ANTIRETROVIRAL DRUG RESISTANCE--CLINICAL AND IMMUNE EFFECTS

AZT是目前唯一被批准用于HIV主要治疗的药物 相关疾病。 最近有报道称， 患者服药时间超过6个月。 但临床 的重要性，机制和相关因素的出现， 耐药的艾滋病毒株仍然未知。 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，我们建议确定的频率和模式， 艾滋病患者中出现抗AZT的艾滋病毒， AZT治疗，并评估对其他抗病毒化合物的耐药性。 到 为了实现这一目标，将对100-120名患者进行检查，以确定 与同时给予的抗病毒药物联合治疗，或 从而影响艾滋病毒耐药株的出现， 确定哪些组合最大限度地抑制发展 阻力 将通过与正常PBL共培养从患者中分离HIV， 对AZT和/或其他化合物的敏感性将在 开始治疗，此后每隔6个月一次。 的 耐药性的发展与病毒负荷的关系 患者（血清P24 Ag）和外周血中免疫应答的标志物 血液（CD 4：CD 8，血清β 2-微球蛋白，淋巴细胞转化， 针对特异性和非特异性抗原的干扰素-γ产生）将 也被评价。 HIV药物开发的临床意义 将通过监测和评估以下方面的变化来进行抵抗 神经行为测试，机会主义发展的频率 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， 协助设计现有治疗药物的管理变更 药物，并帮助确定新的治疗方案，以尽量减少 出现了这样的耐药菌株。 这些信息的发展 可能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.