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Treatment, Interrupted
Conference focuses on strategies for reducing
the drug burden in anti-HIV therapy
by Bob Roehr
nti-HIV therapy has been spectacularly
successful at dramatically reducing pro­
gression and death from the disease dur­
ing the past decade. But the downside to
therapy can he side effects, the selection
of resistant virus and the high cost, particularly in
the developing world.
So it is no surprise that as treatment practices
have matured, patients and physicians have sought
ways to possibly minimize use of those therapies
while at the same time retaining their benefits.
Strategic interruptions of therapy were a major
focus of discussion at the 13th Conference on
Retroviruses and Opportunistic Infections meeting
Feb. 5 to 8 in Denver.
Much of the attention focused on the Strategies
for Management of Anti-Retroviral Therapy
(SMART) trial. As the largest HIV treatment trial
ever, it had enrolled 5,472 of its planned 6,000
patients before being stopped Jan. 11. An interim
analysis revealed that those in the arm that inter­
rupted therapy had more than twice the risk of dis­
ease progression as those who continued on therapy.
The trial design had patients start treatment
when their CD4 cell count dropped below 250.
Half continued therapy uninterrupted, while half
were randomized to stop therapy once their CD4
count climbed above 350.
“The study showed that there was an increased
risk of HIV complications and death in patients
who used anti-HIV treatment intermittently. But
even more surprisingly, they also had more com­
plications,” said Wafaa El-Sadr, a researcher at
Columbia University and a leader of the SMART
study.
“A lot of the complications and deaths were not
due to what we call HIV-related complications,”
she added. They were related to increased risk for
heart, liver and kidney disease. “We don’t under­
stand why. We have a lot to learn about what start­
ing and stopping does.”
When asked what parameters she would be
comfortable with for an interruption trial, El-Sadr
said: “Clearly, we would like to go to a higher
fCD4] threshold for restarting. In the SMART
study, those who had depressed viral loads at base­
line, they did the worst, they had the highest risk
of progression” with interruption.
Mixed signals on interruptions came from a
smaller trial in the Ivory Coast in West Africa that
randomized patients to three arms: continuous
therapy; the same CD4 start/stop criteria of the
SMART trial; or a rotation of two months
off and four months on therapy.
It also stopped the SMART-like arm of
the trial when “it found a 2.6 times higher
rate of serious morbidity in the guided
treatment arm, largely because of bacterial
infections,” said investigator Christine
Danel. The fixed rotation of two months
off and four months on therapy is continu­
ing, as researchers did not see the same type
or number of events, at least not so far.
In contrast, an interruption trial in
Thailand that reinitiated therapy whenever
CD4 counts fell below 350 saw no signifi­
cant differences between that group and
those who were on continuous therapy.
“The general themes are, the more
time you are on therapy the better; the
lower the reinitiation threshold, the high­
AIDS researcher Wafaa El-Sadr describes her findings
er the risk; the shorter the discontinuation
about the ineffectiveness of intermittent HIV treatment.
“WOMEN’S BOOKS AND RESOURCES
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the better,” said John
Mellors, a University of
Pittsburgh researcher and
vice chairman of the
conference. Interruptions
are “something that no
one would advocate for
John Mellors, a University of Pittsburgh researcher, co-chaired the
patients with a low CD4
Conference on Retroviruses and Opportunistic Infections in February.
count, somewhere below
regimen of atazanavir/ritonavir (Reyataz) and
300.”
He added: “There needs to be dialogue as to Combivir, then stopped taking the Combivir.
whether we can even move forward with any of
According to Swindells, after a year on the sin­
these interruption strategies. The downside of gle drug, only three of the 34 patients had a
starting/stopping, starting/stopping, even for brief detectable viral load, though none showed resist­
periods of time...with another study we see 30
ance to atazanavir. Why did those three patients
percent drug resistance. That’s not a gtxxl thing.”
develop detectable levels of virus? Monitoring found
Mike Youle is a researcher at the Royal Free
periodic low levels of the drug in two of the three
Hospital in London who writes for the National
patients with detectable virus, suggesting they did
AIDS Treatment Advocacy Project. In reviewing
not regularly take their medicine.
data on the handful of interruption trials, he
Swindells said the findings “are extremely sim­
acknowledged that the issue is far from simple. It
ilar” to a pilot study using Kaletra monotherapy.
often might depend upon a patient’s coinfections She does not believe nucleoside drugs are powerful
and exposure to other pathogens.
enough to maintain sufficient suppression of the
virus, while a non-nucleoside reverse transcriptase
He also noted that as anti-HIV regimens have
become safe and easier to use, there is a greater
inhibitor can be rendered impotent with a single
willingness to remain on them and less pressure to
viral mutation, so at this point, any single drug
develop strategies such as interruptions to reduce
strategy would have to be based upon a protease
inhibitor.
use of those drugs.
However, one risk of this strategy in using
Another possible strategy for reducing the drug
burden is a simplification approach that uses a stan­ atazanavir is that it does not appear to penetrate
dard cocktail of therapy to knock down the virus
blood-brain barriers very well. One poster presen­
tation found that concentrations of the drug in
and, once viral load is undetectable, to withdraw
part of the regimen.
•
the cerebrospinal fluid “are highly variable and are
100-fold lower than plasma concentrations, even
The theory is that a single drug might be
powerful enough to destroy the small number of with ritonavir boosting.” It warned that these
virus that emerge from sanctuary resting cells and
concentrations might not protect against HIV
replication in the fluid.
tissue compartments without giving resistance a
That raises the possibility of virus replicating
chance to emerge. It would work best with a drug
behind those “walls” in the central nervous system
that requires several mutations for resistance to
and brain, the eyes and the testes. That is a sig­
develop to that drug.
nificant issue for both individual and public health.
Susan Swindells described a small pilot study at
Mellors acknowledged, “That has to be evaluated
University of Nebraska Medical Center. The
very
carefully.’ ©
patients had to be on a regimen containing a
protease inhibitor, with undetectable viral load for
B ob R oehr is a free'lanee reporter based in
at least a year and no previous drug failure. If they
Washington, D.C.
were not on it already, they were switched to a
We cover
both sides
of the fence.
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