August 17, 2006 (AIDSmeds)—Results from a clinical trial presented at the XVI International AIDS Conference (IAC) indicate that maraviroc, Pfizer's experimental entry inhibitor,
may be of limited benefit in HIV-positive people with a specific form
of HIV. However, these data also challenge some concerns that patients
with this particular form of the virus seen in later stages HIV disease
will be harmed by maraviroc and a similar entry inhibitor vicriviroc.
After HIV binds to the CD4 protein on T-cells,
the virus must then latch onto another receptor on the cell's surface –
either CCR5 or CXCR4. Earlier in the course of HIV disease, most people
have HIV that uses the CCR5 receptor. Later on, as HIV disease
progresses, the virus can switch to the CCR4 receptor, although it is
not clear why this happens. The virus' tendency to use CCR5 or CXCR4 is
known as "tropism."
Some people have mixed populations
of virus in their blood, with some of their HIV using CCR5 and other
virus targeting CXCR4. These viruses are known as dual- or mixed-tropic
HIV.
Maraviroc and vicriviroc are specifically active
against virus that uses the CCR5 receptor. These agents are desperately
needed by patients with limited treatment options due to resistance
to currently available agents. Of central concern, however, is the fact
that, because many of these patients have been infected for several
years, they are more likely to have CXCR4-tropic virus or
dual/mixed-tropic virus.
While experts agree that
maraviroc and vicriviroc are not likely to be effective against
CXCR4-tropic virus, they have hoped that these drugs will be effective
against dual/mixed-tropic HIV.
This crucial question
was raised in a maraviroc study, the results of which were reported
today at IAC by Howard Mayer, MD, of Pfizer. It was a 24-week study
designed to evaluate the effects of maraviroc in patients with HIV that
is either CXCR4-tropic or dual/mixed-tropic.
The study
enrolled 186 HIV-positive patients, 167 of whom had dual/mixed-tropic
virus (the rest had CXCR4-tropic virus). A tropism test that determined
whether or not a patient's virus is CCR5-tropic, CXCR4-tropic, or
dual/mixed-tropic was used to screen patients.
The patients were quite advanced in their HIV disease – the average CD4 count was less than 50 and the average viral load upon entering the study was above 100,000.
Study
volunteers were randomized to three treatment groups. In the first
group, patients received optimized background therapy (OBT) – a
combination of approved HIV drugs that patients' viruses were believed
to be at least partially sensitive to – plus placebo. The second group
took oral maraviroc once a day plus OBT. The third group took oral
maraviroc twice a day plus OBT.
While Pfizer was likely
hoping that the addition of maraviroc to OBT would prove to be
virologically beneficial for patients with dual/mixed-tropic virus, it
was not to be. After 24 weeks of treatment, viral loads decreased by
0.97 log in the placebo plus OBT group, 0.91 in the once-daily
maraviroc plus OBT group, and 1.20 log in the twice-daily maraviroc
plus OBT group. The differences between these groups were not
statistically significant, meaning that the slightly better viral load
drop in the twice-daily maraviroc group could have been due to chance.
Dr.
Mayer also reported undetectable viral load results. By the end of the
study, 15.5% in the placebo group had viral loads below 50, compared to
21.1% in the once-daily maraviroc group and 26.9% in the twice-daily
maraviroc group. Again, these differences were not statistically
significant, although the trend toward better viral load results in the
twice-daily maraviroc group is notable.
Encouragingly,
average CD4 count increases were significantly greater in the maraviroc
groups. CD4 counts increased by 59.6 cells in the once-daily maraviroc
group and by 62.4 cells in the twice-daily maraviroc group. In the
placebo group, CD4 counts increased, on average, by 35 cells.
It
is also important to note that some patients who entered the study with
dual/mixed-tropic virus only had detectable CXCR4-tropic virus in the
blood by the end of the study. Some experts have speculated that the
emergence of CXCR4-tropic virus during entry inhibitor therapy would
result in more rapid disease progression. However, patients who ended
the study with CXCR4-tropic virus actually ended up with significantly
greater CD4 cell counts, suggesting that while therapy with a CCR5
inhibitor may not result in significantly greater viral load reductions
in patients with mixed/dual-tropic or CXCR4-tropic virus, it does not
appear to be harmful.
As for side effects, maraviroc
was well tolerated with few differences in the types, frequency, or
severity of adverse events among all three treatment groups. While
there were seven deaths in the study, none of these were considered to
be related to the study drug.
In preparing for the FDA
approvals of maraviroc and vicriviroc, laboratories are beginning to
employ tropism assays and to learn more about their use (Trofile™, from Monogram Biosciences, is emerging as one such test). These
study results underscore the likely importance of these tests, in order
to help treatment-experienced patients determine if they are likely to
respond to these new entry inhibitors. Patients with CCR5-tropic virus
may be expected to respond well to maraviroc or vicriviroc treatment,
whereas those with CXCR4-tropic or dual/mixed-tropic virus may not.
Maraviroc
is now in the final stage of clinical development. The Phase III
clinical trials of maraviroc currently under way are focusing on
patients with CCR5-tropic virus, including those starting HIV treatment
for the first time and those in need of new treatment options. Results
reported thus far from studies involving patients with CCR5-tropic
virus have been encouraging.
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