The Progression of Hepatitis C Among IDUs

描述(由申请人提供)：R01DA016078的主要焦点是艾滋病毒感染者中丙型肝炎病毒(丙型肝炎病毒)相关肝病的进展。在美国，丙型肝炎病毒相关的肝病是艾滋病毒感染者死亡的主要原因之一，主要发生在注射非法药物的人中。然而，艾滋病毒感染在注射吸毒者中增加丙型肝炎病毒肝病风险的程度尚未确定，艾滋病毒如何影响肝病的机制在很大程度上尚不清楚。在注射吸毒者中肝病研究的主要局限是对疾病阶段的衡量。最近，这一挑战已经被克服。我们已经在静脉注射成形术中表明，通过弹性成像评估肝脏硬度，可以准确和安全地测量肝脏疾病。在我们的第一个目标中，我们使用这种方法来检验HIV相关的CD4+淋巴细胞耗尽会加速丙型肝炎病毒感染者肝病进展的假设，并描述这种影响的程度。最终，当出现肝功能衰竭或终末期肝病时，与丙型肝炎相关的肝病会导致死亡。在我们的第二个目标中，我们询问肝脏硬度的测量是否会影响注射吸毒者发生肝功能衰竭的风险，并对这种风险进行表征。虽然正在进行的丙型肝炎病毒复制是丙型肝炎病毒相关肝病进展所必需的，但尚不清楚进展的风险是否受复制程度的影响(正如其他慢性病毒感染所显示的那样)。HIV感染会增加血清中丙型肝炎病毒RNA的水平，但尚不清楚为什么会发生这种情况，以及它是否与更大的疾病进展有关。我们的第三个目标是验证假设，即更大的丙型肝炎病毒增殖会增加肝病进展的风险，并检查这种风险是否会因艾滋病毒感染或CD4+淋巴细胞耗尽而改变。通过使用我们的血清和肝组织存储库，我们将能够通过研究用激光捕获显微镜解剖的血清和特定肝细胞中的丙型肝炎病毒RNA复制来检验这一假设。由于一个经验丰富、有凝聚力的团队将继续使用现有的技术和具有良好特征的人体组织来了解艾滋病毒感染者与丙型肝炎病毒相关的肝病进展，因此这项研究计划有望取得成功。

DESCRIPTION (provided by applicant): The primary focus of R01DA016078 is the progression of hepatitis C virus (HCV)-related liver disease in HIV-infected persons. In the United States, HCV-related liver disease is one of the leading causes of death among HIV infected persons and occurs chiefly among persons who have injected illicit drugs (IDUs). However, the degree to which HIV infection increases HCV liver disease risk among IDUs has not been characterized and the mechanisms of how HIV affects liver disease are largely unknown. The major limitation of liver disease research among IDUs is measurement of disease stage. Recently, this challenge has been overcome. We have shown in IDUs that liver disease can be accurately and safely measured by assessment of liver stiffness by elastography. In our first aim, we use this method to test the hypothesis that HIV-related CD4 + lymphocyte depletion accelerates progression of liver disease among HCV-infected IDUs and to characterize the magnitude of that effect. Ultimately, HCV-related liver disease causes mortality when there is liver failure, or end stage liver disease. In our second aim, we ask whether measurements of liver stiffness affect the risk of developing liver failure among IDUs and characterize this risk. Although ongoing HCV replication is necessary for HCV-related liver disease progression, it is not clear whether the risk of progression is affected by the degree of replication (as has been shown with other chronic viral infections). HIV infection increases the serum level of HCV RNA, but it is unclear why this occurs and whether it is associated with greater disease progression. Our third aim is to test the hypothesis that greater HCV proliferation increases the risk of liver disease progression and to examine whether the risk is altered by HIV-infection or CD4+ lymphocyte depletion. By using our repository of serum and liver tissue, we will be able to test this hypothesis by investigating HCV RNA replication in serum and in specific liver cells dissected by laser capture microscopy. A high likelihood of success is anticipated in this research program as an experienced, cohesive team will continue to use available technology and well characterized human tissues to understand HCV related liver disease progression in HIV infected persons