Topics in HIV Medicine® - International AIDS Society-USA

International AIDS Society–USA
Topics in HIV Medicine
ed, which confirmed that the viral isolates
within this study population had
extensive resistance to currently available
PIs.
At day 14, plasma HIV-1 RNA
responses were as follows: the 500
mg/100 mg arm achieved a reduction in
plasma HIV-1 RNA of 0.87 log 10
copies/mL; the 500 mg/200 mg arm, a
reduction of 0.97 log 10 copies/mL; and
the 750 mg/200 mg arm, a reduction of
1.18 log 10 copies/mL. At day 14, 20% of
participants had no changes made to
their antiretroviral therapy background
regimen due to lack of available active
agents. All study arms maintained at
least a 1.0 log 10 decrease in plasma HIV-
1 RNA from baseline through day 56. All
patients had at least 5 PI mutations at
study entry. Patients were subsequently
grouped according to the number of
mutations: 6 to 10 mutations; 11 to 15
mutations; 15 to 20 mutations; or more
than 20 mutations. The reductions in
plasma HIV-1 RNA from baseline were at
least 0.8 log 10 copies/mL regardless of the
number of baseline PI mutations and, in
the 500 mg/200 mg and 750 mg/200 mg
dosing arms, ranged to 1.2 log 10
copies/mL. Patients in the 500 mg/100
mg dosing arm with more than 20 mutations,
however, did not achieve substantial
reductions in plasma HIV-1 RNA
level, with an average decline of 0.2 log 10
copies/mL.
The 3 study drug regimens were generally
well-tolerated. However, the 750
mg/200 mg study dosing arm had the
highest proportion of participants who
discontinued the study due to adverse
events. Based on the similar antiviral
activity demonstrated by the 500
mg/200 mg and 750 mg/200 mg dosing
arms in this study and the lower frequency
of grade 3 or 4 adverse events
reported in the lower-dose arm compared
to the 750 mg/200 mg arm, the
dose selected for use in phase 3 development
was tipranavir 500 mg/ritonavir
200 mg.
RO-033-4649. RO-033-4649 is a PI developed
through structure-activity analysis
of HIV-1 protease containing 1-5 sitedirected
mutations (Abstract 7). The in
vitro results show potent activity against
a panel of 50 viral strains, each with 10-
fold or greater resistance in a phenotypic
drug resistance assay to 4 of 5 marketed
PIs (median IC 50 100 nM) as well
as wild-type viruses (median IC 50 17
nM). Previous work showed favorable
pharmacokinetic profiles in 3 animal
species. Phase 1 studies are beginning.
TMC114. Arasteh and colleagues presented
the phase 2a data on TMC114 coadministered
with ritonavir in multiple PIexperienced
patients (Abstracts 8, 549,
and 553). Patients with CD4+ counts
greater than 50 cells/µL, plasma HIV-1
RNA greater than 2000 copies/mL, previous
treatment with 2 to 4 PIs for more
than 2 months each, virologic failure on
the current regimen, and no NNRTI use
in the baseline failing regimen were eligible
for study participation. Fifty subjects
were randomized to continue their
background antiretroviral therapy regimen
plus TMC114 300 mg/ritonavir 100
mg twice daily (n=13); to receive
TMC114 600 mg/ritonavir 100 mg twice
daily (n=12); to receive TMC114 900
mg/ritonavir 100 mg once daily (n=13);
or to continue their current PI-based
regimen (control arm; n=12). Median
baseline plasma HIV-1 RNA and CD4+
cell count were 4.3 log 10 copies/mL and
305 cells/µL, respectively. After 2
weeks, TMC114 was stopped and the
antiretroviral regimen changed according
to the practitioner’s wishes. At day
14, according to an ITT analysis, the
median change in plasma HIV RNA
from baseline was -1.24 log 10 copies/mL
in the 300 mg/100 mg arm; -1.13 log 10
copies/mL in the 600 mg/100 mg arm;
-1.50 log 10 copies/mL in the 900 mg/100
mg arm; and +0.02 log 10 copies/mL
in the control arm. The median plasma
HIV-1 RNA change from baseline to
day 14 for the 3 TMC114 study arms
was significantly greater than for the
control arm (P