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Structured Treatment Interruption Study: final results Swiss Cohort Study
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"A Prospective Trial of Structured Treatment Interruptions in Human
Immunodeficiency Virus Infection"
Archives of Internal Medicine. May 26, 2003. Vol 163, No 10, 1220-1226
Catherine Fagard, MD et al for the Swiss HIV Cohort Study
comments from Jules Levin: This study on STIs has been reported countless
times at conferences as well as when I had the prime auther Bernard Hirschel on
my radio show 2 years ago. The final paper is published this month in this
journal and here is the abstract telling us of the study findings. At this point
the research community and I hope doctors treating patients realize full well
that there is no real evidence that taking structured treatment interruptions
has a significant benefit in terms of stimulating an immune response
(autovaccination) that will control HIV when the patient is off therapy. It is generally
accepted that these interruptions to treatment can, however, be unsafe to
patients. There is a risk that HIV drug resistance can develop, particularly if a
patient is on an NNRTI regimen since NNRTIs remain the blood at decreasing
levels for several days after stopping a regimen. If patients had underlying HIV
drug resistance that is being suppressed by their current regimen, repeated
interruptions of therapy may lead to the emergence of drug resistance. Although
the study described in this article did not find HIV drug resistance as a
problem other studies have found this problem. Studies show that therapy
interuptions can risk CD4 count decreases to levels where patients could be at risk
for opportunistic infections. There is also the risk that once viral load
rebounds off therapy that the patient may not be able to resuppress viral load.
There is no evidence from studies to support that time-limited interruptions of
therapy will have a large and lasting impact on elevated lipids (cholesterol,
triglycerides, etc) or on body changes. If a patient is not going to be
adherent and may therefore develop resistance to the HAART regimen they are on it may
be of benefit to consider an interruption. If a patient wants to interrupt
therapy it is important to discuss it with the doctor/care provider and to be
aware of the risks involved. Many patients started HAART when their CD4 counts
were over 500 because the older Public Health Service Guidelines recommended
that. More recent Guidelines recommend HAART when CD4s are 350. Of course when
to begin therapy is a personal decision between patient and doctor. Some prefer
to begin therapy earlier and some prefer to delay therapy. There are few
clear answers regarding the long-term benefits and outcomes regarding health and
survival based on when a person starts therapy. Studies have found that waiting
to begin therapy until CD4s are 200 can have increased risks to long-term
outcome. Some studies show that patients beginning therapy when CD4s are over 500
have better longer-term outcomes in terms of health & survival. While some
studies show that waiting until CD4s are 350 yields similar outcomes as
beginning at 500. However, if a patient started therapy when CD4s were 500 or more
because the PHS Guidelines recommended that the considerations in whether to
interrupt therapy may be different than described above regarding STIs in other
types of situations. There may still be risks regarding HIV drug resistance.
According to the "autovaccination hypothesis," reexposure to human
immunodeficiency virus
(HIV) during treatment interruptions may stimulate the HIV-specific immune
response and lead to low viremia after withdrawal of highly active
antiretroviral treatment (HAART). Many patients who started HAART earlier in their disease
course than is currently recommended would like to discontinue, but it is
unknown whether it is safe to do so.
The study objective was to determine whether repeated treatment interruptions
of HAART (1) stimulated the cytotoxic HIV-specific immune response and
whether such stimulation correlated with low viremia off treatment, and (2) were
safe with respect to clinical complications, development of viral resistance, and
decline in CD4 cell counts. The study was conducted at outpatient clinics of
university hospitals in Switzerland and Spain. A total of 133 patients
receiving HAART, with a median CD4 cell count of 740/µL, and whose viral load had
been undetectable for a median of 21 months.
HAART was interrupted for 2 weeks, restarted, and continued for 8 weeks.
After 4 such cycles, treatment was indefinitely suspended 40 weeks after study
entry.
Measures HIV-specific cytotoxic T-cell responses were evaluated by
interferon enzyme-linked immunospot analysis. The proportion of "responders" (viral
load <5000 copies/mL) was measured at weeks 52 and 96. HIV-related diseases and
CD4 cell counts were recorded.
Seventeen percent of patients (95% confidence interval, 11%-25%) were
responders at week 52, and 8% at week 96. Low pre-HAART viral load and lack of
rebound during weeks 0 to 40 predicted response. HIV-specific CD8+ T cells increased
between week 0 (median, 343 spot-forming cells per million peripheral blood
lymphocytes [SFC/106 PBL]) and week 52 (median, 1930 SFC/106 PBL), but there
was an inverse correlation between response and the number of spot-forming
cells. Eighty-five (64%) of 133 patients stopped therapy for at least 12 weeks, and
55 (41%) for at least 56 weeks. The median CD4 cell count decreased from
792/µL to 615/µL during
the first 12 weeks without treatment, but stabilized thereafter. One patient
(0.75%) developed drug resistance necessitating salvage treatment. There were
no AIDS-related clinical complications.
The study authors concluded that the results of this study do not favor the
autovaccination hypothesis. Treatment interruptions did not provoke clinical
complications, and there was little drug resistance. Comparative trials will
have to show what benefit, if any, is associated with
intermittent, as opposed to continuous treatment.
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