ACTG A5146: THERAPEUTIC DRUG MONITORING ON VIRAL LOAD, PI-EXPERIENCED HIV-1 PTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。A5146是一种开放标签、随机、多中心试验。A5146的目标是确定修改剂量的蛋白酶抑制剂(PI)是否改善了PI经验受试者的病毒学反应。在体外，耐PI的HIV需要比PI敏感的HIV更高的PI水平才能被抑制。A5146将使用治疗药物监测(TDM)来优化PI药物浓度。最佳药物水平将通过确定在步骤1研究进入时开始的受试者挽救方案中每个PI的归一化抑制商(NIQ)来计算。NIQ考虑了受试者通过血浆PI药物水平与受试者病毒对该药物的抗药性程度的关系(见下文计算)。目标是使受试者的血浆PI谷值高于抑制受试者S病毒所需的药物水平。NIQ为1意味着受试者的智商高于对相同PI反应良好的受试者的智商。NIQ=1意味着受试者智商低于对相同PI反应良好的受试者的智商。低药物水平或高水平的病毒耐药性都会导致NIQ低(=1)。在本研究中，所有PI的目标NIQ为1.0。筛查：病毒学上至少有一种含有PI的抗逆转录病毒联合方案失败的有治疗经验的受试者，在继续使用失败的方案时，将使用虚拟表型进行筛查耐药性测试。A5146分为三个步骤如下：步骤1：步骤1：确定哪些受试者具有NIQS=1或1。在进入步骤1时，受试者将基于筛查时执行的虚拟表型启动新的抢救方案。入选两周后，所有受试者将在新的抢救方案中获得定时的血浆样本，以检测PI谷值。这一低谷水平将与筛选虚拟表型的IC50的倍数变化一起用于计算NIQ。所有受试者将在第四周前收到NIQ结果，以确定他们是否有资格在第二步进入随机分组或ARM分配。第二步：在第二步进入时，总共180名NIQ=1的受试者将被随机分为标准护理(SOC)组(ARM A)或TDM+SOC组(ARM B)。此外，50名NIQ&GT；1的受试者将在观察组(C组)中接受跟踪。注：ARM C在达到目标应计项目后于07/28/04年度结束。有2周NIQ和GT；1的受试者将被永久停止研究。NIQS=1的受试者将根据预先指定的剂量调整算法获得PI剂量递增。PI剂量算法由A5146研究团队药理学家得出，并定期更新，以包括额外的三PI组合方案、FDA新批准的PI药物以及基于新的可用安全信息修订的剂量建议。研究小组将使用这些剂量调整算法来确定是否应该在NIQ=1的有资格接受TDM的受试者中增加PI剂量。PI剂量调整建议将以电子报告的形式发送到现场。在步骤2中的受试者在第24周或以后没有病毒学失败，将在步骤2中继续在他们原来分配的治疗臂上进行跟踪，直到第48周。病毒学在24周或以后失败的受试者可以选择进入步骤3。步骤3：步骤3是向在步骤2中初始方案失败的受试者提供TDM的选项，与他们最初的治疗臂随机化或分配无关。在步骤2中的任何一组中，在第24周或之后血浆HIV-1 RNA浓度确认为=1000拷贝/毫升的受试者将有资格进入步骤3并接受第二次虚拟表型耐药性测试。抗性试验的结果将被用来设计第三步抢救方案。第三步打捞方案将获得重复的PI药物水平(S)，并将为所有受试者提供第三步打捞方案中任何PI的NIQ值。所有NIQ=1的受试者将被给予接受剂量调整PI治疗的选项，使用与步骤2，TDM+SOC ARM中的受试者相同的剂量调整算法。步骤3中的PI剂量调整不能晚于参与研究的第44周。登记到第三步后，受试者将在第三步中被跟踪最多24周，但不超过研究进入后48周(第0周，第一步)。请参阅此架构末尾的图表。在第二步进入A或B组或被分配到C组的受试者，在第一步进入后将被跟踪48周。在第4周，NIQ=1的受试者将被随机分配到A或B组，NIQ&GT；1的受试者将被分配到C组。ARM A：SoC ARM B：TDM+SOC ARM C：在第二步进入到第24周后，C组(观察组)的观察性受试者将得到与随机进入A组(SOC)的受试者完全相同的治疗方式，唯一的区别是他们第2周的NIQ结果(ARM A：NiQ=1；ARM C：NiQ&GT；1)。注：ARM C在达到目标应计项目后于07/28/04年度结束。抗逆转录病毒治疗方案将由受试者的临床医生根据虚拟表型耐药性测试结果进行选择和处方。A5146不会提供任何抗逆转录病毒药物。

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. A5146 is an open-label, randomized, multicenter trial. The goal of A5146 is to determine whether dose modification of protease inhibitors (PIs) improves virologic response in PI-experienced subjects. PI-resistant HIV needs higher PI levels to be suppressed than PI-sensitive HIV in vitro. A5146 will use therapeutic drug monitoring (TDM) to optimize PI drug concentrations. Optimal drug levels will be calculated by determining the normalized inhibitory quotient (NIQ) for each PI in the subjects salvage regimen that is initiated at Step 1 study entry. An NIQ takes into account the subjects trough plasma PI drug level in relation to the degree of resistance of the subjects virus to that drug (see calculation below). The goal is to have the subjects plasma PI trough level be higher than the drug level required to inhibit the subject¿s virus. An NIQ of > 1 means that the subjects IQ is more than the IQ of subjects who had a good response to the same PI. An NIQ = 1 means that the subjects IQ is lower than the IQ of subjects who had a good response to the same PI. Either a low drug level or a high level of viral resistance can cause an NIQ to be low (= 1). The target NIQ in this study is 1.0 for all PIs. Screening: Treatment-experienced subjects who have virologically failed at least one PI-containing antiretroviral combination regimen will have a screening resistance test performed using a virtual phenotype while they remain on their failing regimen. A5146 is divided into three steps as follows: Step 1: Step 1 is to determine which subjects have NIQs = 1 or > 1. At entry to Step 1, subjects will initiate a new salvage regimen based on the virtual phenotype performed at screening. Two weeks after entry, all subjects will have a timed plasma sample obtained for PI trough levels on the new salvage regimen. This trough level will be used with the fold-change in IC50 from the screening virtual phenotype to calculate an NIQ. All subjects will receive NIQ results before week 4 in order to determine their eligibility for randomization or arm assignment at Step 2 entry. Step 2: At Step 2 entry, a total of 180 subjects with NIQs = 1 will be randomized to standard of care (SOC) (Arm A) or to TDM+SOC (Arm B). In addition, 50 subjects with NIQs > 1 will be followed in an Observational Arm (Arm C). NOTE: Arm C closed on 07/28/04 after reaching target accrual. Subjects with a week 2 NIQ > 1 will be permanently discontinued from the study. Subjects with NIQs = 1 will receive PI dose escalations according to pre-specified dose adjustment algorithms. The PI dosing algorithms were derived by the A5146 study team pharmacologists and are updated periodically to include additional triple-PI combination regimens, newly FDA-approved PI agents, and revised dosing recommendations based on new available safety information. These dose adjustment algorithms will be used by the study team to determine whether a PI dose should be escalated for an NIQ = 1 in a subject who is eligible to receive TDM. The PI dose adjustment recommendation will be transmitted in an electronic report to the site. Subjects in Step 2 without virologic failure at week 24 or later will continue to be followed in Step 2 on their original assigned treatment arms through week 48. Subjects with virologic failure at week 24 or later may choose to enter Step 3. Step 3: Step 3 is to provide the option of TDM to subjects who failed their initial regimen on Step 2, independent of their original treatment arm randomization or assignment. Subjects in any of the Step 2 arms who have a confirmed plasma HIV-1 RNA concentration of = 1000 copies/mL at or after week 24 will be eligible to enter Step 3 and receive a second virtual phenotype drug resistance test. The results of the resistance test will be used to design a Step 3 salvage regimen. Repeat PI drug level(s) will be obtained on this Step 3 salvage regimen, and NIQ values for any PIs in the Step 3 salvage regimen will be provided for all subjects. All subjects with NIQs = 1 will be given the option to receive dose-adjusted PI therapy, using the same dose adjustment algorithms that were used for subjects in the Step 2, TDM+SOC arm. PI dose adjustments in Step 3 cannot occur any later than week 44 of study participation. After registering to Step 3, subjects will be followed for a maximum of 24 weeks on Step 3 but not more than 48 weeks after study entry (week 0, Step 1). See diagram at the end of this schema. Subjects randomized at Step 2 entry to Arm A or B, or assigned to Arm C, will be followed for 48 weeks after Step 1 entry. At week 4, subjects with NIQ = 1 will be randomized to Arms A or B, and subjects with NIQ >1 will be assigned to Arm C. Arm A: SOC Arm B: TDM+SOC Arm C: Observational Subjects in Arm C (Observational) will be treated in exactly the same manner as subjects randomized to Arm A (SOC) after Step 2 entry through week 24, the only difference being their week 2 NIQ result (Arm A: NIQ = 1; Arm C: NIQ >1). NOTE: Arm C closed on 07/28/04 after reaching target accrual. Antiretroviral regimens will be selected and prescribed by the subject's clinician based on the results of virtual phenotypic resistance testing. A5146 will not provide any antiretroviral drugs.