDS conditions and poly-morbidity will continue to increase as the HIV population ages. Identifying safe treatments that target this pathology represents a major unmet need for older HIV positive patients. We propose a randomized placebo-controlled trial of losartan (100mg daily) among n=120 antiretroviral-treated HIV positive persons age >50 years receiving effective ART with undetectable HIV RNA levels. We will study the treatment effects of losartan on changes in IL-6 levels over 6 months and changes in peripheral blood CD4 count over 12 months. We hypothesize that losartan treatment will: a) reduce systemic inflammation that will be accounted for through reductions in monocyte activation within peripheral blood, and b) lead to immune recovery, as reflected in blood CD4+ count, via down-regulating immune activation and TGF-β-mediated fibrosis in lymphatic tissues that will improve T- cell homeostasis and survival of naive T-cells. Our investigative team has helped define the role of inflammation in non-AIDS disease risk as well as developed the model that links lymph node fibrosis with impaired T-cell homeostasis. This work directly informed our choice of outcomes, which both test fundamental HIV pathogenesis questions and will determine if losartan improves immune activation and immune recovery to a degree that may be clinically relevant. Our methods and hypotheses are innovative, our intervention is novel in the context of HIV infection, and our approach provides essential randomized data to inform and justify the expense of subsequent clinical outcome trials. In summary, this translational trial addresses a high priority HIV research agenda to identify disease-modifying strategies for non-AIDS conditions among older patients.