PHARMACOKINETICS AND ANTIVIRAL EFFECT OF T 20 ADMINISTERED TO HIV 1 ADULTS

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Teh observation that resistance has been reported for all of the currently approved antiretroviral HIV agents together with unique toxicities that limit their clinical effectivenss establishes a need for development of new, safe and mechanistically distinct antiviral agents for the treatment of HIV. The investigational agent, T-20 , is a 36-amino acid synthetic peptide. T-20 is a linear moecule composed of naturally occurring 1-amino acid residues. The pirmary sequence of T-20 was derived from a naturally occurring motif (amino acid residues 643-678) within gp41 transmembrane glycoprotein of HIV-1. The results of nonclinical mechanism of action studies indicate that T-20 exhibits potent and selective inhibition of de novo infection and cell to cell virus transmission by binding to a critical region of gp41 which regulates the fusion of virus to host cell membranes. Nonclinical safety studies conducted in rodents and primates indicate that the intravenous administration of T-20 twice daily for 28 consecutive days is not associated with any markers of either clinical or laboratory toxicity. This trial will be studying the safety, pharmacokinetics, and antiviral activity of T-20 given by continuous subcutaneous injection to HIV-1 positive adults with HIV-RNA levels greater than 5,000 copies/ml and who have been treated with a 3-drug antiviral regimen containing 2 nucleoside reverse transcriptase inhibitors and indinavir. During this study, the patient will be randomized to receive treatment with one of four dose levels of T-20 alone by continuous subcutaneous infusion (CSI) or one dose level by intermittent subcutaneous injection ten days and then he/she will receive T-20 by CSI along with nevirapine, nelfinavir, and saquinavir for approximately 24 weeks.