HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
Integrase
Inhibitor Raltegravir Demonstrates Potent Activity Against HIV at 16-24 Weeks
This
week at the 14th Conference on Retroviruses and Opportunistic Infections in Los
Angeles, researchers presented the latest data on 2 experimental antiretroviral
drugs that work by novel mechanisms:
In
a press conference on Tuesday, John Mellors, MD, of the University of Pittsburgh
said that the latest findings are the most exciting developments in the field
of HIV therapy since the advent of protease inhibitors in the mid-1990s, especially
for heavily treatment-experienced patients.
Raltegravir
Data
In 2
presentations, researchers described results from the BENCHMRK-1 and BENCHMRK-2
studies, identical, ongoing Phase III randomized controlled trials involving highly-treatment
experienced patients. BENCHMRK-1 included 350 participants in Europe, Asia and
Peru; BENCHMRK-2 included 349 patients in North and South America.
Participants
in the 2 study arms were generally similar. About 90% in both studies were men,
with a mean age of about 45 years. Subjects had virus resistant to all 3 major
antiretroviral drug classes, a mean CD4 cell count of about 150 cells/mm3, and
HIV viral loads above 1000 copies/mL (mean range 30,000-50,000 across arms).
Participants
were randomly assigned to receive either 400 mg oral raltegravir twice-daily or
placebo, in addition to an optimized background regimen. Results were stratified
based on whether they had additional active drugs in their regimens.
Results
from 16 weeks of follow-up were available for all participants in both studies,
and the researchers also presented data from about 60% of subjects who had reached
24 weeks. The studies are planned to continue through 48 weeks.
Results
•
In the 2
studies combined, 61-62% of patients in the raltegravir arms achieved virological
suppression below 50 copies/mL, compared with 33-36% of those receiving placebo
(p < 0.001).
•
In
both trials, 77% in the raltegravir arms achieved viral loads below 400 copies/mL,
compared with 41-43% of those in the placebo arms (P < 0.001).
•
Among
patients with no other active drugs in their regimen, 61% achieved a viral load
below 400 copies/mL with raltegravir, compared to only 5% with placebo.
•
In
contrast, among subjects who started both enfuvirtide (T-20; Fuzeon) and darunavir
(Prezista) at the same, 98% achieved virological suppression (< 400 copies/mL)
with raltegravir compared to 87% with placebo.
•
Among
patients with baseline HIV RNA below 100,000 copies/mL, 88% in the raltegravir
arm and 55% in the placebo arm achieved virological suppression (< 400 copies/mL),
compared with 64% and 19%, respectively, of those with higher baseline viral loads.
•
Among
subjects with CD4 counts above 200 cells/mm3, 88% in the raltegravir arm and 59%
in the placebo arm achieved viral loads below 400 copies/mL; for those with fewer
than 50 cells/mm3 at baseline, the corresponding figures were 63% and 24%
•
The
rates of virological failure were 16% in the raltegravir arms and 51% in the placebo
arms
•
Subjects
in the raltegravir arms gained about 85 CD4 cells/mm3, compared with 30-40 cells/mm3
in the placebo arms.
•
Raltegravir
was generally well tolerated, with adverse events similarly distributed across
arms when considering both trials together.
•
In
all arms, the rate of serious drug-related adverse events was 2.5% or less.
•
1.7%
of subjects in the raltegravir arm discontinued due to adverse events in both
studies (vs the placebo groups, 3.4% in BENCHMRK-1 and 0.8% in BENCHMRK-2).
•
Based
on limited data, there appeared to be 2 distinct pathways to raltegravir resistance,
involving the N155H and Q148K/R/H mutations.
Conclusion
The
researchers concluded that raltegravir "demonstrated potent and superior
antiretroviral activity" compared with placebo in combination with optimized
background therapy in patients with triple-class resistant HIV.
An
expanded access program for raltegravir is currently open. Merck expects to
file for regulatory approval of raltegravir (to be sold under the brand name Isentress)
by the end of 2007.
03/02/07
References
D
Cooper, J Gatell, J Rockstroh, and others. Results from BENCHMRK-1, a phase III
study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor,
in patients with triple-class resistant virus. 14th Conference on Retroviruses
and Opportunistic Infections (CROI). Los Angeles, February 25-28, 2007. Abstract
105aLB.
R Steigbigel,
P Kumar, J Eron, and others. Results from BENCHMRK-2, a phase III study evaluating
the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients
with triple-class resistant virus. 14th CROI. Los Angeles, February 25-28, 2007.
Abstract 105bLB.
