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感染有响应，对PA-07-338 HIV治疗依从性研究有部分响应。人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）的共感染是一个新兴的医疗保健问题，因为在美国大约三分之一的HIV感染患者共感染HCV。HIV和HCV感染可引起许多认知、精神和中枢神经系统异常。越来越多的人有理由相信，即使没有艾滋病毒或其他cormorbid条件下，HCV本身是神经致病性的。HCV的主要治疗是聚乙二醇干扰素α和利巴韦林（PEG-IFN/RBV）。治疗的成功与患者是否能耐受处方剂量和治疗持续时间有关。研究还没有集中在患者是否可能错过或跳过剂量，类似的情况已经在艾滋病毒单一感染的研究。考虑到HCV持续缓解率相对较低（约40-50%），并且考虑到持续一段时间服用有效药物组合的困难（大多数将接受48周的治疗），可以合理地假设次优依从性可能对治疗失败负有一定责任。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，以及共病HIV感染改变这种反应的程度;（2）与基线表现相比，达到SVR的参与者是否表现出神经功能的统计学和临床显著改善，以及（3）参与者坚持抗HCV药物治疗方案的程度影响神经功能以及获得持续病毒学应答的可能性。我们特别感兴趣的是确定共病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名受试者，其中165名为HIV/HCV合并感染者，165名为HCV单一感染者，以获得200名完成治疗的受试者的最终样本。在开始治疗前、治疗开始后12周以及治疗完成后12周，将采用一系列神经心理学和精神病学指标对研究受试者进行评估。嵌套队列将在每个研究时间点接受质子磁共振波谱（MRS）和弥散张量成像（DTI）。我们将采用增长模型和多组路径分析作为主要的分析技术。项目叙述：人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）的共同感染越来越被认为是一个紧迫的公共卫生问题，因为在美国，由于HCV而死亡的人数很快就会超过由于HIV而死亡的人数。虽然有治疗HCV的药物经常有效，但这些药物也是有毒的，可能会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的共感染如何影响大脑，HCV治疗如何影响脑功能，以及对HCV药物的依从性如何影响对治疗和神经功能的反应。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.