PH I & II MULTICENTER COMPARE FOUR ANTIRETROVIRAL REGIMENS ACTG 377

迄今为止，很少有研究涉及抗逆转录病毒药物组合在经历过抗逆转录病毒治疗且病情稳定的艾滋病毒感染儿童中的疗效。 目前，儿童持续稳定治疗的疗效持续时间尚未确定。 此外，改变儿童抗逆转录病毒疗法时机的指征也不明确。 因此，重要的是要确定新的抗逆转录病毒药物治疗组合的持久性和疗效的儿童。本试验的目的是比较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 log或更多的疗效，以及在临床稳定和经历过抗逆转录病毒治疗的儿童中将病毒抑制维持在“不可检测”水平的能力。 这项多中心试验涉及240名年龄在4个月至17岁之间的临床稳定的HIV感染儿童，将测试的4种组合包括：A组：d4 T，奈韦拉平，利托那韦B组：d4 T，3 TC，奈非那韦C组：d4 T，奈韦拉平，奈非那韦D组：d4 T、3 TC、奈韦拉平、奈非那韦HIV感染后免疫功能最早的缺陷之一是细胞介导的对回忆抗原的应答丧失，即使CD 4的消耗并不明显。 此外，随着Walter Reed分期的进展，对HIV抗原的淋巴增殖反应似乎逐渐丧失。 直到最近，通过测量CD 4 T细胞数量或百分比的增量或减量变化来评估对治疗干预的成功反应。 目前尚不清楚CD 4 T细胞的任何增加是否会导致功能改善，特别是因为尚不清楚恢复的细胞是免疫学幼稚的还是有经验的。 最近的一项研究指出，ZDV治疗后辅助性T细胞功能的一些重建，与CD 4 T细胞数量的改善无关。 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功效的有效标准。 HIV感染儿童淋巴细胞亚群的研究表明，CD 4（辅助）和CD 8（细胞毒性抑制）T细胞的幼稚CD 45 RA亚群被耗尽，而CD 45 RO（记忆）T细胞相对保留。 这一观察结果可能与对新抗原刺激的反应能力降低有关。 在接受利托那韦治疗的成人中，Kelleher注意到幼稚和记忆CD 4细胞显著增加，并改善了淋巴细胞对有丝分裂原、回忆抗原和HIV特异性蛋白的增殖反应。 此外，几项初步研究表明，在HIV感染的成人淋巴细胞上，活化标志物如CD 38和DR的表达发生显著变化，CD 28的表达改变，L选择素CD 621的上调。 这些标志物在体外的表达可以作为HAART方案治疗受试者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。 关于NRTI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，在本方案所含的高活性方案中对这些表面标志物和体外LPR进行的研究将增加有关方案的实质性信息，该方案旨在通过在逆转录酶抑制剂中加入蛋白酶抑制剂将病毒载量快速降低至不可检测水平。

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.