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Special
International AIDS Society Section
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To Break or Not to Break,
That is Still the Question
by Charles E. Clifton
Ever since Dr. Anthony Fauci
presented data on the seven-day-on, seven-day-off structured
treatment interruption study in Durban in 2000, a debate has
raged over whether or not a Structured Treatment Interruption
(STI) provides more benefit than harm to individuals living
with HIV. Clinicians, physicians and treatment advocates go
back and forth over the long-term and short-term consequences
of interrupting HAART (Highly Active Antiretroviral Therapy)
in any situation, whether in clinical trials or clinical practice.
At the International AIDS
Society Conference (IAS) this July, in Paris, the debate was
renewed. Gregg Gonsalves of the Gay Men’s Health Crisis,
New York City, moderated a panel entitled, “There is
More Risk Than Value in Treatment Interruption.” The
premise of the debate, as outlined by Gonsalves, was to determine
if, based on evidence rather than theory, individuals could
stop therapy for a considerable amount of time and retain
the efficacy of anti-HIV drugs when therapy is re-started.
As stated, if this strategy is a real possibility it would
be an important cost savings not only for developing countries
struggling to address and treat the AIDS epidemic, but domestically,
as states struggle to keep ADAP (AIDS Drug Assistance Programs)
and Medicaid programs afloat.
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The panel included Dr. Diane
Havlir (Professor of Medicine at the University of California,
San Francisco and Chief of the AIDS division at San Francisco
General Hospital) and Dr. Bernard Hirschel (Chief of the HIV/AIDS
division of the Geneva University Hospital). Dr. Havlir took
the “pro” stance in the debate, arguing that there
is indeed more risk than value, and Dr. Hirschel took the
“con” position, arguing that there is more value
than risk in treatment interruption.
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Dr. Havlir presented several
interesting theories and data supporting her position against
structured treatment interruptions. As the data collected
over the last 10 years has proven, therapy works; therapy
improves the immune system; CD4 T-cells increase, viral load
and opportunistic infections decrease. As a result we have
observed dramatic reductions in morbidity and mortality in
the era of HAART. A series of studies have shown that anti-HIV
therapy has also reduced the rates of perinatal transmission
(see “Perinatal
Transmission and Birth Options”).
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If this strategy
is a real possibility it would be an important cost savings
for developing countries struggling to address and treat
the AIDS epidemic.
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Dr. Havlir also put forth
a theory that there is an increased risk of developing drug
resistance during treatment interruptions. However, as she
indicated, many ongoing and completed studies are not conducted
long enough to get answers or do not look at this occurrence
at all. Drugs are often selected because of the pressure they
can put on the virus. However, because of different half-lives,
many drugs are also vulnerable to a single mutation. When
therapy is stopped the immune system is exposed to high levels
of viral replication. Unwittingly, the individual can expose
himself or herself to dual or mono-therapy as drugs are cleared
from the body. As a result, sometimes a single mutation can
eliminate the availability of drugs from an entire class,
as in the case of NNRTIs. At least six studies listed at IAS
this year looked at the development of drug resistance and
treatment failure with STIs. At this point, as Dr. Havlir
stated, we still cannot determine who is going to develop
resistance if they stop therapy, but it is an area in need
of further research.
Another interesting theory
put forth by Dr. Havlir is what she described as a “reticence
to resume therapy” or the “I feel fine, I don’t
need to resume therapy” syndrome, observed in clinical
trial settings and in clinical practice. Who can blame someone
for delaying the re-initiation of therapy as long as possible,
when what waits are the toxicities associated with antiretroviral
therapy? The drawback is that while being off therapy might
feel wonderful, it affords the virus to silently go about
its dirty work. The bottom line is that individuals on therapy
like treatment interruptions and once they’ve had one
they want to do it again. The dilemma physicians and HIV positive
individuals face once the STI is introduced is where to draw
the line, when to re-start therapy?
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Following some anecdotal observations,
Dr. Bernard Hirschel made the following statement: “No
clinical benefit has ever been shown for early, as opposed
to late start of HAART.” He continued, “the same
is true for patients starting treatment during primary HIV
infection and for those patients, there is more value than
risk in treatment interruption.” Evidence, you might
ask?
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Dr. Hirschel presented interesting
perspectives on alternatives to not stopping therapy; what
to expect in stopping treatment; and lessons learned from
the SSITT (Swiss-Spanish Intermittent Treatment Trial) study
and the Swiss HIV Cohort Study. In SSITT, the protocol for
restarting therapy was a rebound of viral load above 5,000
copies, but according to Dr. Hirschel, neither participants
nor physicians accepted these levels and the decision to restart
therapy following the STI was actually based on a viral load
somewhere between 50,000–100,000. The second criterion
was based on a drop in CD4 T-cell count. The median T-cell
count for participants was about 700. It was expected that
a fall of about 200 cells during the first four to 12 weeks
would level off to about 50 to 100 per year. Participants
who had less than 350 T-cells when treatment was interrupted
had a greater chance of having to restart treatment sooner
than individuals with more T-cells. However, Hirschel stressed
that the variations between individuals were enormous and
that interruptions require proper monitoring.
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The best treatment
plan is an individualized treatment plan carefully monitored
by a HIV physician or other knowledgeable healthcare provider.
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The Swiss HIV Cohort Study
follows more than 4,000 HIV positive individuals not enrolled
in clinical trials, so this study is a good marker for what
is going on in clinical practice. The study monitors whether
individuals are on HAART, are treatment naïve, or have
been treated and have interrupted treatment. The interesting
observations from this study are that in general clinical
practice approximately 16% of HIV positive individuals have
interrupted their treatment at some point and the median duration
of a STI is 13 months.
One alternative to not interrupting
treatment is to continue treatment. With the average age of
HIV positive individuals being 39, and average life expectancy
around 80, that means an additional 40-odd years of continuous
therapy. And realistically as Hirschel stated, “prolonged
courses of continuous HAART are not an option for most HIV-infected
individuals, because of the short and long term problems associated
with a variety of regimens.”
What about the risks of resistance?
Hirschel clarified that while SSITT had more than 600 total
treatment interruptions, it was not geared to properly measure
the development of resistance. The participants in that trial
were all treatment naïve and had no virologic (viral
load) failure while on HAART. Hirschel went on to say that
while the risk of developing resistance is real during any
STI, we need to keep resistance in the proper context. Back
in 1992 there was no real chance of constructing useful treatment
options. In 1996, an individual basically had one shot and
if resistance developed that shot was gone. Today, however,
he emphasized, that with appropriate care, improved drugs,
new targets to attack the virus and careful monitoring, we
now have several chances. “Resistance,” Hirschel
concluded, “is not what it used to be.”
So what do we know? Treatment
interruptions place the individual at a higher risk for drug
resistance, increase the risk for transmission of the virus,
and place the individual at risk for disease progression and
opportunistic infections, particularly for individuals with
low T-cells. As Dr. Havlir pointed out, this group has the
greatest risk of returning to the lowest T-cell count they’ve
had after therapy is discontinued.
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However, as Dr. Hirschel clearly
pointed out, the likelihood of an individual remaining on
therapy for 40, 50 years plus is not conceivable with the
therapeutic options currently available. There is mounting
evidence demonstrating the benefits of structured treatment
interruptions in general clinical practice.
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Which takes us nearly full
circle to when to start therapy. Hit Hard, Hit Early? Hit
Later, Hit Lighter? What’s the best procedure in treating
chronic and acute infection, treatment experienced and treatment
naïve patients? The best answer at this point appears
to be what many treatment advocates and physicians have been
saying all along—the best treatment plan is an individualized
one carefully monitored by an HIV physician or other knowledgeable
healthcare provider. If we can ever figure out a way to eradicate
the toxic part of the drugs we may finally begin to see the
most benefits of antiretroviral therapy and treatment interruptions.
Additional reports from
IAS and the upcoming ICAAC will be included in the November/December
issue of Positively Aware.
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