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.
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