ACTG A5095: 3 PROTEASE INHIBITOR-SPARING REGIMENS FOR INITIAL TREATMENT OF HIV

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这是一项随机、双盲比较三种蛋白酶抑制剂（PI）保留方案用于HIV感染的初始治疗，目标是抑制和维持HIV-1水平<200拷贝/ml。还将确定3种初始PI保留方案的安全性和耐受性。进行本研究的依据是，目前的治疗指南推荐2种核苷类似物与PI或非核苷逆转录酶抑制剂（NNRTI）的联合方案作为HIV感染初始治疗的首选疗法。然而，目前方案的疗效受到其复杂性、药代动力学特征、短期和长期副作用以及病毒学失败时的耐药性特征的限制。因此，需要确定新的初始治疗方案，这些方案更简单，耐受性更好，在病毒学失败的情况下保留治疗选择，并提高抗逆转录病毒效力。此外，最近对PI的长期毒性和现有PI之间广泛的交叉耐药性的担忧导致了对“PI保留”方案的测试。方法包括以下步骤：第1步：随机选择患者接受3种盲法治疗方案之一：阿巴卡韦（ABC）/拉米夫定（3 TC）/齐多夫定（ZDV）/依法韦仑（EFV）、ABC/3 TC/ZDV或3 TC/ZDV/EFV。第1步确认病毒学失败且确认血浆HIV RNA水平≥ 10，000拷贝/ml的患者必须登记至第2步。第1步确认病毒学失败且血浆HIV RNA <10，000拷贝/ml的患者可继续参加第1步或登记参加第2步。第二步：第二步是开放标签。方案包括2种核苷逆转录酶抑制剂（NRTI）与EFV或BMS-232632联合给药。根据基因型耐药结果，NRTI复方制剂可能是3 TC/ZDV或以下两种药物的固定剂量复方制剂：ZDV、去羟肌苷（ddI）、3 TC、司他夫定（d4 T）和ABC;但是，不允许ZDV/d4 T复方制剂。临床评估和实验室评价在入组时、第2、4、6、8、12、16、20、24周进行，然后在研究期间每8周一次。当进行方案允许的药物替代时，也需要进行评价。此外，正在进行2个子研究：依法韦仑的神经病学子研究和BMS-232632的药理学子研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a randomized, double-blind comparison of three protease inhibitor (PI)-sparing regimens for the initial treatment of HIV infection with the goal being to suppress and maintain HIV-1 levels <200 copies/ml. The safety and tolerability of the 3 initial PI-sparing regimens will also be determined. The rationale for conducting this study is that current treatment guidelines recommend combination regimens of 2 nucleoside analogues with either a PI or a nonnucleoside reverse transcriptase inhibitor (NNRTI) as the preferred therapy for the initial treatment of HIV infection. However, the efficacy of current regimens is limited by their complexity, pharmacokinetic characteristics, short- and long-term side effects, and drug-resistance profiles at the time of virologic failure. Consequently, the identification of new initial regimens that are simpler, better tolerated, preserve treatment options in the event of virologic failure, and improve on antiretroviral potency is needed. In addition, recent concern over the long-term toxicities of PIs and the extensive cross-resistance among the available PIs have led to the testing of "PI-sparing" regimens. The methodology consists of the following: Step 1: Patients are randomly selected to receive 1 of 3 blinded treatment regimens: abacavir (ABC)/lamivudine (3TC)/zidovudine (ZDV)/efavirenz (EFV), ABC/3TC/ZDV, or 3TC/ZDV/EFV. Patients with confirmed virologic failure on Step 1 and confirmed plasma HIV RNA levels of 10,000 copies/ml or greater must register to Step 2. Patients with confirmed virologic failure on Step 1 and plasma HIV RNA < 10,000 copies/ml may remain on Step 1 or register to Step 2. Step 2: Step 2 is open label. Regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either EFV or BMS-232632. Based on genotypic resistance results, the NRTI combination may be a fixed-dose combination of 3TC/ZDV or 2 of the following: ZDV, didanosine (ddI), 3TC, stavudine (d4T), and ABC; however, the ZDV/d4T combination is not permitted. Clinical assessments and laboratory evaluations are done at entry, at Weeks 2, 4, 6, 8, 12, 16, 20, 24, and then every 8 weeks thereafter for the duration of the study. Evaluations are also required when a protocol-allowed drug substitution is made. In addition, 2 substudies are being conducted: a neurology substudy for efavirenz and a pharmacology substudy for BMS-232632.