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Treatment
Interruptions in Chronic HIV Infection
Adverse
side effects, viral resistance, and the high cost of antiretroviral
therapies remain obstacles in the way of turning HIV/AIDS into a
manageable chronic disease. Structured treatment interruptions (STIs)
in individuals who have good viral control on therapy have been
proposed as a strategy for overcoming these obstacles.
The
initial hope that STIs would help patients achieve greater viral
control has so far not been supported by data from clinical trials,
but interrupting treatment has also been proposed as a strategy
to reduce the cost of long-term therapy and drug-associated toxicity.
Luis
Montaner and colleagues now report results from a randomized trial
of 42 participants (75% on their second to fourth regimen, 66% on
regimens containing non-nucleoside reverse-transcriptase inhibitors)
who received either continuous therapy for 40 weeks or three successive
treatment interruptions of two, four, and six weeks, followed by
a final open-ended interruption for both groups.
The
study (view article) was designed to be able to detect a difference of
four weeks or greater between the two groups for the time to viral
rebound during the open-ended interruption—the primary
outcome. No difference between the two groups was seen (median time
for the group on continuous treatment was four weeks, and for the
STI group was five weeks).
Secondary
outcomes included serious adverse events (disease
progression, acute
retroviral syndrome, therapy
failure, or opportunistic
infections at any point in the study), changes in
CD4 count on therapy,
immune reconstitution changes (CD4 recall responses and CD4 naïve/memory
T cell distribution), and detection of viral mutations
There
were no study-related serious
adverse events in either group and no increase of
therapy failure in the STI arm. CD4 counts fluctuated between the
start and end of each monitored treatment interruption, but levels
recovered after resuppression of virus, with retention of recall
responses throughout.
Viral resistance
was detected in
both groups (in seven of 21 patients in the continuous treatment
group and ten of 21 patients in the STI group), but it was more
commonly detected (50% versus 18%) in the STI group during the open-ended
final interruption, even though all subjects suppressed virus upon
reinitiating the same therapy.
Possible
risks and benefits of STIs remain controversial, but data from this
and other published trials do not support short-term clinical benefits
of treatment interruptions. However, because they do not see increased
therapy
failure and find preservation of immune function
in the STI group, the authors conclude that, in light of the possibility
of reducing costs and drug-related toxicity, additional trials of
STIs are warranted.
Particularly
important in the debate over the safety of STIs is whether the detection
of resistant mutants
should be of concern. The authors point out that all participants
were able to resuppress the mutant virus when they resumed their
previous drug regimens but state that it remains undetermined to
what extent resistant mutations are a signal for future therapy
failure. Moreover, viral replication and rebound—which eventually
occurred in all participants—is seen by some researchers as inherently
detrimental, and these experts argue that treatment interruptions
are unsafe and their use should be discontinued.
In
conclusion, the authors write, “What seems clear is that STIs have
no place outside controlled clinical trials and that questions regarding
long-term safety remain unanswered. At least a dozen additional
trials that examine STIs are currently recruiting patients and will
help answer these questions.”
01/19/04
Reference
Treatment
Interruptions in Chronic HIV Infection. Treatment Interruptions
in Chronic HIV Infection. PLoS Medicine 1(3): e70. December
2004.
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