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

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。艾滋病毒感染儿童和成人的最新管理状况决定了使用联合疗法，通常由两种核苷逆转录酶抑制剂（NRTIs）和一种蛋白酶抑制剂（PI）组成。然而，现有的儿童治疗方案是有限的。在适合幼儿的配方中，很少有可获得的pi。此外，由于不完全的病毒学抑制，许多儿童在目前的含pi方案中开始经历病毒学失败，这总是导致耐药性和病毒学反弹。对复杂治疗方案的不良依从性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。根据艾滋病毒临床实践中的家长报告，超过30%的家庭认为自己对孩子的药物治疗方案的依从性很差，超过50%对联合治疗反应不佳的儿童不依从。开发有效且给药方案不那么复杂的强效联合疗法对于改善感染艾滋病毒儿童的治疗结果至关重要。在美国，只有五种食品和药物管理局（FDA）批准使用的pi；沙奎那韦，利托那韦，茚地那韦，奈非那韦和安替那韦。它们在结构上都是相似的（拟肽物），并且它们之间产生不同程度的交叉抗性。迫切需要对治疗经验丰富的受试者所携带的毒株保持病毒学活性的新pi。BMS-232632是一种体外抑制HIV-1的新型PI。来自成人研究的最新数据表明，基线病毒耐药性模式（基于基因型分析）可能预测对挽救方案的不良反应；他们预测积极回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挽救治疗的结果。新技术的进步使我们能够在合理的周转时间内获得基因型和表型抗性数据。

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.