HIV-1基因型耐药特征及其衍生动态研究

Acquired immunodeficiency syndromes (AIDS) is mainly caused by human immunodeficiency virus type 1 (HIV-1), which widely spread across the whole China and severely threatened the public health. Antiretroviral therapy (ART) has been successfully developed and well employed in the therapy of HIV/AIDS patients, which dramatically improves the life quality and reduces the mortality of this infectious disease. Unfortunately, the occurrence and subsequent transmission of drug resistant strains by failing ART became a major barrier to the continued and expanding administration of ART in HIV/AIDS population. Therefore, it's important and necessary to understand the genetic dynamic process of occurence and transmission of drug resistance, and explore its respective influencing factors for the widely efficient application of ART therapy..A prospective cohort including 150 to 200 individuals from the onset of ART, and another ART-failure cohort of 80 to 100 individuals are expected to be established simultaneously. The follow-up and maintenance on these two cohorts will be continuous during the next four years. Single genome amplification and sequencing technique (SGA-PCR) is used to detect the quasispecies and genetic diversity of HIV-1 pol gene. Bayes evolutionary theory is employed to explore the existence of minority drug resistant strains, and its dynamic evolution and significance. Based on the two-level analysis of the longitudinal ART therapic process and ART failure individual, combining with inquiry investigation, we expect to illustrate the genetic dynamic process of occurrence and transmission of drug resistance, and reveal its potential influencing factors for the widely efficient application of ART..This project might delineate the characteristics of genotypic drug resistance of HIV-1 and its transmission, explore the dynamic genesis of drug resistance and its influencing factors. We hope the observations and findings in this project would provide preliminary data for HIV/AIDS prevention and control, and optimizing ART regimens, which also facilitates a lot to fulfill the great strategy of lessening the morbidity, reducing the mortality and improving the life quality.

HIV/AIDS是一种广泛流行并严重危害公共卫生安全的传染病。实施抗逆转录病毒治疗（ART），能够有效地提高感染者生命质量、降低病死率；但是，耐药毒株的产生和传播严重制约着ART的实施。了解耐药发生水平和特征，探索耐药发生衍变特征及其影响因素，对有效实施ART治疗具有重要意义。本研究拟通过分别建立150-200例接受ART治疗队列和80-100例ART治疗失败病例队列，进行随访监测；运用单基因组扩增和测序技术及Bayesian进化理论探讨劣势耐药突变毒株进化动态及其与抗病毒治疗失败的关系；从ART治疗耐药发生和治疗失败原因分析两个层面，结合流行病学问卷调查、免疫学和病毒学指标，动态分析耐药毒株发生衍变特征及其影响因素。.本研究将阐明HIV耐药毒株特征和传播，探索基因型耐药发生衍变特征及其影响因素，为艾滋病疫情防控和有效抗逆转录病毒治疗干预，实现"两降一升"的防控策略提供实验室数据支持。

HIV/AIDS是一种广泛流行并严重危害社会公共卫生安全的传染病。实施抗逆转录病毒治疗（ART），能够有效地提高HIV-1感染者生命质量、降低病死率；但是，耐药毒株的产生和传播严重制约着ART的实施。了解耐药发生水平和特征，探索耐药发生衍变特征及其影响因素，对有效实施ART治疗具有重要意义。.自2012年9月-2013年4月，在北京佑安医院性病艾滋病诊疗中心对初始接受抗逆转录病毒治疗（anti-retroviral therapy, ART）病例进行招募、采集静脉抗凝全血进行基线传播性耐药检测，并对病例进行随访检测。共募集324例ART治疗基线病例和200例治疗失败病例符合入组条件，完成相关病例的随访和基因型耐药检测工作，完成入列样本基线耐药检测和随访病例耐药检测。治疗病例队列维持率较高，约90.4%病例在课题基本结束时，仍在北京佑安医院接受ART治疗。但是，仍有失访病例17例，12例因为不同原因停止服药；死亡和转诊到其他医疗机构各1例。.共29个病例在随访中存在一次或多次病毒学失败，发生率为8.95%。.有13例患者具有传播性耐药（SDRM发生率为4.0%）；但是，23.1%（3例）的TDR发展或加重为ADR。部分病例在接受ART治疗早期（0.2-0.5年）就发生药物选择压力下的基因型耐药突变，从而导致治疗失败。.有25例具有基因型耐药突变但是没有被认定为SDRM突变，有4个病例在治疗过程中存在治疗失败（发生率为16.0%）。卡方检验显示，具有SDRM突变和其他基因突变对治疗失败统计学显著差异（χ2=0.285, P>0.05）.有22个病例（7.7%）基线治疗没有HIV-1 pol基因型突变，但在治疗过程中出现一次或多次病毒学治疗失败，对当前一线治疗药物方案存在不同程度的耐受。在强化依从性训练或更换治疗方案后，大部分能够达到病毒学有效抑制。.加强基线基因型耐药检测，具有相关突变能够导致16-23%的耐药发生水平。在一线治疗方案的早期，0.2-0.5年就可能出现病毒学治疗失败伴有基因型耐药发生。因此，在扩大治疗大背景下，加强新入组病例依从性教育，优化治疗方案，按时按量服药，确保抗逆转录病毒抑制率，提高机体免疫力和生命质量，降低病死率。