TDM ON VIRAL LOAD RESPONSE TO PROTEASE INHIBITOR CONTAINING SALVAGE THERAPY

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。设计：A5146是一项开放标签、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)是否改善了有PI经验的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受试者-S抢救方案中每个PI的归一化抑制商(NIQ)来计算，该方案在第一步研究进入时开始。ANNIQ考虑受试者？S谷血浆PI药物水平与受试者耐药程度的关系？病毒对该药物的影响(见下面的计算)。我们的目标是让受试者？S的血浆皮谷水平高于抑制受试者S病毒所需的药物水平。NIQ为1意味着被试S的智商高于对同一PI反应良好的被试的智商。NIQ？1是指被试S的智商低于对同一PI反应良好的被试的智商。无论是药物水平低还是病毒抗药性水平高，都会导致NIQ低(？1)。在本研究中，所有PI的目标NIQ为1.0。持续时间：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。样本量：样本量目标是让230名受试者进入第二步(TDM+SOC组各90名受试者，观察组50名受试者)。为了实现这一目标，将需要大约360名受试者进入这项研究。基于奥那那韦方案的受试者登记人数限制为36人，占进入研究第一步的估计受试者数量的10%。人口：男、女18岁。病毒学上至少有一种含PI的联合抗逆转录病毒方案失败的HIV-1感染者(即，对失败方案的数量没有上限。

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. Design: 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 subject?s salvage regimen that is initiated at Step 1 study entry. An NIQ takes into account the subject?s 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 subject?s plasma PI trough level be higher than the drug level required to inhibit the subject?s virus. An NIQ of 1 means that the subject?s IQ is more than the IQ of subjects who had a good response to the same PI. An NIQ ?1 means that the subject?s 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. Duration: 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. Sample Size: The sample size goal is to have 230 subjects enter Step 2 (90 subjects each in the TDM+SOC arms, and 50 in the Observational Arm). In order to achieve this goal, approximately 360 subjects will be required to enter the study. Enrollment of subjects onatazanavir-based regimens is limited to 36, representing 10% of the estimated number of subjects entering Step 1of the study. Population: Men and women18 year of age. HIV-1 infected subjects who have viirologically failed at least one PI-containing combination antiretroviral regimen (i.e., there is no upper limit on the number of failed regimen.