Natural history of acute and chronic HCV in blood donors

描述（由申请人提供）：输血环境中的研究对HCV感染的流行病学、发病机制和自然史产生了重要的见解。 虽然通过输血传播现在很少见，但美国血液中心每年确定约10，000名无症状HCV感染的献血者，这对需要临床管理的已知感染者的数量有很大贡献。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，这使得能够在重要的病毒血症、原发性感染的血清转化前阶段检测献血者，并将血清阳性献血者区分为假定的已解决感染和慢性感染。因此，献血中心是急性、慢性和已消退的社区获得性HCV无症状患者的理想招募场所。 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HCV学术中心（UCSF，约翰霍普金斯大学）的合作者组成，具有独特的优势来研究这些人群。 我们建议：1）通过邮寄调查和死亡指数搜索约10，000名确认的HCV血清阳性献血者和年龄匹配的对照者，确定病因特异性发病率和死亡率以及医疗随访和治疗状态; 2）表征HCV抗体阳性/RNA阴性献血者中病毒清除的决定因素，以及晚期清除率和复发性病毒血症。 自1999年4月以来筛查的献血者有现有的HCV RNA结果（和存档的献血标本），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“已解决”和匹配的“未解决”供体进入一项简单对照研究。 这将使我们能够检查流行病学的相关性的决议和持久性，调查的基础上的答复。 此外，我们将获得随访标本，以确定晚期消退或复发性病毒血症的发生率，并建立细胞和血浆的“消退储存库”，以研究清除的宿主遗传和免疫相关性。 3)调查丙型肝炎病毒的基因进化和细胞免疫反应在急性感染献血者与解决与慢性感染。 我们将每年招募并前瞻性随访约25名被确定为HCV急性感染（RNA阳性/抗体阴性）的供体。 我们将在六个月内每月跟踪这些捐赠者。 沿着我们的合作者，我们将研究标本，以确定病毒和免疫学相关的决议在关键的急性感染阶段。 这些调查将产生重要的见解，HCV的发病机制，并澄清了疾病的自然史，为大量的HCV感染者通过供体筛选确定。

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.