Abstract
Background. T-1249 is a 39-amino acid synthetic peptide fusion inhibitor (FI) shown to preserve antiretroviral activity in vitro against human immunodeficiency virus (HIV) isolates that have decreased susceptibility to enfuvirtide (ENF). Methods. A 10-day phase 1/2 study of the safety and antiretroviral activity of T-1249 was conducted in 53 HIV-1-infected adults with detectable viremia while on an ENF-containing treatment regimen. Results. From FI-naive baseline levels, the geometric mean (GM) decrease in susceptibility to ENF was 116.3-fold and the GM decrease in susceptibility to T-1249 was 2.0-fold. Patients continued to administer their failing treatment regimen but replaced ENF with T-1249 at a dose of 192 mg/day. T-1249 was generally well tolerated; injection site reactions, which were generally mild, were the most commonly reported adverse event (64% of patients). The median change from levels of HIV-1 RNA at baseline to levels on day 11 was -1.26 log101 copies/mL (95% confidence interval, -1.40 to -1.09 log10 copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of ≥1.0 log10 copies/mL was seen in 73% of patients. Antiretroviral activity, as measured by levels of HIV-1 RNA, was not predicted by baseline susceptibility to T-1249 or to ENF; genotypic substitutions that emerged during T-1249 treatment were identified in virus from some patients. Conclusions. These results indicate that FIs constitute an expanding class of antiretroviral agents with the potential to be sequenced. © 2005 by the Infectious Diseases Society of America. All rights reserved.