NEEDLESTICK HCV EXPOSURE: VIROLOGIC & IMMUNOLOGIC EVENTS

通过针刺事件将丙型肝炎病毒（HCV）从患者传播给卫生保健工作者（HCW）是一个重要但未得到重视的问题。在美国国立卫生研究院资助的R03试点研究中，我们观察到6.6%的卫生保健工作者通过针头接触HCV阳性患者的血液获得感染；这一观察结果与先前的报告一致，当源患者被记录为病毒血症时，传播率为10%。随着住院患者中丙型肝炎病毒感染率的上升，特别是在像我们这样的城市环境中，这一问题的严重性将会增加。例如，在参与这项提案的巴尔的摩医院联盟中，卫生保健工作者在过去一年中报告了150多例针头接触丙型肝炎病毒的病例。此外，我们了解到，在过去一年中，这些医院至少发生了5起HCV传播事件。为了解决这个问题，我们将对巴尔的摩医院发生的针刺事件进行多中心前瞻性观察试验。我们将通过高危针刺事件确定HCV传播的风险，并确定源患者病毒特征和HCV特异性抗体反应对病毒传播的影响。暴露的卫生保健工作者将在暴露时登记，并随访12个月。将在基线和暴露后2、4、6、8、12、24和52周收集血清和外周血单个核细胞，进行详细的病毒学和免疫学分析。源患者HCV也将被表征，包括病毒滴度和基因型，准物种多样性和抗体结合。为了验证源患者血清中中和抗体可能防止传播的假设，我们将检测源血清中的抗e2抗体（NOB小于中和结合大于检测）。通过这些调查，我们将深入了解传播的危险因素以及与防止传播有关的因素。我们将描述急性HCV感染后发生的免疫学和病毒学事件。外周血CD4对免疫显性T细胞表位的增殖反应外周血CTL对特定肽的反应；并在感染早期收集的血液样本中测量培养淋巴细胞细胞因子反应谱（Th1/Th2/Th0）。HCV-E2特异性抗体反应将随时间测量，根据病毒准种进化进行检查，并与感染结果相关。我们将通过早期感染的过程来探索HCV对外周血单核细胞群的趋向性，以确定宿主抗体对病毒/细胞相互作用的影响。通过建立参与医院联盟，与全市一线员工健康从业人员协同合作，我们将更好地确定丙型肝炎病毒传播的风险，确定急性丙型肝炎病毒感染的早期事件，并创建一个平台，可以在未来评估预防干预措施。

Transmission of Hepatitis C Virus (HCV) from patients to health care workers (HCW) through needlestick events is a significant and underappreciated problem. In an NIH funded R03 Pilot Study, we have observed that 6.6 percent of health care workers exposed through needlestick to blood from HCV positive patients acquired infection; this observation is in keeping with a previous report of 10 percent transmission when source patients were documented to be viremic. As prevalence rates of HCV infection among hospitalized patients rise, particularly in urban settings such as ours, this problem will increase in magnitude. For instance, among the coalition of Baltimore hospitals collaborating in this proposal, more than 150 needlestick exposures to HCV were reported by health care workers during the past year. Furthermore, we are aware of at least 5 episodes of HCV transmission occurring in those same hospitals over the past year. To address this problem, we will perform a multicenter prospective observational trial of needlestick events occurring at hospitals in Baltimore. We will define the risk of HCV transmission through high-risk needlestick events, and determine the influence of source patient virus characteristics and HCV-specific antibody responses on viral transmission. Exposed HCWs will be enrolled at the time of exposure, and followed through twelve months. Serum and peripheral blood mononuclear cells will be collected at baseline, and at 2, 4, 6, 8, 12, 24 and 52 weeks following exposure, for detailed virologic and immunologic analyses. Source patient HCV will also be characterized, including viral titer and genotype, quasispecies diversity, and antibody binding. To examine the hypothesis that neutralizing antibody in source patient sera may protect against transmission, we will assay source sera for anti-E2 antibodies (NOB less than neutralization of binding greater than assay). Through these investigations, we will gain insight into the risk factors for transmission, and factors associated with protection from transmission. We will characterize immunologic and virologic events occurring in response to acute HCV infection. Peripheral blood CD4 proliferative responses to immunodominant T cell epitopes; peripheral blood CTL responses to specific peptide; and cultured lymphocyte cytokine response profiles (Th1/Th2/Th0) will be measured in blood samples collected through the earliest stages of infection. HCV-E2 specific antibody responses will measured over time, examined in light of of viral quasispecies evolution, and correlated with outcome of infection. We will explore the tropism of HCV for peripheral blood mononuclear cell populations through the course of early infection, to determine the influence of host antibody on viral/cell interactions. Through the creation of the coalition of participating hospitals, in a synergistic collaboration with front-line employee health practitioners across the city, we will better define the risk of HCV transmission, define early events in acute HCV infection, and create a platform from which prophylactic interventions may be evaluated in the future.