PH I & II MULTICENTER COMPARE FOUR ANTIRETROVIRAL REGIMENS ACTG 377

到目前为止，很少有研究涉及抗逆转录病毒药物组合对有抗逆转录病毒经验和稳定的艾滋病毒感染儿童的疗效。目前，儿童持续稳定治疗的有效时间尚不确定。此外，儿童抗逆转录病毒治疗的改变时机的适应症尚不清楚。因此，为儿童确定新的抗逆转录病毒药物治疗组合的持久性和有效性是重要的。这项试验的目标是比较4种不同的抗逆转录病毒药物组合在12周时将病毒复制减少2.2个对数或更多的效果，以及联合使用在临床稳定和有抗逆转录病毒经验的儿童中将病毒抑制保持到“无法检测”的水平的能力。在这项涉及240名4个月至17岁的临床稳定的艾滋病毒感染儿童的多中心试验中，将测试的4种组合包括：A组：D4T，奈韦拉平，利托那韦B组：D4T，3TC，奈非那韦C组：D4T，奈韦拉平，奈非那韦D组：D4T，3TC，奈韦拉平，奈非那韦。艾滋病毒感染后免疫功能最早的缺陷之一是失去细胞介导的回收抗原的反应，即使在CD4磨损不明显的情况下也是如此。此外，随着沃尔特里德分期的推进，对HIV抗原的淋巴增殖反应似乎逐渐丧失。直到最近，对治疗干预的成功反应都是通过测量CD4T细胞数量或百分比的增减变化来评估的。目前还不清楚CD4T细胞的任何增加是否会导致功能的改善，特别是因为还不清楚恢复中的细胞是免疫幼稚的还是有经验的。最近的一项研究注意到ZDV治疗后辅助T细胞功能的一些重建，与改善的CD4T细胞数量无关。由于抗逆转录病毒治疗的最终目标是使免疫功能正常化，因此T细胞功能的测量将是确定治疗效果的有效标准。对HIV感染儿童淋巴细胞亚群的研究表明，CD4(辅助)和CD8(细胞毒性抑制)T细胞的幼稚CD45RA亚群被耗尽，而相对保留了CD45RO(记忆)T细胞。这种观察可能与对新的抗原刺激的反应能力降低有关。Kelleher指出，在接受利托那韦治疗的成年人中，幼稚和记忆的CD4细胞显著增加，并改善了淋巴细胞对有丝分裂原、召回抗原和艾滋病毒特异性蛋白的增殖反应。此外，一些初步研究表明，HIV感染者淋巴细胞上CD38和DR等活化标志的表达发生了显着变化，CD28的表达发生了变化，L的选择素CD621的表达也发生了上调。这些标记物的体外表达可作为HAART方案治疗对象的疾病进展和免疫重建的替代指标。这些疗法对T细胞数量和功能的影响尚未在大量儿童中进行研究。有关NRTIs和蛋白酶抑制剂联合治疗效果的初步数据应来自PRAM-1(ACTG 338)。然而，对这些表面标志物和该方案中包含的高活性方案的体外LPR的研究将为通过在逆转录酶抑制剂中添加蛋白酶抑制剂来迅速将病毒载量降低到无法检测的水平而设计的方案提供大量信息。

To date, there have been few studies involving the efficacy of combinations of antiretrovirals in HIV-infected children who are antiretroviral experienced and stable. And currently, the duration of efficacy of continuing stable therapy in children is undefined. In addition, the indications for timing of changes of antiretroviral therapy in children are not clear. It is therefore important for the durability and efficacy of new therapeutic combinations of antiretrovirals be identified for children. The goal of this trial is to compare the efficacy of 4 different combinations of antiretroviral agents to reduce viral replication by 2.2 logs or more at 12 weeks and the ability of the combination to maintain viral suppression to "undetectable" levels in children who are clinically stable and antiretroviral experienced. The 4 combinations to be tested in this multi- center trial involving 240 clinically stable, HIV-infected children between the ages of 4 months and 17 years include: Arm A: d4T, nevirapine, ritonavir Arm B: d4T, 3TC, nefinavir Arm C: d4T, nevirapine, nelfinavir Arm D: d4T, 3TC, nevirapine, nelfinavir One of the earliest defects in immune function after HIV infection is a loss of cell-mediated responses to recall antigens, even when CD4 attrition is not evident. In addition, there appears to be a progressive loss of lymphoproliferative responses to HIV antigens with advancing Walter Reed stages. Until recently, successful responses to therapeutic interventions have been assessed by measuring incremental or decremental changes in CD4 T cell numbers or percentages. It was never clear whether any increase in CD4 T cells resulted in improved function, particularly since it is unknown if the recovering cells are immunologically naive or experienced. A recent study noted some reconstitution of helper T cell function after ZDV therapy, without correlation to improved CD4 T cell numbers. Since the ultimate goal of Antiretroviral therapy is to normalize immune function, a measurement of T cell function would be a valid criteria for determining treatment efficacy. Studies of lymphocyte subsets in HIV infected children suggest that naive CD45RA subsets of both CD4 (Helper) and CD8 (cytotoxic suppressor) T cells are depleted with relative preservation of CD45RO (Memory) T cells. This observation may be related to decreased ability to respond to new antigenic stimuli. In adults treated with ritonavir, Kelleher noted significant increases in naive and memory CD4 cells, and improved lymphocyte proliferation responses to mitogen, recall antigens and HIV-specific proteins. In addition several preliminary studies have suggested significant changes in expression of activation markers such as CD38 and DR as well as altered expression of CD28 and up regulation of L selectin CD621 on the lymphocytes of HIV infected adults. Expression of these markers in vitro may act as surrogate indicators of disease progression and immune reconstitution in subjects treated with HAART regimens. The effects of these therapies on T cell numbers and function have not been studied in large numbers of children. Preliminary data on the effects of combination therapy with NRTIs and Protease inhibitors should be forthcoming from PRAM-1 (ACTG 338). However, study of these surface markers and in vitro LPR in the highly active regimens contained in this protocol will add substantial information on regimens designed to rapidly reduce viral loads to undetectable levels by addition of protease inhibitors to the reverse transcriptase inhibitors.