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T-1249
Retains Potent Antiretroviral Activity in Patients with Virological
Failure While on Enfuvirtide-containing Regimen
T-1249 is an experimental fusion (entry) inhibitor (FI)
that demonstrates anti-HIV activity in vitro against HIV
isolates that have decreased susceptibility to enfuvirtide/ENF
(Fuzeon). 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 to evaluate the drug’s activity in vivo.
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. As with ENF, 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 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.
The authors conclude, “These results
indicate that FIs constitute an expanding class
of antiretroviral agents with the potential to
be sequenced.”
Discussion
These results confirm that
T-1249 retains potent antiretroviral activity in
patients who had experienced viral
failure (VF) while on an ENF-containing treatment
regimen. Presumably because of the lack of therapeutic
alternatives or perceived sustained benefits, patients
in the present study continued to take ENF
for a median of 65 weeks after VF. Thus, these
patients did not experience early VF but had
been exposed to ENF for a prolonged interval
as part of a failing treatment regimen.
This study provides proof
of the concept that FIs have the potential
to be an expanding class of ARVs with the
possibility of being sequenced. Longer-term studies
of T-1249 and/or next generation FIs are needed
to assess the potential of FI sequencing as
a therapeutic strategy.
03/14/05
Reference
J P Lalezari
and others. T-1249 Retains Potent Antiretroviral
Activity in Patients Who
Had Experienced Virological Failure
while on an Enfuvirtide-Containing
Treatment Regimen. The Journal of Infectious Diseases 191(7): 1148-1164. April 1, 2005.
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