Neurobehavioral Deficits in HIV/HCV Infection Pre/Post Anti-HCV Therapy

描述（由申请人提供）：本申请对PA-07-089中枢神经系统HIV感染有反应，部分对PA-07-338 HIV治疗依从性研究有反应。人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）的合并感染是一个新兴的医疗保健问题，在美国，大约三分之一的HIV感染患者合并感染HCV。感染艾滋病毒和丙型肝炎病毒可引起一系列认知、精神和中枢神经系统异常。越来越多的人有理由相信，即使在没有艾滋病毒或其他并发症的情况下，丙型肝炎病毒本身也是神经致病性的。HCV的主要治疗方法是聚乙二醇化干扰素和利巴韦林（PEG-IFN/RBV）。治疗成功与否与患者能否耐受处方剂量和治疗持续时间有关。研究的重点还在于患者是否可能错过或跳过剂量，这与在单HIV感染中得到充分研究的情况类似。考虑到HCV持续缓解率相对较低（约40-50%），考虑到长期服用强效药物组合的困难（大多数将治疗48周），有理由认为，依从性不佳可能是治疗失败的部分原因。这项为期五年的纵向研究旨在确定：(1)PEG- IFN/RBV治疗对神经认知、神经精神和神经影像学参数的影响，以及合并症HIV感染改变这种反应的程度；(2)与基线表现相比，达到SVR的参与者是否在统计学和临床上表现出显著的神经功能改善；(3)坚持抗hcv药物治疗方案对神经功能的影响程度以及获得持续病毒学反应的可能性。我们特别感兴趣的是确定合并症HIV感染如何（或是否）改变治疗相关神经变化的表达。我们将招募330名参与者，165名HIV/HCV合并感染者和165名HCV单一感染者，以获得200名完成治疗的参与者的最终样本。研究参与者将在开始治疗前、治疗开始后12周以及治疗结束后12周接受一系列神经心理学和精神病学评估。嵌套队列将在每个研究时间点进行质子磁共振波谱（MRS）和扩散张量成像（DTI）。我们将采用增长模型和多群体路径分析作为主要的分析技术。项目简介：人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）的合并感染日益被认为是一个紧迫的公共卫生问题，因为在美国，HCV导致的死亡人数将很快超过HIV。虽然有一些治疗丙肝病毒的药物通常是有效的，但这些药物也有毒性，可能对大脑功能产生不利影响，并导致药物依从性问题。这项研究将确定HIV和HCV合并感染如何影响大脑，HCV治疗如何影响大脑功能，以及坚持使用HCV药物如何影响对治疗的反应和神经功能。特别令人感兴趣的是艾滋病毒合并感染如何影响对治疗的反应。

DESCRIPTION (provided by applicant): This application is responsive to PA-07-089 HIV Infection of the Central Nervous System and partially responsive to: PA-07-338 HIV Treatment Adherence Research. Co-infection with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) is a burgeoning healthcare concern, as approximately one third of all HIV-infected patients in the United States are co-infected with HCV. Infection with HIV and HCV can give rise to a host of cognitive, psychiatric and central nervous system abnormalities. Increasingly, there is reason to believe that HCV, even in the absence of HIV or other cormorbid conditions, is itself neuropathogenic. The main treatment for HCV is pegylated interferon alfa and ribavirin (PEG-IFN/RBV). Treatment success is linked to whether patients can tolerate prescribed dosages and duration of therapy. Research has yet to focus on whether patients may miss or skip doses, an analogous situation to what has been well studied in HIV mono-infection. Given the relatively low rates of sustaining HCV remission (approximately 40-50%) and given the difficulty of taking a potent combination of medications for a sustained period of time (most will be on treatment for 48 weeks), it is reasonable to assume that suboptimal adherence might share some responsibility for treatment failure. This five year longitudinal study seeks to determine: (1) The impact of treatment with PEG- IFN/RBV on neurocognitive, neuropsychiatric, and neuroimaging parameters and the degree to which comorbid HIV infection alters this response; (2) whether participants who achieve a SVR demonstrate statistically and clinically significant improvements in neuro-function compared to baseline performance and (3) the degree to which adherence to participants' anti-HCV medication regimen impacts neural function as well as the likelihood of obtaining a sustained virologic response. We are particularly interested in determining how (or if) co-morbid HIV infection alters the expression of treatment related neuro-changes. We will enroll 330 participants, 165 who are HIV/HCV co-infected and 165 who are HCV mono-infected in order to obtain an ultimate sample of 200 participants who complete therapy. Study participants will be evaluated with a series of neuropsychological and psychiatric measures prior to beginning treatment, 12 weeks after treatment has been initiated, and then 12 weeks following treatment completion. A nested cohort will undergo proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) at each study timepoint. We will employ growth modeling and multiple group path analysis as the primary analytic techniques. Project Narrative: Co-infection with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) is increasingly recognized as a pressing public health concern as the number of deaths due to HCV will soon outpace deaths due to HIV in the United States. While there are medications for HCV that are frequently effective, these drugs are also toxic and may adversely affect brain function and cause problems with medication adherence. This study will determine how co-infection with both HIV and HCV affects the brain, how treatment for HCV affects brain function, and how adherence to HCV medications affects response to treatment and neurological functions. Of particular interest is how HIV co-infection affects response to treatment.