Moving Towards More Individualized Therapies in HIV/HCV Co-infected Patients

描述（由申请人提供）：在美国，估计有270 - 390万人患有慢性HCV感染，约占人口的1.3-1.9%。由于共有的传播途径，在15-40%的人类免疫缺陷病毒（HIV）慢性感染者中发生HCV合并感染。现在，在有效的联合抗逆转录病毒治疗（ART）的背景下，肝病已成为艾滋病毒感染者死亡和医疗资源利用的主要原因。最近发现的宿主IL 28 B基因上游的单核苷酸多态性（rs 12989760）已被报道为HCV治疗反应、自发病毒清除、脂蛋白水平和脂肪变性的预测因子。HCV病毒粒子和脂蛋白的相互作用已被充分描述。这项研究计划的长期目标是确定ART诱导的脂蛋白升高对HIV/HCV合并感染者肝脏疾病的作用。本研究的目的是通过以下几个具体的目标来实现：（1）探讨抗逆转录病毒诱导的脂蛋白升高与HIV/HCV合并感染患者中HCV发病机制的关系;（2）确定降脂化合物治疗对HIV/HCV合并感染患者中HCV发病机制的影响;（3）在候选基因方法中，研究IL 28 B基因型作为HIV/HCV共感染者ART相关脂蛋白增加和HCV病毒载量增加风险的宿主基线预测因子。（4）确定宿主遗传学对HIV/HCV共感染患者在基线和pegIFN/RBV治疗时ISG差异表达和脂蛋白生物合成的影响。具体目标1将使用一个大型的描述良好的队列库来实现，以确定HIV/HCV合并感染患者开始ART后脂蛋白参数和HCV RNA增加的相关性。具体目标2和3将通过一项HIV/HCV合并感染患者的前瞻性研究设计来实现，这些患者将开始接受利托那韦增强的蛋白酶抑制剂为基础的ART治疗。患者将随机分为降脂治疗组和蛋白酶抑制剂单独治疗组。将在基线时采集患者DNA用于宿主基因分型。具体目标4将通过使用基于干扰素的HCV治疗方案治疗的HIV/HCV合并感染患者的良好描述的临床队列来实现;这将与NIAID的研究者合作完成。PBMC将用于基因表达微阵列，基线DNA将用于宿主基因分型。这些具体目标将有助于证明在HIV/HCV合并感染患者中进行更个性化治疗的可行性。这些结果将阐明进一步研究在评估降脂药物和IL 28 B多态性在治疗HIV/HCV合并感染患者中的作用方面的效用，特别是在新的联合治疗（包括直接作用于HCV的抗病毒药物）时代。随着SVR率的提高，但更昂贵的联合治疗方案，关于HCV治疗的效用和益处的个体化治疗决策的能力将是至关重要的。 公共卫生相关性（由申请方提供）：由于共有传播途径，HIV和HCV合并感染很常见;在有效的联合抗逆转录病毒治疗（ART）背景下，肝病已成为HIV感染者死亡和医疗资源利用的主要原因。本研究旨在为HIV/HCV合并感染患者人群中HIV和HCV的个体化治疗提供证据，重点关注抗逆转录病毒诱导的代谢并发症和IL 28 B基因多态性。本研究的结果将直接转化为难以治疗患者人群的临床护理，最终目标是改善长期肝脏相关发病率和死亡率。

DESCRIPTION (provided by applicant): In the United States it is estimated that 2.7-3.9 million persons are living with chronic HCV infection, which accounts for approximately 1.3-1.9% of the population. Due to shared routes of transmission, co-infection with HCV occurs in 15-40% of persons chronically infected with human immunodeficiency virus (HIV). Now, in the context of effective combination antiretroviral therapy (ART), liver disease has emerged as a predominant cause of death and of healthcare resource utilization in HIV-infected persons. A recently discovered host single nucleotide polymorphism upstream of the IL28B gene (rs12989760) has been reported as a predictor of HCV treatment response, spontaneous viral clearance, lipoprotein levels, and steatosis. The interaction of HCV virions and lipoproteins is well described. The long-term objective of this research proposal is to determine the role of ART-induced lipoprotein increases on liver disease in HIV/HCV co-infected individuals. The objective will be achieved through several specific aims: (1) Explore the association of antiretroviral-induced lipoprotein increases on HCV pathogenesis in HIV/HCV co-infected patients; (2) Determine the effect of treatment with lipid lowering compounds on HCV pathogenesis in HIV/HCV co-infected patients; (3) In a candidate gene approach investigate the IL28B genotype as a host baseline predictor for risk of ART-related lipoprotein increases and increased HCV viral load in HIV/HCV co-infected patients at months 6 and 12 following ART initiation; (4) Determine the impact of the host genetics on differential ISG expression and lipoprotein biosynthesis in HIV/HCV co-infected patients at baseline and on pegIFN/RBV therapy. Specific Aim 1 will be achieved using a large well-described cohort repository to determine the correlation of increases in lipoprotein parameters and HCV RNA after the initiation of ART in HIV/HCV co-infected patients. Specific Aims 2 and 3 will be achieved using a prospective study design of HIV/HCV co-infected patients initiating ritonavir-boosted-protease inhibitor-based ART. Patients will be randomization into a lipid lowering therapy arm versus protease inhibitor therapy alone. Patient DNA will be collected at baseline for host genotyping. Specific Aim 4 will be achieved using a well-described clinical cohort of HIV/HCV co-infected patients treated with interferon based regimens for HCV; this will be done in collaboration with investigators at the NIAID. PBMCs will be used for gene expression microarray and baseline DNA will be used for host genotyping. These Specific Aims will help demonstrate the feasibility of more individualized therapy in HIV/HCV co-infected patients. The results will clarify the utility of further study in assessing the role of lipid lowering agents and the IL28B polymorphism in the treatment of HIV/HCV co-infected patients, especially in the era of new combination therapies that will include directly acting antivirals for the treatment of HCV. With improved SVR rates, but more expensive combination regimens, the ability to individualize treatment decisions regarding the utility and benefit of HCV therapy will be critical. PUBLIC HEALTH RELEVANCE (provided by the applicant): Due to shared routes of transmission, co-infection with HIV and HCV is common; in the context of effective combination antiretroviral therapy (ART), liver disease has emerged as a predominant cause of death and of healthcare resource utilization in HIV-infected persons. This study proposes to provide evidence for individualized therapy of HIV and HCV in the HIV/HCV co-infected patient population with a focus on antiretroviral induced metabolic complications and the IL28B gene polymorphism. Results from this study would directly translate to the clinical care of this difficult to treat patient population with the ultimate goal to improve long-term liver related morbidity and mortality.