DEVELOPMENT OF RESISTANCE OF HIV IN PATIENTS RECEIVING AZT, DDC, OR DDI

接受 AZT、DDC 或 DDI 的患者出现 HIV 耐药性

• 批准号: 3853268
• 负责人: H MITSUYA
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3853268
• 关键词: 2'3' dideoxynucleoside; AIDS; HIV infections; antiAIDS agent; dosage; drug resistance; human immunodeficiency virus 1; human tissue; inosine; monocyte; tissue /cell culture

We asked whether patients with AIDS or ARC receiving long-term therapy with AZT, ddC, or ddI developed resistance to these drugs, and if so, to explore its biochemical basis. Primary HIV strains were obtained from peripheral blood mononuclear cells (PBM) from adult patients with AIDS or ARC who received an alternating regimen of AZT and ddC (AZT/ddC) for 15-41 months or who received ddI for 12-16 months. Isolates were obtained before and during antiviral therapy. All virions were isolated by coculturing patient's PBM and phytohemagglutinin (PHA)- stimulated PBM from healthy volunteers. The sensitivity of primary HIV-1 isolates to AZT, ddC or DDI was assessed by drug concentrations (uM) that brought about 50% p24 Gag negative wells (CN50) when HIV p24 Gag protein production by PHA-PBM exposed to a fixed dose of each viral isolate was determined in 10-12 days culture 4-8 replicates. We found that AZT therapy can induce AZT-resistant HIV variants as early as 2 months; and once acquired, AZT resistance may remain after switching to ddI therapy for 1 year in some patients. HIV appears to develop resistance to ddC and ddI less easily than to AZT, while these data do not provide basis for concluding that AZT/ddC or ddI are inferior, equivalent, or superior to AZT as therapy of AIDS. In addition, more research is needed to make clinical correlations between in vitro drug sensitivities of HIV and clinical outcome in HIV infection.

我们询问艾滋病患者或ARC患者是否接受长期治疗 使用AZT、ddC或ddi对这些药物产生抗药性，如果是这样的话， 探索其生化基础。主要的艾滋病毒毒株是从 成人艾滋病患者外周血单个核细胞的检测 或ARC，接受AZT和ddC(AZT/ddC)交替方案治疗 15-41个月或接受DDI 12-16个月。分离的菌株是 在抗病毒治疗之前和期间获得。所有的病毒粒子都被分离出来了 通过共培养患者的PBM和植物血凝素(PHA)刺激 来自健康志愿者的PBM。HIV-1主要分离株的敏感性研究 对AZT、ddC或DDI的药物浓度(Um)进行评估 当HIV p24 Gag蛋白时，约50%的p24 Gag阴性孔(CN50) PHA-PBM在每个病毒分离物的固定剂量下产生 测定在10-12天内培养4-8个重复。 我们发现，AZT疗法可以很早就诱导出对AZT具有耐药性的HIV变异株 2个月；一旦获得，AZT的耐药性可能会在 部分患者改用DDI治疗1年。艾滋病病毒似乎 与AZT相比，对ddC和ddi不太容易产生耐药性，而这些 数据不能作为得出AZT/ddC或DDI是 在治疗艾滋病方面不如、相当或优于AZT。在……里面 此外，还需要更多的研究来使两者之间的临床相关性 HIV的体外药物敏感性与临床转归 感染。