STUDY OF PROTEASE INHIBITOR BMS 232632 IN HIV INF INFANTS, CHILDREN

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。对感染艾滋病毒的儿童和成人的最新管理要求使用联合疗法，通常包括两种核苷逆转录酶抑制剂(NRTI)和一种蛋白酶抑制剂(PI)。然而，可用于儿童的治疗方案有限。在适合幼儿的配方中，几乎没有可用的PI。此外，由于不完全的病毒学抑制，许多儿童开始在他们目前含有PI的方案中经历病毒学失败，这总是导致耐药性和病毒学反弹。对复杂治疗方案的依从性差是显著影响药物组合选择以及随后的病毒学反应的一个重要因素。根据父母在HIV临床实践中的报告，超过30%的家庭表示自己对孩子的服药计划依从性较差，而对联合治疗反应较差的儿童中超过50%是不依从性的。开发有效、有效但给药程序不那么复杂的联合疗法对于改善感染艾滋病毒的儿童的结局至关重要。在美国，只有五种经食品和药物管理局(FDA)批准使用的原料药：沙奎那韦、利托那韦、依地那韦、奈非那韦和氨丙那韦。它们在结构上都是相似的(模拟多肽)，它们之间的交叉耐药性发展到不同程度。迫切需要新的PI来保持对治疗经验丰富的受试者所藏匿的菌株的病毒学活性。BMS-232632是一种新的PI，具有较强的体外抑制HIV-1活性。来自成人研究的最新数据表明，基线病毒耐药模式(基于基因分析)可能预测对抢救方案的不良反应；它们预测阳性反应的能力是显而易见的。初步数据表明，病毒耐药性的表型分析也可以预测抢救治疗的结果。新的技术进步使得能够在合理的周转时间内获得基因和表型耐药性数据。

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. State of the art management of HIV-infected children and adults dictates the use of combination therapies, generally consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI). However, the available treatment regimens for children are limited. There are few PIs available in formulations appropriate for young children. Moreover, many children are beginning to experience virologic failure on their present PI-containing regimens due to incomplete virologic suppression, which invariably leads to drug resistance and virologic rebound. Poor adherence to complicated treatment regimens is an important factor that significantly impacts the choice of drug combinations, as well as subsequent virologic response. Based on parental reports taken in clinical HIV practice, more than 30% of families describe themselves as poorly compliant with their children's medication schedules, and over 50% of children with a poor response to combination therapy were noncompliant. The development of potent combination therapies with proven efficacy but less complicated dosing schedules is critical to improving the outcome for HIV-infected children. There are only five Food and Drug Administration (FDA)-approved PIs for use in the United States; saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir. They are all similar structurally (peptidomimetics), and cross-resistance among them develops to variable degrees. New PIs that retain virologic activity against strains harbored by treatment-experienced subjects are desperately needed. BMS-232632 is a new PI with potent in vitro inhibition of HIV-1. Recent data from adult studies suggest baseline viral resistance patterns (based on genotypic assays) may predict poor response to salvage regimens; their ability to predict a positive response is clear. Preliminary data suggest that phenotypic analysis of viral resistance may also predict outcome of salvage therapy. New technologic advances have led to the ability to obtain genotypic and phenotypic resistance data with a reasonable turnaround time.