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

描述(申请人提供)：在美国，估计有270-390万人患有慢性丙型肝炎病毒感染，约占总人口的1.3-1.9%。由于共同的传播途径，15%-40%的慢性人类免疫缺陷病毒(HIV)感染者会与丙型肝炎病毒合并感染。现在，在有效的联合抗逆转录病毒疗法(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IL28B基因上游的宿主单核苷酸多态(Rs12989760)被报道为预测丙型肝炎治疗应答、自发病毒清除、脂蛋白水平和脂肪变性的指标。丙型肝炎病毒粒子和脂蛋白之间的相互作用得到了很好的描述。这项研究计划的长期目标是确定ART诱导的脂蛋白增加在HIV/丙型肝炎合并感染者肝脏疾病中的作用。这一目标将通过几个特定的目的来实现：(1)探讨抗逆转录病毒诱导的脂蛋白增加与HIV/丙型肝炎病毒混合感染患者的丙型肝炎病毒发病机制的关系；(2)确定降脂化合物治疗对艾滋病毒/丙型肝炎混合感染患者丙型肝炎病毒发病的影响；(3)在候选基因方法中，研究IL28B基因型作为宿主基线预测因子，在ART启动后6个月和12个月时，艾滋病毒/丙型肝炎病毒载量增加和ART相关脂蛋白增加的风险；(4)确定宿主遗传学对HIV/丙型肝炎病毒混合感染患者基础状态下ISG差异表达和脂蛋白生物合成的影响，以及对PEGIFN/RBV治疗的影响。具体目标1将利用一个描述良好的大型队列资料库来确定艾滋病毒/丙型肝炎病毒混合感染患者在开始抗逆转录病毒治疗后脂蛋白参数和丙型肝炎病毒RNA增加的相关性。具体目标2和3将通过一项前瞻性研究设计实现，该研究设计为HIV/丙型肝炎病毒混合感染患者启动利托那韦增强的蛋白酶抑制剂抗逆转录病毒疗法。患者将被随机分成降脂治疗组和单独接受蛋白酶抑制剂治疗的组。患者DNA将在基线上收集，用于宿主基因分型。具体目标4将通过使用以干扰素为基础的丙型肝炎病毒治疗方案治疗的艾滋病毒/丙型肝炎病毒混合感染患者的良好描述的临床队列来实现；这将与NIAID的研究人员合作完成。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对艾滋病毒/丙型肝炎混合感染患者进行更个体化治疗的可行性。这一结果将阐明进一步研究在评估降脂剂和IL28B多态在治疗艾滋病毒/丙型肝炎混合感染患者中的作用方面的效用，特别是在包括直接作用的抗病毒药物治疗丙型肝炎病毒的新组合疗法时代。随着SVR率的提高，但联合方案的成本更高，根据丙型肝炎病毒治疗的有效性和益处做出个性化治疗决定的能力将是至关重要的。

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.