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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。A5146是一项开放标签、随机、多中心试验。A5146的目的是确定蛋白酶抑制剂（pi）的剂量调整是否能改善pi患者的病毒学反应。在体外实验中，PI抵抗型HIV需要比PI敏感型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第1步研究开始时受试者挽救方案中每个PI的归一化抑制商（NIQ）来计算。NIQ通过血浆PI考虑受试者药物水平与受试者病毒对该药物的耐药程度的关系（见下文计算）。目标是使受试者血浆PI谷水平高于抑制受试者病毒所需的药物水平。NIQ值为bb0.1意味着受试者的智商高于对相同PI有良好反应的受试者的智商。如果NIQ = 1，则该受试者的智商低于对相同PI有良好反应的受试者的智商。低药物水平或高病毒耐药性都可能导致NIQ低（= 1）。本研究中所有pi的目标NIQ为1.0。筛选：有治疗经验的受试者在病毒学上至少有一种含pi的抗逆转录病毒联合治疗方案失败，在他们继续接受失败的治疗方案时，将使用虚拟表型进行筛选抗性试验。A5146分为以下三个步骤：步骤1：步骤1确定哪些受试者的niq = 1或> 1。在进入第1步时，受试者将根据筛选时执行的虚拟表型启动新的挽救方案。入组两周后，所有受试者将在新的挽救方案中获得PI低谷水平的定时血浆样本。该波谷水平将与筛选虚拟表型的IC50的折叠变化一起用于计算NIQ。所有受试者将在第4周之前收到NIQ结果，以确定他们在第2步进入时是否符合随机分组或分组的资格。步骤2：在步骤2进入时，共有180名niq = 1的受试者将被随机分配到标准护理组（SOC） （a组）或TDM+SOC （B组）。此外，在观察组（C组）中，将对50名NIQs为bb101的受试者进行随访。注：在达到目标应计收益后，C臂于2004年7月28日关闭。在第2周NIQ达到bb0.1的受试者将永久停止研究。niq = 1的受试者将根据预先规定的剂量调整算法接受PI剂量递增。PI给药算法由A5146研究小组的药理学家推导，并定期更新，包括额外的三重PI联合方案、fda新批准的PI药物，以及基于新的可用安全性信息修订的给药建议。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时增加有资格接受TDM的受试者的PI剂量。PI剂量调整建议将以电子报告的形式传送到现场。在第2步中，在第24周或之后没有病毒学失败的受试者将继续在第2步中按原指定的治疗组进行随访，直至第48周。在第24周或之后病毒学失败的受试者可以选择进入步骤3。步骤3：步骤3是为在步骤2中初始方案失败的受试者提供TDM的选择，独立于他们最初的治疗组随机分配或分配。在第24周或之后，任何第2步组中确认血浆HIV-1 RNA浓度为= 1000拷贝/mL的受试者将有资格进入第3步并接受第二次虚拟表型耐药试验。抗性试验的结果将用于设计第三步挽救方案。将在第3步挽救方案中获得重复PI药物水平，并为所有受试者提供第3步挽救方案中任何PI的NIQ值。所有niq = 1的受试者将选择接受剂量调整PI治疗，使用与步骤2 TDM+SOC组受试者相同的剂量调整算法。步骤3中的PI剂量调整不能迟于参与研究的第44周。在注册到步骤3后，受试者将在步骤3中进行最多24周的随访，但在研究进入后不超过48周（第0周，步骤1）。请参阅此模式末尾的图表。在第2步进入A组或B组或被分配到C组的受试者将在第1步进入后随访48周。星期4,受试者NIQ = 1将随机武器A或B,和主题NIQ > 1将分配给手臂C臂:SOC臂B: TDM + SOC手臂C:观察受试者手臂C(观测)将以完全相同的方式作为受试者随机手臂(SOC)步骤2条目通过24周后,唯一的区别是他们的第2周NIQ结果(手臂:NIQ = 1;手臂C: NIQ > 1)。注：在达到目标应计收益后，C臂于2004年7月28日关闭。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测试的结果选择和处方。A5146将不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.