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 log(10) copies/mL (95% confidence interval, -1.40 to -1.09 log(10) copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of >/=1.0 log(10) 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.
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 log(10) copies/mL (95% confidence interval, -1.40 to -1.09 log(10) copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of >/=1.0 log(10) 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.
Authors: Brett D Welch; J Nicholas Francis; Joseph S Redman; Suparna Paul; Matthew T Weinstock; Jacqueline D Reeves; Yolanda S Lie; Frank G Whitby; Debra M Eckert; Christopher P Hill; Michael J Root; Michael S Kay Journal: J Virol Date: 2010-08-18 Impact factor: 5.103
Authors: Neelanjana Ray; Jessamina E Harrison; Leslie A Blackburn; Jeffrey N Martin; Steven G Deeks; Robert W Doms Journal: J Virol Date: 2007-01-24 Impact factor: 5.103
Authors: Ronald S Veazey; Thomas A Ketas; Per Johan Klasse; Donna K Davison; Morgan Singletary; Linda C Green; Michael L Greenberg; John P Moore Journal: Proc Natl Acad Sci U S A Date: 2008-07-22 Impact factor: 11.205
Authors: Paolo Ingallinella; Elisabetta Bianchi; Neal A Ladwa; Ying-Jie Wang; Renee Hrin; Maria Veneziano; Fabio Bonelli; Thomas J Ketas; John P Moore; Michael D Miller; Antonello Pessi Journal: Proc Natl Acad Sci U S A Date: 2009-03-18 Impact factor: 11.205