TDM ON VIRAL LOAD RESPONSE TO PROTEASE INHIBITOR CONTAINING SALVAGE THERAPY

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。设计：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）的剂量调整是否可改善经历PI的受试者的病毒学应答。在体外，PI耐药HIV比PI敏感HIV需要更高的PI水平才能被抑制。A5146将使用治疗药物监测（TDM）优化PI药物浓度。通过确定受试者中每个PI的归一化抑制商（NIQ）计算最佳药物水平？在第1步研究入组时开始的挽救治疗方案。 NIQ是否考虑了主题？血浆PI药物谷浓度与受试者耐药程度的关系？病毒对药物的影响（见下面的计算）。目标是让受试者？患者的血浆PI谷水平是否高于抑制受试者所需的药物水平？S病毒。NIQ为1意味着受试者？的智商比对同一PI有良好反应的被试的智商高。NIQ？1是指主体？的智商低于对同一PI有良好反应的受试者的智商。低水平的药物或高水平的病毒耐药性都可能导致NIQ低（？1）。本研究中所有PI的目标NIQ均为1.0。 持续时间：在第2步入组A组或B组或分配至C组的受试者将在第1步入组后接受48周随访。 样本量：样本量目标是230例受试者进入步骤2（TDM+SOC组各90例受试者，观察组50例受试者）。为了实现这一目标，将需要约360例受试者入组研究。基于奥那扎韦方案的受试者入组限于36例，占进入研究第1步的受试者估计数量的10%。 人口：男性和女性18岁。至少一种含PI的联合抗逆转录病毒方案（即，失败的疗程数目没有上限。

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.