ANTIRETROVIRAL DRUG RESISTANCE--CLINICAL AND IMMUNE EFFECTS

AZT是目前唯一被批准用于艾滋病毒初级治疗的药物 相关疾病。最近报告了对这种药物的抗药性。 接受药物治疗6个月以上的患者。然而，临床上 其产生的意义、机制和影响因素 耐药的艾滋病毒株仍不清楚。这一现象表明， AZT耐药性的发展可能部分解释了随后的临床 恶化。 在这个项目中，我们建议确定频率和模式 艾滋病患者体内出现对AZT具有耐药性的HIV AZT治疗，并评估对其他抗病毒化合物的耐药性。至 达到这一目标，将对100-120名患者进行检查，以确定是否 同时给予抗病毒药物的联合治疗或 从而影响艾滋病毒耐药株的出现，并 确定哪些组合最大限度地抑制了癌症的发展 抵抗。 患者的HIV将通过与正常PBL共培养的方式分离出来，以及 对AZT和/或其他化合物的敏感性将在 开始治疗，此后每隔6个月治疗一次。这个 猪传染性支气管炎病毒负荷与抗药性发展的关系 患者(血清P24Ag)和外周免疫反应标志物 血液(CD4：CD8、血清β2-微球蛋白、淋巴细胞转化和 干扰素-伽马对特定和非特定抗原的产生)将 也要接受评估。艾滋病药物开发的临床意义 将通过监测和评估 神经行为测试，发展机会主义的频率 感染，以及体重和其他临床参数的变化 研究病人。 了解抗药性发展的自然历史应该 协助设计现有治疗药物给药的变化 并帮助确定新的治疗方案以最大限度地减少 出现了这样的抗药性菌株。这些信息的发展 可能会直接影响患者的护理实践和结果。

AZT is the only currently approved agent for the primary therapy of HIV related disease. Resistance to this agent has recently been reported in patients receiving the drug for more than 6 months. However, the clinical significance, the mechanisms and factors relating to the emergence of resistant HIV strains remains unknown. This phenomenon suggests that the development of AZT resistance may, in part, explain subsequent clinical deterioration. In this project we propose to determine the frequency and patterns of emergence of AZT resistant HIV from patients with HIV disease who are on AZT therapy and to evaluate resistance to other antiviral compounds. To accomplish this goal, 100-120 patients will be examined to determine if combination therapy with antivirals administered simultaneously or sequentially affects the emergence of HIV resistant strains, and to determine which combinations maximally inhibit the development of resistance. HIV from patients will be isolated by co-cultivation with normal PBLs, and the sensitivity to AZT and/or other compounds will be evaluated prior to initiation of therapy and at 6 monthly intervals thereafter. The relationship of the development of resistance to the virus burden of the patient (serum P24Ag), and markers of the immune response in peripheral blood (CD4:CD8, serum beta 2-microglobulin, lymphocyte transformation, and interferon-gamma production to specific and non-specific antigens) will also be evaluated. The clinical relevance of the development of HIV drug resistance will be pursued by monitoring and assessing changes in neurobehavioral testing, the frequency of development of opportunistic infections, and changes in weight and other clinical parameters of the study patients. Understanding the natural history of development of resistance should assist in designing changes in the administration of existing therapeutic agents and help identify the novel therapeutic regimens to minimize the emergence of such resistant strains. The development of this information could directly affect patient care practices and outcome.