TDM ON VIRAL LOAD RESPONSE TO PROTEASE INHIBITOR CONTAINING SALVAGE THERAPY

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。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。通过确定受试者每个PI的归一化抑制商（NIQ）来计算最佳药物水平。在第1步研究进入时启动的挽救方案。NIQ是否考虑到主题？血浆PI波谷与受试者耐药程度的关系？病毒感染该药物（见下面的计算）。我们的目标是有主题？血浆PI谷水平是否高于抑制受试者所需的药物水平？年代的病毒。NIQ为1表示受试者？a的智商高于对同样的PI有良好反应的受试者的智商。NIQ ？1的意思是主语？他的智商低于对同样的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。持续时间：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。样本量：样本量目标是有230名受试者进入步骤2 （TDM+SOC组各90名，观察组50名）。为了实现这一目标，大约需要360名受试者进入研究。基于onatazanvir方案的受试者入组限制为36人，占进入研究第1步的受试者估计数量的10%。人口：18岁男女。HIV-1感染的受试者病毒学上至少有一种含pi的联合抗逆转录病毒治疗方案失败（即，失败方案的次数没有上限）。

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.