Hoping for a Holiday: Structured
Treatment Interruptions
by Tim Horn
Not too long ago, the idea
of stopping anti-HIV therapy was a laughable notion. After
all, possible eradication of the virus was at stake. But the
hope of curing HIV using highly active antiretroviral therapy
(HAART) has faded. Still, experts continued to warn against
stopping therapy, including short-term drug holidays. There
was a threat that nasty drug-resistant strains of the virus
would emerge, along with the possibility that immune function
would quickly decline and send patients’ health spiraling
downwards.
Preliminary results of several
small studies reported at the recent 7th Conference on Retroviruses
and Opportunistic Infections (CROI) suggest that not only
may drug holidays be feasible and safe, but they may also
be good for the immune system. While proving these suggestions
will require a fair amount of additional research (none of
the recent reports offer any guarantees) a dose of springtime
optimism is certainly in the air.
Backgrounder
Let’s face it. HAART
is not all that its cracked up to be. For people who started
therapy “early,” that is, while their viral loads
were low and CD4+ cell counts were high, popping pills every
day in the face of side effects has been a herculean task.
At the same time, there are also patients who desperately
needed therapy to bring their high viral loads down and CD4+
cell counts out of the red. Now that many of these folks have
been saved, that is, have seen their viral load stay undetectable
and their CD4+ cell counts linger at healthy levels, a fundamental
question remains: “Why do I need to stay on this stuff?”
It’s not at all clear
what comes next. There are a number of different possibilities,
all of which will drive research over the next few years.
Researchers might prove that all patients, once they’ve
started therapy, should remain on it. Another avenue to explore
is the possibility of treating HIV like many other chronic
diseases, initiating therapy when the immune system shows
signs of damage or when a patient experiences symptoms of
HIV disease, then stopping therapy when their health improves.
And let’s not forget new treatments, including novel
anti-HIV drugs and immune-based therapies, that may prove
to be the magic bullet everyone is waiting for.
In essence, figuring out how
to treat HIV remains in a constant state of uncertainty. Structured
treatment interruptions, more commonly referred to as “drug
holidays,” represent the first experimental approach
to break with the current HAART model. While drug holidays
are by no means ready for the “real world” of HIV
care (in other words, they are not yet considered to be safe
or effective enough for patients to try them at home) they
are definitely the research trend to watch in the coming months.
Structured treatment interruptions
While it would be nice to
think that patients “sick of it all” were the driving
force behind structured treatment interruption (STI) research,
the scientific rationale can actually be traced back to a
phenomenon seen in a single patient living in Germany. A few
years ago, Dr. Franco Lori, a researcher with labs in Pavia,
Italy and Georgetown, reported on the highly irregular circumstances
of an unnamed patient who, after a series of interruptions
in his drug therapy, appeared to have cleared HIV from his
body.
The “Berlin Patient,”
as he has come to be known by the world, was participating
in a clinical trial for recently infected patients. He entered
the study approximately two months after an unsafe sexual
experience which, as he feared, resulted in HIV infection.
Once enrolled, he started a triple-drug regimen involving
indinavir (Crixivan), ddI (Videx), and hydroxyurea (Hydrea),
but went off of his drugs after two weeks due to a bacterial
infection. He stopped his medication for three days, and predictably,
saw his viral load increase. After restarting therapy, his
viral load became undetectable. Four months later, he developed
hepatitis A, causing his liver enzymes to increase dramatically,
requiring that he go off therapy again. But this time, his
viral load did not rebound; it stayed undetectable. While
he opted to start therapy yet again after his hepatitis got
better, he changed his mind and has been off therapy ever
since and continues to enjoy an undetectable viral load.
Has he been cured? Dr. Lori
says no. He still has a traceable amount of HIV in his lymph
nodes. Instead, it appears as if the immune system of this
very lucky patient has been able to keep his HIV in check,
much like other viral infections that are never totally eradicated
from the body (e.g., varicella, the virus responsible for
chickenpox).
While no one is sure why this
happened, Dr. Lori and his colleagues have offered an intriguing
hypothesis. HAART is designed to drastically reduce the amount
of virus in the body. While this is definitely a good thing
with respect to protecting the immune system from additional
damage, it may prevent the immune system from doing what it
should be doing in terms of fighting HIV. Perhaps with so
little virus in the blood and the lymph nodes, the immune
system “forgets” that HIV is there. In turn, it
calls off cells programmed to search and destroy the virus.
If HAART is stopped, the virus comes back with a vengeance.
If HAART is not restarted, the amount of virus will grow considerably,
often to levels that overwhelm the immune system.
The key, Dr. Lori argues,
is to keep the amount of virus at a controllable level, just
enough to keep the immune system active, but not enough to
dominate it. This may have been what happened during the brief
breaks, the structured treatment interruptions, in the Berlin
Patient’s therapy. During the first three-day STI, it’s
possible that just the right amount of virus was released
and then controlled to spark the immune system. Then, upon
stopping therapy the second time, the immune system was ready
and waiting, able to control HIV on its own.
Fast-forward: New data
Unfortunately, the Berlin
Patient is still a unique case. No other patient who has taken
an STI, whether in a clinical trial or more discreetly with
a doctor, has come close to achieving this level of success.
But, in light of some new data presented at CROI in early
February, STIs may still offer some benefits.
Dr. Lori presented one study
that received a considerable amount of attention, this time
involving a cohort of nine patients taking hydroxyurea in
combination with ddI, a relatively weak regimen in comparison
to the triple-drug therapies used by most people. For the
sake of seeing what would happen upon stopping therapy, these
patients were compared to a group of eight patients being
treated with a protease inhibitor-based regimen (HAART) who
also elected to do an STI.
Seven of the eight patients
receiving HAART had undetectable viral loads while on therapy.
Within six weeks after the STI, five of these patients saw
their viral load increase to levels above 100,000 copies/mL.
Among patients receiving only hydroxyurea and ddI, only one
of whom had an undetectable viral load while on therapy, none
saw their viral load increase to levels greater than 10,000
copies/mL during the six-week period off treatment.
In discussing these results,
Dr. Lori suggested that hydroxyurea and ddI succeeded in keeping
patients’ viral loads low, but not undetectable. This
allowed for small amounts of the virus to circulate in the
blood and in the lymph nodes, keeping the immune system stimulated
and ready to kick in once therapy was stopped. This might
also explain why the HAART-treated patients saw a dramatic
increase in viral load, along with a decrease in their CD4+
cell counts, after stopping therapy; keeping levels of the
virus low allowed for the immune system to be caught off guard
once therapy was halted.
In another study, Dr. Lydia
Ruiz and her colleagues in Spain randomized 25 patients—all
of whom had undetectable viral loads for more than two years
while on HAART—either to continue on therapy or to undergo
an STI. Therapy was interrupted for 30 days or until patients
saw their viral loads increase to levels greater than 3,000
copies/mL, whichever came first. After 30 days off therapy,
treatment was resumed for an additional 90 days followed by
a second STI.
After the first STI, viral
load failed to rebound in two of the patients during the 30-day
drug holiday. Upon restarting therapy, all patients who took
a drug holiday did so without any problems—their viral
load went undetectable again and it did not appear that any
had developed drug resistance while off therapy. Thus, while
more data are needed to see what happens to the patients’
viral loads and CD4+ cell counts during and after the second
STI, these early results suggest that STIs may be safe. That
is, there does not appear to be any immediate danger associated
with STIs in patients who have undetectable viral loads upon
stopping therapy, at least in these 25 Spanish patients.
Also of interest was a late-breaking
report from an international team comprised of researchers
in New York, Switzerland, and Spain. According to their report,
ten HIV-infected patients treated with HAART for 52 weeks,
all of whom had undetectable viral loads for at least 32 weeks,
underwent three STIs (one month each) separated by six months
of the same triple-drug therapy.
While therapy was stopped
three times during this study, upon restarting therapy, all
patients were able to drive their viral loads to undetectable
levels each time. This helps to confirm Dr. Ruiz’ finding
that STIs may at least be safe for patients with undetectable
viral loads while on therapy. But the news doesn’t stop
there. An interesting thing occurred in four of the nine patients
during the second STI. While their viral loads increased significantly
within a few weeks, the amount of virus in their blood samples
began to drop all by themselves. What’s more, CD4+ and
CD8+ cells collected from these patients during the second
STI had taken on important HIV-specific characteristics that
are not usually present in people who are either on HAART
or have yet to start treatment.
Data from a study conducted
at Massachusetts General Hospital in Boston have also added
to the current level of optimism. Enrolled in this study were
seven newly infected patients who were treated with HAART
and willing to undergo two STIs lasting two months each. After
the first STI, all seven patients saw major increases in their
viral loads. But during the second STI, their viral loads
failed to go any higher than 5,000 copies/mL. According to
the presenters of these results, it seemed as if HAART followed
by STIs during the earliest days of HIV infection could help
preserve necessary components of the immune system needed
to control the virus. Because these immune responses aren’t
usually seen in most HIV-infected patients, these results
are of major interest.
Fast-forward: New data
Now that the foundation has
been laid—we have preliminary data suggesting that STIs
might be safe for people who have been on HAART and have undetectable
viral loads—it’s time to do some heavy-duty research.
It will be important to determine if STIs are safe for people
who have been on anti-HIV therapy and have a detectable viral
load upon deciding to temporarily stop treatment. As for the
potential benefits of STIs, a number of questions remain:
Do STIs help patients recover
from side effects, such as lipodystrophy?
Will STIs help boost the immune
system’s response to HIV for prolonged periods of time?
Will these immune responses help slow HIV’s destructive
activity in the body?
Can STIs be used in combination
with immune-based therapies to help boost the immune system
responses to HIV even more and help patients live longer healthier
lives without anti-HIV drugs?
It’s not entirely clear
if the data presented at CROI will convince anyone of anything.
The results are preliminary and have yet to be duplicated
by large clinical trials. Results of these studies are eagerly
awaited. And while the race is on to address the uncertainties
of STIs, the present message remains clear: do not try a drug
holiday at home, at least not without the cooperation and
direct supervision of a health-care provider.
According to one case report
presented at CROI, an STI can go terribly wrong. The report
came from researchers at the University of Alabama in Birmingham
and involved a patient who secretly stopped therapy due to
financial reasons on the same day he received a vaccination
against the flu. Even though the patient had an undetectable
viral load and a CD4+ count of almost 750 cells/mm3, his viral
load shot up to more than 1 million copies/mL and his CD4+
count dropped to 164 cells/mm3 within three weeks. What’s
more, the patient required hospitalization due to flu-like
symptoms. While the reason for this lightening-fast progression
of HIV disease has not been fully evaluated, it’s likely
that the flu vaccine had a lot to do with it (vaccines have
been shown to have a strong effect on viral load in patients
not taking anti-HIV therapy). Still, this case report warns
that STIs are by no means fail proof, and may in fact be dangerous
in some cases.
Reprinted with permission from the spring
issue of CRIA Notes. Visit www.criany.org.
Tim Horn is the executive editor of The PRN Notebook,
published by Physicians’ Research Network in New York,
and a member of CRIA’s Research Advisory Committee. Editor's
Note: More recent data found 17 new AIDS-related events among
165 German patients undergoing an STI. Visit www.prn.org.
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