HIV Immune Reconstitution Inflammatory Syndrome in Uganda

描述（由申请人提供）：HIV免疫重建炎症综合征（IRIS）是抗逆转录病毒治疗（ART）的一种新认识的并发症，其中一部分开始抗逆转录病毒治疗的晚期HIV患者随后由于对隐匿性、潜伏性或先前治疗过的感染的夸大炎症反应而经历矛盾的临床恶化。艾滋病毒IRIS已成为撒哈拉以南非洲抗逆转录病毒治疗的常见并发症。我们的长期目标是了解IRIS的发病机制，以便我们能够开发优化的抗逆转录病毒治疗方案，以最大限度地减少资源有限地区与IRIS相关的发病率和死亡率。我们目前正在乌干达艾滋病毒感染者中进行一项研究，因为他们开始抗逆转录病毒治疗，以便更好地了解综合免疫系统在撒哈拉以南非洲的影响。这项正在进行的研究的目的是评估IRIS的发病率、严重程度和临床特征，并确定发生IRIS的hiv感染乌干达患者的临床结果是否比未发生IRIS的患者更差。我们在100名感染艾滋病毒的乌干达病人开始抗逆转录病毒治疗后，对他们进行为期一年的前瞻性跟踪调查。其中，50例患者在开始ART治疗时没有活动性成骨不全，50例患者在前2个月内诊断为隐球菌性脑膜炎。除了确定这些患者开始抗逆转录病毒治疗后IRIS的发生率、严重程度和临床特征外，我们还将确定IRIS事件的发生是否会对抗逆转录病毒治疗的依从性产生负面影响，以及这是否会影响治疗成功。对于这项R03拨款申请，我们计划使用正在进行的队列研究中获得的患者血液标本来评估免疫激活。具体目的是通过比较开始抗逆转录病毒治疗后发生IRIS的患者和未发生IRIS的患者外周血中的免疫激活来确定IRIS的预测性和诊断性生物标志物。我们将前瞻性地收集开始抗逆转录病毒治疗前后的全血RNA，并使用Affymetrix微阵列比较发生IRIS的患者和未发生IRIS的患者的免疫激活基因表达。通过这种方式，我们将确定与IRIS相关的特定生物标志物，这些生物标志物可用于诊断IRIS或预测未来的IRIS。我们的目标是确定生物标记物，这些生物标记物可用于简单、廉价的检测，如实时PCR或ELISA，可用于临床诊断IRIS或监测有IRIS风险的患者。IRIS生物标志物的鉴定也将为IRIS病理生理学基础上的免疫激活途径提供重要的见解。公共卫生相关性：艾滋病毒免疫重建炎症综合征（IRIS）已在撒哈拉以南非洲出现，是抗逆转录病毒治疗艾滋病毒感染的重要并发症。IRIS患者在开始抗逆转录病毒治疗后，由于免疫系统改善而发生的炎症反应，导致临床恶化。这项研究的目的是开发临床血液测试，用于诊断IRIS，并在患者发病前预测其发展风险。

DESCRIPTION (provided by applicant): HIV immune reconstitution inflammatory syndrome (IRIS) is a newly recognized complication of anti- retroviral therapy (ART) whereby a portion of patients with advanced HIV who initiate ART subsequently experience paradoxical clinical worsening due to exaggerated inflammatory responses to occult, latent, or previously treated infections. HIV IRIS has emerged as a frequent complication of ART in sub-Saharan Africa. Our long term goal is to understand the pathogenesis of IRIS so we can develop optimized ART regimens to minimize the morbidity and mortality associated with IRIS in resource limited regions. We are currently performing a study in HIV-infected patients in Uganda as they initiate ART to better understand the impact of IRIS in Sub-Saharan Africa. The goals of the ongoing study are to evaluate the incidence, severity and clinical features of IRIS and to determine if HIV-infected Ugandan patients who develop IRIS have worse clinical outcomes compared to patients who do not develop IRIS. We are prospectively following 100 HIV-infected Ugandan patients for one year after they initiate ART. Of these, 50 patients have no active OI at time of ART initiation, and 50 patients have a diagnosis of cryptococcal meningitis within the previous 2 months. In addition to determining the incidence, severity, and clinical features of IRIS after initiation of ART in these patients, we will also determine whether the development of an IRIS event has a negative effect on ART compliance and whether this impacts treatment success. For this R03 grant application, we plan to use blood specimens obtained from patients in our ongoing cohort study to evaluate immune activation. The specific aim is to identify predictive and diagnostic biomarkers of IRIS by comparing immune activation in the peripheral blood of patients who develop IRIS versus those who do not develop IRIS after initiation of ART. We will prospectively collect whole blood RNA before and after initiation of ART and will use Affymetrix microarrays to compare immune activation gene expression between patients who develop IRIS and patients who do not develop IRIS. In this way, we will identify specific biomarkers associated with IRIS that are diagnostic of IRIS or predictive of future IRIS. A goal is to identify biomarkers that can be adapted into simple, inexpensive assays, such as real time PCR or ELISA, that can be used clinically to diagnose IRIS or monitor patients at risk for IRIS. The identification of biomarkers of IRIS will also provide important insight into the immune activation pathways that underlie the pathophysiology of IRIS. PUBLIC HEALTH RELEVANCE: HIV immune reconstitution inflammatory syndrome (IRIS) has emerged in sub-Saharan Africa as an important complication to antiretroviral therapy to treat HIV infection. Patients who develop IRIS exhibit clinical worsening due to inflammatory reactions that occur as their immune systems improve after starting antiretroviral therapy. The goal of this study is to develop clinical blood tests that could be used to diagnose IRIS and predict patients who are at risk for its development before they become ill.