title: T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen.
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 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.affiliation: Quest Clinical Research, San Francisco, California, USA.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Lalezari
authors.forename: Nicholaos C
authors.initials: NC
authors.lastname: Bellos
authors.forename: Kunthavi
authors.initials: K
authors.lastname: Sathasivam
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Richmond
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Cohen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Myers
authors.forename: David H
authors.initials: DH
authors.lastname: Henry
authors.forename: Claire
authors.initials: C
authors.lastname: Raskino
authors.forename: Tom
authors.initials: T
authors.lastname: Melby
authors.forename: Hugh
authors.initials: H
authors.lastname: Murchison
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Spence
authors.forename: Michael L
authors.initials: ML
authors.lastname: Greenberg
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Demasi
authors.forename: G Diego
authors.initials: GD
authors.lastname: Miralles
mesh_terms: D000328:Adult; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D005260:Female; D005838:Genotype; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D011247:Pregnancy; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D017211:Treatment Failure
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; C474741:peptide T1249; D000077560:Enfuvirtide