Natural history of acute and chronic HCV in blood donors

描述(由申请人提供)：在输血环境中的研究已经对丙型肝炎病毒感染的流行病学、发病机制和自然病史产生了重要的见解。尽管通过输血传播现在很少见，但美国血液中心每年识别约10,000名无症状的丙型肝炎病毒感染者，这大大增加了需要临床治疗的已知感染者的数量。1999年，在所有美国献血者的丙型肝炎病毒抗体筛查中增加了常规的丙型肝炎病毒RNA检测，这使得能够在初次感染的重要病毒期、血清转换前阶段检测献血者，并将血清阳性献血者区分为推定的已解决感染和慢性感染。因此，献血中心是无症状的急性、慢性和社区获得性丙型肝炎病毒感染者的极佳招募地点。我们的团队由来自美国两个最大的献血项目(BSI，ARC)和两个主要的丙型肝炎学术中心(加州大学旧金山分校，约翰·霍普金斯大学)的合作者组成，在研究这些人群方面具有独特的地位。我们建议：1)通过对约10,000名确诊的丙型肝炎病毒血清阳性献血者和年龄匹配的对照进行邮寄调查和死亡指数搜索，确定特定原因的发病率和死亡率以及医学随访和治疗状况；2)表征丙型肝炎抗体阳性/RNA阴性献血者病毒清除的决定因素，以及晚期清除和复发病毒血症的比率。自1999年4月开始筛查的捐献者有现有的丙型肝炎病毒RNA结果(和存档的捐赠标本)，确定他们可能是持续或已解决的感染。我们将把720名“已决定”和匹配的“未决定”捐献者纳入一项轻松对照研究。这将使我们能够根据调查答复检查解决和持久性的流行病学相关性。此外，我们将获得后续标本，以确定晚期解决率或复发性病毒血症，并建立一个细胞和血浆的“解析器储存库”，以研究宿主遗传和免疫学清除的相关性。3)研究急性感染与慢性感染献血员丙型肝炎病毒基因进化及细胞免疫应答。我们每年将招募约25名被确认为急性感染丙型肝炎病毒(RNA阳性/抗体阴性)的捐赠者，并进行前瞻性跟踪。我们将在六个月内每月跟踪这些捐赠者。与我们的合作者一起，我们将研究样本，以确定在危急急性感染阶段解决问题的病毒和免疫学相关性。这些研究将对丙型肝炎病毒的发病机制产生重要的见解，并澄清通过捐赠者筛查确定的大量丙型肝炎病毒感染者的自然病史。

DESCRIPTION (provided by applicant): Studies in transfusion settings have yielded major insights into the epidemiology, pathogenesis and natural history of HCV infection. Although transmission by transfusion is now rare, U.S. blood centers identify ~10,000 asymptomatic HCV-infected donors each year, contributing substantially to the pool of known infected persons requiring clinical management. The addition of routine HCV RNA testing to HCV antibody screening of all U.S. blood donors in 1999 has enabled both detection of donors in the important viremic, pre-seroconversion phase of primary infection, and discrimination of seropositive donors into presumptive resolved and chronic infections. Blood donation centers are therefore excellent recruitment sites for asymptomatic persons with acute, chronic and resolved community-acquired HCV. Our group, composed of collaborators from the two largest blood donor programs in the U.S. (BSI, ARC) and two major HCV academic centers (UCSF, Johns Hopkins University), is uniquely positioned to study these populations. We propose to: 1) Determine cause-specific morbidity and mortality and medical follow-up and treatment status by mail surveys and death index searches of~10,000 confirmed HCV seropositive blood donors and age-matched controls; 2) Characterize determinants of viral clearance in HCV antibody-positive/RNA-negative donors, and rates of late clearance and recurrent viremia. Donors screened since April 1999 have existing HCV RNA results (and archived donation specimens), identifying them as probable persistent or resolved infections. We will enroll 720 "resolved" and matched "non-resolved" donors into a ease-control study. This will enable us to examine epidemiologic correlates of resolution and persistence, based on survey responses. In addition, we will obtain follow-up specimens to define rates of late resolution or recurrent viremia, and to establish a "resolver repository" of cells and plasma to investigate host genetic and immunologic correlates of clearance. 3) Investigate HCV genetic evolution and cellular immune responses during acute infection in blood donors with resolving versus chronic infections. We will enroll and prospectively follow approximately 25 donors per year who are identified as acutely infected with HCV (RNA-positive/antibody-negative). We will follow these donors monthly for six months. Along with our collaborators, we will study specimens to identify viral and immunologic correlates of resolution during the critical acute infection phase. These investigations will yield important insights into HCV pathogenesis and clarify the natural history of disease for the large number of HCV infected persons identified through donor screening.