HIV Immune Reconstitution Inflammatory Syndrome in Uganda

描述(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)的一种新的并发症，部分启动ART的晚期HIV患者随后由于对隐匿性、潜伏性或先前治疗的感染的夸大炎症反应而经历矛盾的临床恶化。在撒哈拉以南非洲，HIV IRIS已成为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，这样我们就可以开发优化的ART方案，将资源有限地区与IRIS相关的发病率和死亡率降至最低。我们目前正在对乌干达的艾滋病毒感染者进行一项研究，因为他们正在发起抗逆转录病毒治疗，以更好地了解IRIS在撒哈拉以南非洲地区的影响。这项正在进行的研究的目标是评估IRIS的发病率、严重性和临床特征，并确定与未患IRIS的患者相比，患有IRIS的感染艾滋病毒的乌干达患者的临床结果是否更差。我们正在前瞻性地跟踪100名感染艾滋病毒的乌干达患者，在他们开始抗逆转录病毒治疗后一年。在这些患者中，50名患者在开始抗逆转录病毒治疗时没有活动性OI，50名患者在过去2个月内被诊断为隐球菌性脑膜炎。除了确定这些患者在开始抗逆转录病毒治疗后的IRIS的发生率、严重性和临床特征外，我们还将确定IRIS事件的发展是否对ART依从性产生负面影响，以及这是否影响治疗成功。对于R03赠款的申请，我们计划使用我们正在进行的队列研究中从患者那里获得的血液样本来评估免疫激活。其具体目的是通过比较ART启动后发生IRIS的患者和未发生IRIS的患者外周血中的免疫激活情况，确定IRIS的预测和诊断生物标记物。我们将前瞻性地收集ART启动前后的全血RNA，并将使用Affymetrix微阵列来比较发生IRIS的患者和未发生IRIS的患者之间的免疫激活基因表达。通过这种方式，我们将识别与IRIS相关的特定生物标记物，这些标志物可以诊断IRIS或预测未来的IRIS。一个目标是确定可用于简单、廉价的分析的生物标记物，如实时荧光聚合酶链式反应或酶联免疫吸附试验，可用于临床诊断IRIS或监测有IRIS风险的患者。IRIS生物标志物的识别也将为了解IRIS病理生理学基础上的免疫激活途径提供重要的见解。与公共卫生相关：在撒哈拉以南非洲，艾滋病毒免疫重建炎症综合征(IRIS)已成为抗逆转录病毒疗法治疗艾滋病毒感染的一个重要并发症。患有IRIS的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，表现出临床恶化。这项研究的目标是开发临床血液测试，可用于诊断IRIS，并在患者患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.