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

对 HIV/HCV 合并感染患者进行更加个体化的治疗

基本信息

批准号：
8293010
负责人：
Susanna Naggie
金额：
$ 8.87万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8293010
关键词：
AIDS clinical trial group Accounting Acquired Immunodeficiency Syndrome Anabolism Anti-Retroviral Agents Antiviral Agents Candidate Disease Gene Caring Cause of Death Chronic Hepatitis C Clinical Clinical Research Collaborations Combined Modality Therapy DNA Disease Exposure to Functional disorder Gene Expression Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals HIV Healthcare Hepatitis C virus Hepatocyte Individual Infection Interferons Life Lipids Lipoproteins Literature Liver Liver diseases Low-Density Lipoproteins Mentors Metabolic Modeling Molecular Morbidity - disease rate National Institute of Allergy and Infectious Disease Natural History Omega-3 Fatty Acids Pathogenesis Patients Pegylated Interferon Alfa Persons Pilot Projects Population Prospective Studies Protease Inhibitor RNA Randomized Regimen Reporting Research Design Research Institute Research Personnel Research Proposals Resources Ribavirin Risk Ritonavir Role Route Sampling Single Nucleotide Polymorphism Time Translating United States Viral Viral Load result Virion World Health Organization antiretroviral therapy arm atorvastatin base clinical care cohort improved innovation mortality patient population repository response standard of care transmission process treatment effect treatment response

项目摘要

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.

描述（由申请人提供）：在美国，估计有 2.7-390 万人患有慢性 HCV 感染，约占总人口的 1.3-1.9%。由于传播途径相同，慢性感染人类免疫缺陷病毒 (HIV) 的人中有 15-40% 会同时感染 HCV。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。据报道，最近发现的 IL28B 基因上游宿主单核苷酸多态性 (rs12989760) 可作为 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 病毒颗粒和脂蛋白的相互作用已有详细描述。本研究计划的长期目标是确定 ART 诱导的脂蛋白增加对 HIV/HCV 合并感染个体肝病的作用。该目标将通过几个具体目标来实现：(1) 探索抗逆转录病毒诱导的脂蛋白增加与 HIV/HCV 合并感染患者的 HCV 发病机制之间的关系； (2)确定降脂化合物治疗对HIV/HCV合并感染患者HCV发病机制的影响； (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，预测 ART 相关脂蛋白增加的风险以及 HIV/HCV 共感染患者在开始 ART 后第 6 个月和第 12 个月时 HCV 病毒载量增加的风险； (4) 确定宿主遗传学对 HIV/HCV 合并感染患者的基线 ISG 差异表达和脂蛋白生物合成以及 pegIFN/RBV 治疗的影响。具体目标 1 将使用一个描述良好的大型队列存储库来实现，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 将通过对 HIV/HCV 合并感染患者启动基于利托那韦增强蛋白酶抑制剂的 ART 的前瞻性研究设计来实现。患者将被随机分为降脂治疗组和单独的蛋白酶抑制剂治疗组。将在基线时收集患者 DNA 以进行宿主基因分型。具体目标 4 将通过使用基于干扰素的 HCV 方案治疗的 HIV/HCV 共感染患者的详细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 HIV/HCV 合并感染患者进行更个体化治疗的可行性。这些结果将阐明进一步研究评估降脂药和 IL28B 多态性在治疗 HIV/HCV 合并感染患者中的作用的效用，特别是在包括直接作用抗病毒药物治疗的新联合疗法时代丙肝病毒。随着 SVR 率的提高，但联合治疗方案更加昂贵，关于 HCV 治疗的效用和益处的个体化治疗决策的能力将至关重要。