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A second first
Data on a second first-in-class
drug, the CCR5 inhibitor maraviroc, was also presented
at CROI.
For HIV to successfully infect
an immune cell, it must first bind to the CD4
receptor on the surface of the host T cell. This
causes a change in viral shape, which allows the
virus to proceed to step two — co-receptor
binding. Here, the virus attaches either to CCR5
and/or to CXCR4. Its preference, called "viral
tropism" is poorly understood, but we do know
that the CCR5 receptor is the most common choice.
Like the data on raltegravir,
24-week results of MOTIVATE I and II — two
studies also conducted in treatment-experienced
patients — were very encouraging. Sixty percent
of those on maraviroc achieved a viral load of
less than 400 copies/mL, compared with 30% of
those on placebo. Roughly half of patients in
the treatment arm reached less than 50 copies/mL,
compared to 20% of those receiving placebo.
Maraviroc also seems to be well
tolerated. Other CCR5 receptors have made it to
trial in the past but were plagued by safety concerns.
Aplaviroc was discontinued due to liver toxicity
and vicriviroc, which is still in ongoing phase
2 studies, showed signs of causing malignancies.
The data on maraviroc will be
presented to the FDA advisory committee on April
24.
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Nearly two thirds of the hardest-to-treat
patients saw their HIV load plummet to undetectable
levels after just 16 weeks of treatment with the new
integrase inhibitor raltegravir, while 75% reached levels
of a very manageable 400 copies/mL or less, according
to interim data presented at the 14th Conference on
Retroviruses and Opportunistic Infections (CROI) in
Los Angeles on February 27. Integrase inhibitors are
drugs designed to block HIV replication by preventing
the virus from inserting its genetic material into the
host's DNA.
Ever since the Phase 2 data was
reported at the International AIDS Conference in Toronto
last August, experts have been eagerly awaiting a first
glimpse at the data coming out of BENCHMRK 1 and 2.
The two randomized, double-blind, placebo-controlled
Phase 3 trials included 699 patients who had developed
resistance to all three major classes of antiretroviral
drugs.
"The results so far are very consistent,"
says Dr Roy Steigbigel, State University of New York
at Stony Brook professor and lead investigator of BENCHMRK-2.
"We now have a much more detailed analysis showing the
drug is at least as good as previous data would suggest."
Although we're still in the early
days — 48-week data is expected at a conference
in Australia this summer — there's already a palpable
atmosphere of enthusiasm among researchers. "It's fantastic,"
says Dr Mark Wainberg, director of the McGill AIDS Centre.
"It's really great news for patients."
"About as good as you can
do is 80% in intent to treat analysis" [and that's]
among treatment naòve patients," beamed Dr John
Mellors, vice chair of the conference scientific committee,
during a news conference.
Raltegravir is one of two first-in-class
drugs expected to gain FDA approval by year's end (see
"A Second First").
SAFE
AT FIRST
In the two studies combined, 77% of patients receiving
the drug plus optimized background therapy (OBT) achieved
HIV RNA levels below 400 copies/mL, compared to 41-43%
of those getting placebo. Roughly 60% had levels below
50 copies/mL, compared to 33-36% of patients in the
placebo arm. CD4 cell counts were as much as three times
higher in patients receiving raltegravir.
Dr Steigbigel is pleased with the
drug's efficacy, but the lack of side effects is what
impressed him most. "It's nice to see such a total lack
of toxicity," he says. "This is a relatively short period
of time, granted, but it's of great interest."
Resistance to the drug did develop:
virological failure was three times more likely in patients
receiving the drug than those on placebo, but Dr Steibigel
says that's to be expected. "In this heavily treated
group, this isn't bad. If resistance doesn't develop,
that means the drug isn't working." And for him, what's
more important is understanding just how competent the
mutated virus is. "A virus that mutates to develop resistance
is usually weakened," he explains. "But I don't have
that data yet."
Dr Steibigel says new classes of
antiretroviral drugs are needed, and not only for those
whose treatment options are running out. A growing number
of patients, he says, are becoming infected with treatment-resistant
virus from the get-go. "Ten years ago, the virus of
newly infected patients was sensitive to all meds. Now,
in many places 15% of patients who are newly infected
have resistant virus. If you look for subtle resistance
markers, that number can rise to 50%," he says.
Dr Wainberg says it's possible
raltegravir might even be good enough to replace one
of the currently used drugs entirely. "Right now, [raltegravir]
is being tested mainly in treatment-experienced patients,
but the company is also doing studies as first line
therapy. If those work well," he explains. "It may be
a drug that changes the way we do HIV therapeutics."
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