DETERMINANTS OF HEPATITIS C & E MORBIDITY IN EGYPT

利用新的分子病毒学技术，非甲非乙型肝炎患者现在被归类为感染丙型肝炎病毒(丙型肝炎病毒)和戊型肝炎病毒(HEV)的患者。丙型肝炎病毒是一种通过肠道外传播的黄病毒，而戊型肝炎病毒是一种通过粪便和口腔传播的类似戊型肝炎的病毒。世卫组织估计，有1.7亿人感染了丙型肝炎病毒，这是慢性病毒性肝炎(CVH)、坏死性肝硬变和肝细胞癌(HCC)的最常见原因。HEV主要在发展中国家传播，在那里它是急性病毒性肝炎(AVH)和重型肝炎的最常见原因，特别是在孕妇中。我们和其他人已经证明，世界上丙型肝炎病毒，也可能是戊型肝炎病毒的最高流行率发生在埃及。我们已经建立了一个由埃及人和美国人组成的网络，他们正在研究病毒性肝炎及其给国家带来的成本。在这份ICIDR提案中，我们将扩大该网络的工作范围，以包括：(1)宿主基因组对丙型肝炎病毒感染后的慢性和肝硬变的影响(项目1)；(2)肝细胞癌和(因为丙型肝炎病毒具有淋巴和肝脏营养性)非霍奇金淋巴瘤(NHL，项目2)的宿主、病毒和环境决定因素；以及戊型肝炎病毒的流行病学和并发症(项目3)。项目1和2将进行病例对照研究。前者将比较：(A)慢性丙型肝炎病毒RNA携带者与清除感染的受试者，以及(B)出现肝硬变的丙型肝炎患者与没有疾病迹象的人；而后者将肝细胞癌或非霍奇金淋巴瘤患者与年龄和性别匹配的对照组进行比较。项目1-3将对抗-丙型肝炎病毒流行率分别为9%和24%以及抗-丙型肝炎病毒流行率分别为51%和70%的两个村庄的10,000名居民进行前瞻性队列研究。他们的目标将是确定肝硬变(项目1)、肝细胞癌和非霍奇金淋巴瘤(项目2)以及戊型肝炎病毒感染和疾病(项目3)的发病率和风险决定因素。将对一组孕妇和儿童进行研究，以评估怀孕期间HEV的发病率以及婴儿时期的暴露和疾病。将对家养动物和家养附近的啮齿动物进行研究，以确定在埃及HEV是否含有人畜共患病成分。将分析病毒基因类型、宿主I和II类等位基因和候选基因，例如趋化因子受体和可能的丙型肝炎病毒受体高密度脂蛋白，以及环境暴露及其对宿主基因的影响(P53基因指纹)。由于科学、管理、后勤和实验室网络已经到位，而且丙型肝炎病毒和戊型肝炎病毒在埃及都有很高的流行率，这些调查很有可能早日成功。这些非常重要的问题的解释可以用其他地方可以找到的成本和时间的一小部分来获得，结果应该会导致开发更好的干预措施，以预防世界上两个最重要的肝病原因。

By using new molecular virological techniques, Non-A Non-B hepatitis patients have now been categorized into those infected with hepatitis C virus (HCV), a parenterally transmitted flavivirus, and hepatitis E virus (HEV), a fecal-oral transmitted "hepatitis E-like virus." WHO estimates that 170 million are infected with HCV, the most common cause of chronic viral hepatitis (CVH), post-necrotic cirrhosis of the liver and hepatocellular carcinoma (HCC). HEV is primarily transmitted in developing countries where it is the most common cause of acute viral hepatitis (AVH) and fulminating hepatitis, particularly in pregnant women. We and others have documented that the highest prevalence of HCV, and also possibly HEV, in the world occurs in Egypt. We have established a Network of Egyptians and Americans who are studying viral hepatitis and its cost to the country. In this ICIDR proposal, we will extend the work of this Network to include investigations of: (1) the effect that the host genome has on chronicity and cirrhosis following HCV infection (Project 1); (2) the host, viral, and environmental determinants of HCC and (because HCV is lymphotrophic as well as hepatotrophic) non-Hodgkins lymphoma (NHL, Project 2); and the epidemiology and complications of HEV (Project 3). Projects 1 & 2 will have case-control studies. The former will compare: (a) chronic carriers of HCV RNA vs. subjects who clear infection and (b) those with HCV who develop cirrhosis vs. those that show no signs of disease; while the latter compares HCC or NHL cases vs. age- and gender-matched controls. Projects 1-3 will have prospective cohort studies of 10,000 inhabitants of two villages with prevalence of anti-HCV of 9% and 24% and anti-HCV of 51 and 70%, respectively. Their goals will be to determine incidence of, and risk determinants for cirrhosis (Project 1), HCC and NHL (Project 2), and HEV infection and disease (Project 3). A cohort of pregnant women and children will be studied to assess HEV morbidity in pregnancy and exposures and disease in infancy. Domestic animals and peri-domestic rodents will be studied to determine whether HEV has a zoonotic component in Egypt. Viral genotypes, host class I and II alleles and candidate genes, e.g., chemokine receptors and HDL, a possible HCV receptor, and environmental exposures and their impact on host genes (p53 genetic fingerprinting) will be assayed. Because the scientific, administrative, logistic and laboratory network is in place and both HCV and HEV have such a high prevalence in Egypt, these investigations have a high probability of early success. Explanations for these very important questions can be obtained at a fraction of the cost and time as they could be found elsewhere, and the results should lead to the development of better interventions to prevent the two most important causes of liver disease in the world.