HIV感染者微生物移位对肝纤维化转归影响及其炎性机理队列研究

Liver fibrosis and related complications are currently the major disease burden and causes of death for HIV-infected patients. Epidemiological surveillance and clinical observational studies reveal that both incidence and disease progression of liver fibrosis are more severe in HIV-infected people than in general population. However, the pathogenic mechanisms are yet to be understood. Recent studies suggest that HIV infection stimulates and enhances intestinal microbial translocation (MT) which in turn stimulates inflammatory responses that are significantly associated with development of a variety of chronic complications. Therefore, using a prospective cohort study design in the proposed project, we aim to establish a cohort of 650 newly reported HIV-infected patients with liver fibrosis in Dehong prefecture of Yunnan province. Participants will receive highly active antiretroviral therapy (HAART) immediately after a baseline survey and will receive 3 consecutive follow-up surveys during a three-year follow-up observation period. Through the aforementioned periodic surveys including epidemiological questionnaire interviews, HBV and HCV testing, testing for blood MT biomarkers including lipopolysaccharides (LPS), LPS binding proteins such as LBP and MT-related inflammatory cytokines such as connective tissue growth factor (CTGF), we expect to determine dynamic changes of liver fibrosis progression, MT and related inflammatory responses before and after HAART, and to explore relationship between MT and liver fibrosis progression and its inflammatory mechanisms among HIV-infected patients under HAART.

肝纤维化及其并发症已成为当前艾滋病病毒（HIV）感染者主要的疾病负担和死因。流行病学监测和临床观察性研究显示HIV感染者肝纤维化率和病情显著重于普通人群，但其病理机制尚未明确。近年研究提示HIV感染诱导和促使肠道微生物移位（MT），通过刺激炎性反应而促进多种慢性并发症发生发展。本项目拟采用前瞻性队列研究设计，以云南省德宏州650例新报告且合并肝纤维化的HIV感染者组成研究队列，入组基线调查后接受高效抗逆转录病毒治疗（HAART）和包括3次随访调查的持续3年的队列研究。通过定期调查和检测HBV和HCV感染状态、血液脂多糖（LPS）及其结合蛋白LBP等4种MT标志物及结缔组织生长因子（CTGF）等10种炎性细胞因子水平，掌握HIV感染者HAART下肝纤维化发展转归、MT及相关炎性反应的动态变化规律，探讨HAART下HIV感染者微生物移位与肝纤维化之间的关联及其炎性机制。

项目建立了由665例新报告发现的HIV感染者组成的研究队列，分别于入组时基线、启动抗病毒治疗后第12、24、36月时进行了流行病学调查和血液生化、免疫缺陷和HIV病毒载量检测、肝纤维化评估（FIB-4），并检测分析了血液肠道微生物移位标志物和有关炎性因子和代谢物等。研究显示：研究对象HBV、HCV合并感染率分别为6.62%与18.8%，重度（FIB-4 >3.25）、中度（1.45≤FIB-4≤3.25）肝纤维化患病率分别为9.2%和29.0%。抗病毒治疗总体改善感染者的肝纤维化程度、肠道微生物移位和炎性因子水平；研究对象全因死亡率在肝纤维化始终呈轻度、重度-轻度、轻度-重度、始终呈重度组分别为1.47、2.17、8.93、9.92/100人年。多因素logistic回归分析显示，血浆高水平细胞因子IL-1β、IL-6、IL-7、IL-12、IL-17、GM-CSF、IFN-γ、IL-4、IL-10、MCP-1、Eotaxin和FGF-Basic与重度肝纤维化有显著正相关；其中，FGF-Basic（OR=1.82，95%CI: 1.26-2.66；p=0.002）经Bonferroni多种比较校正仍具有显著性意义。无论是基线还是随访调查时，血浆肠道微生物移位标志物sCD14、LBP高水平均与重度肝纤维化有显著正相关，提示HIV感染者肠道微生物移位是其肝纤维化发生发展的重要因素之一。代谢组学分析显示，谷氨酸-谷氨酰胺代谢通路改变是HIV感染者合并HCV感染的重要标志，而苯丙氨酸-酪氨酸-天门冬氨酸生物合成通路是HIV/HCV合并感染者肝纤维化进展的关键机制，具有很好的预测价值。研究结果为预防控制HIV感染者肝纤维化发生发展、降低HIV感染者终末期肝病和病死率提供了重要干预靶点。