T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen.
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.
Lalezari
Jacob P
JP
Quest Clinical Research, San Francisco, California, USA.
Bellos
Nicholaos C
NC
Sathasivam
Kunthavi
K
Richmond
Gary J
GJ
Cohen
Calvin J
CJ
Myers
Robert A
RA
Henry
David H
DH
Raskino
Claire
C
Melby
Tom
T
Murchison
Hugh
H
Zhang
Ying
Y
Spence
Rebecca
R
Greenberg
Michael L
ML
Demasi
Ralph A
RA
Miralles
G Diego
GD
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
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; C474741:peptide T1249; D000077560:Enfuvirtide