Natural history of acute and chronic HCV in blood donors

描述（由申请人提供）：在输血环境下的研究已经对HCV感染的流行病学、发病机制和自然史产生了重要的见解。虽然输血传播现在很少见，但美国血液中心每年发现约10,000名无症状丙型肝炎病毒感染的献血者，这大大增加了需要临床治疗的已知感染者。1999年，在所有美国献血者的HCV抗体筛查中增加了常规HCV RNA检测，这使得在重要的病毒血症、原发性感染的血清前转化阶段检测献血者，以及将血清阳性献血者区分为推定的解决和慢性感染成为可能。因此，对于急性、慢性和已治愈的社区获得性HCV无症状患者，献血中心是极好的招募地点。我们的团队由来自美国两个最大的献血者项目（BSI， ARC）和两个主要的HCV学术中心（UCSF, Johns Hopkins University）的合作者组成，在研究这些人群方面具有独特的优势。我们建议：1)通过邮件调查和死亡指数搜索，确定约1万名确诊HCV血清阳性献血者和年龄匹配对照者的病因特异性发病率和死亡率以及医疗随访和治疗状况；2)表征HCV抗体阳性/ rna阴性供者病毒清除率的决定因素，以及晚期清除率和复发病毒血症的发生率。自1999年4月以来筛选的献血者有现有的HCV RNA结果（和存档的捐献标本），将其确定为可能的持续性或已解决的感染。我们将招募720名“已决定”和匹配的“未决定”捐赠者参加一项易于控制的研究。这将使我们能够根据调查结果检查决心和坚持的流行病学相关性。此外，我们将获得随访标本，以确定晚期消退或复发病毒血症的比率，并建立细胞和血浆的“消退库”，以研究宿主遗传和免疫相关的清除。3)研究丙型肝炎病毒在献血者急性感染和慢性感染期间的遗传进化和细胞免疫反应。我们每年将招募并前瞻性随访大约25名被确定为急性感染HCV （rna阳性/抗体阴性）的献血者。我们将每月跟踪这些捐赠者六个月。与我们的合作者一起，我们将研究标本，以确定关键急性感染阶段的病毒和免疫相关性。这些调查将对HCV的发病机制产生重要的见解，并阐明通过供体筛查确定的大量HCV感染者的疾病自然史。

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.