BIO + MED
New AIDS Drugs
Watch out, viruses: the recent FDA
approval of two new classes of antiretroviral
medications promises to turn the tables in
the fight against HIV/AIDS. While several
powerful drug treatments have appeared
in the last few years, the HIV virus’s capacity
for rapid mutation continues to thwart
treatment. The slippery virus mutates
so quickly that resistant strains appear
quickly – sometimes breaking through
every combination of drugs that doctors
can throw at it. For patients with highly
resistant viruses, the new drugs – maraviroc,
from Pfizer, Inc., and raltegravir, from Merck
& Co. - help overcome this problem by
targeting the virus in different stages of
its reproduction. In combination with the
currently available medications, these new
drugs are able to control even the most
resistant strains of the virus, helping many
more patients live relatively normal lives
in the face of the infection. The drugs
completed the last stage of clinical testing
at Stanford Positive Care Clinic, where they
have been creating dramatic results in Bay
Area patients with advanced-stage HIV
infections.
The Plan of Attack
The two new drugs are a leap forward in the
field because they attack the HIV virus in
completely new ways. The most important
existing drug classes, the protease inhibitors,
nucleoside inhibitors, and non-nucleoside
inhibitors, target two very specific aspects of
the virus life cycle: the reverse transcription
process, where the virus copies its RNA
stanford scientific
written by ADRIENNE SUSSMAN
Two new classes of medications
complete clinical trials at Stanford
into DNA, and the cleaving of long chains
of polyproteins into new viruses after
that transcription is complete. Since their
release in the 1990s, these medications have
greatly controlled the HIV/AIDS epidemic
and the severity of the disease in those
infected. After prolonged use of the existing
medications, however, some patients
develop new, resistant infections, which are
no longer suppressed by the drugs they
have been using.
This is where the new medications step in.
Maraviroc is a CCR5 inhibitor, which blocks
the AIDS virus from entering the T-cells
of the immune system through its usual
molecular entrance, a cytokine coreceptor
called CCR5. Raltegravir, on the other hand,
is an integrase inhibitor, which means that
it prevents a newly transcribed strand of
viral DNA from joining with the cell’s own
DNA and reproducing. These two molecular
targets are key points in the virus’s life
cycle, and so blocking these processes
can powerfully suppress the virus’s spread.
More importantly, these are completely
new targets, so even the resistant viruses
which no longer respond to protease,
nucleoside, or non-nucleoside inhibitors
might be conquered by an integrase or
CCR5 inhibiting drug.
The Lazarus Effect
The evidence for just how effective these
new blocking mechanisms can be was
demonstrated in the recent clinical trial at
Stanford Positive Care Clinic. The clinic is a
14-year-old research and treatment center
located on the Veterans Hospital campus
which specializes in virology and the study
of resistance. Researchers at the clinic have
been involved in hundreds of clinical trials
and treated thousands of patients.
The director of the clinic, Dr. Andrew Zolopa,
was excited by the responses he saw in
his patients during the trials. Dr. Zolopa
compares the dramatic effects that these
new medications can have, to the medical
turning point ten years ago when protease
inhibitors were first introduced on the
market. At that point, Zolopa says, “we
saw and heard reports of these Lazarus-like
effects, of patients who were near death
with end stage AIDS, recovering fully and
getting back to work and back to life.”
Unfortunately, protease inhibitors weren’t
a miracle-cure for all. As Zolopa explains,
even the drugs of the 1990s “still left a
number of patients who didn’t have a
completely suppressive regimen, had too
much resistance coming into their new
treatment regimes. Those patients have
been kind of hanging on for most of this
past decade.” The new drugs, however, have
been successfully treating these extremely
resistant patients, offering relief where the
protease inhibitors were not strong enough.
As an example of the transforming effect of
these medications, Dr. Zolopa tells the story
of one of his own patients who recently
started treatment with raltegravir. “He had
zero T-cells for the last five years, I mean
no T-cells,” Zolopa explains, “and then with
the new drugs, he’s been able to get viral
loads almost fully suppressed, and his T cells
are coming back again. So it really is like a
second wave of these Lazarus-like recoveries
in patients who have been waiting a long,
long time to find an effective regimen.”
As exciting as the new medications are, they
have their limitations. Maraviroc may not be
helpful for some advanced stage patients, as
the HIV virus tends to evolve to utilize other
pathways for entering the cell. This means
Target Resistant Virus
that for patients who have been infected
for a long time – the patients who are most
desperate for new drugs - CCR5 inhibitors
like maraviroc may not be effective.
Raltegravir, on the other hand, does help
patients at every stage of infection, as
integrase, its target, directs one of the vital
steps in the virus lifecycle.
A Treatment, Not a Cure
As culmination to several years of rapid
drug development, in the past two years
alone researchers have developed two new
types of protease inhibitors, as well as a new
kind of non-nucleoside inhibitor. The new
drugs attack the same aspect of the virus’s
reproduction as their predecessors, but are
more powerful and have fewer debilitating
side-effects. In other developments,
pharmaceutical researchers have created
a single multi-drug pill that is effective for
newly infected patients, simplifying the
often complicated drug regimen of most
HIV/AIDS patients. In short, things look
bright in HIV/AIDS treatment, and most
patients are now able to suppress the virus
almost fully.
Still, while a huge step forward, these
new drugs are not a panacea, but rather a
useful weapon when combined with the
existing arsenal of options. The HIV virus
can still develop resistance to these drugs
if they are administered alone; the drugs
must be used as part of a multi-medication
regimen. When multiple drugs are taken
together, the infection becomes so weak
that it is much more difficult for the virus to
develop resistance. The average HIV patient
needs a drug cocktail of 3 or more active
medications to fully suppress the virus – a
regimen that can be complicated and taxing
for the patient.
The newly available drugs will not simplify
the course of therapy, nor will they
After prolonged
guarantee against the appearance of new
resistant virus strains. However, Dr. Zolopa
use of the existing
predicts that resistance, while it may occur, medications,
will reach an asymptote with the new drugs.
“There are fewer and fewer patients who are however, some
breaking through their third line and fourth
line and fifth line regimens. With each new patients develop
wave of development, we are able to fully
new, resistant
suppress and successfully treat another
portion of the patients,” he explains. infections, which
Exciting as these new developments are, are no longer
Zolopa cautions that the HIV/AIDS epidemic
is far from controlled. The number of suppressed by the
infections is growing, both in the United
States and around the world, and as few drugs they have
as 10% of those infected are receiving
treatment. In addition to the simple
been using. This
problem of inadequate access to therapy,
Dr. Zolopa describes a balance between
is where the new
the benefits and risks that new medications medications step in.
bring. While new drugs are extremely
valuable, they also bring the slight risk of
creating ever more resistant versions of the
virus. Moreover, the availability of such
powerful treatments in this country has
perhaps led to a relapse of risky behaviors,
allowing the infection to spread to a greater
number of people. Despite the continued
need for prevention measures, thanks to
these new drugs, the future looks bright for
those in treatment.
ADRIENNE SUSSMAN graduated last year with a degree in biology and will begin a PhD
program at the University of Washington in the fall.
To Learn More
Credit: sxc.com
For more information on raltegravir, maraviroc, and other AIDS treatmets and research, visit
www.aidsinfo.nih.gov. For information on the AIDS virus and epidemic, visit www.cdc.gov/HIV.
volume VII