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Effect
of Granulocyte Macrophage-colony Stimulating Factor (GM-CSF) on
CD4 Cell Count and Viral Load During Treatment Interruption
In
a previous trial, (Swiss Spanish Intermittent Therapy Trial or SSITT1),
patients had two weeks of treatment interruption, followed by eight
weeks of treatment . After four such
cycles, treatment was permanently interrupted.
Virus
rebound occurred in almost all patients, but then spontaneously
declined. However, only 17% of patients stabilized their viral load
at levels < 5000 HIV RNA copies/ml.
These
results suggest that additional measures are necessary in
order to decrease the viral rebound during treatment interruption.
Cytokines appear to be promising candidates. Several studies have
suggested that GM-CSF may stimulate the immune response to various
antigens.
The aim of this
study was to explore the effect of granulocyte macrophage colony stimulating
factor (GM-CSF) on viral load and CD4 cell count during interruption
of highly active antiretroviral therapy (HAART).
Patients
on effective HAART (CD4 cell count >
400 × 106/l; viral load <
50 HIV RNA copies/ml) were randomized to one of two groups:
(1) 12 weeks' treatment interruption plus, during the first 4 weeks, 300 microgram
GM-CSF (Leucomax-Novartis) by subcutaneous injection three times
weekly (GM-CSF group); or
(2) 12 weeks' scheduled treatment interruption (STI-only group).
Viral load, CD4
cell count, clinical events and side effects of treatment were monitored.
Thirty-three
patients, 15 in the GM-CSF group and 18 in the STI-only group, were
evaluated according to the intention-to-treat principle. The two
groups were well matched with regard to pre-HAART viral loads and
CD4 cell counts.
During STI, viremia
was approximately two to three times lower in the group receiving
GM-CSF (max 4.97 versus 5.45 in STI-only group; P = 0.03).
Fifteen
out of 17 patients in the STI-only group showed a decrease in their
CD4 cell count between weeks 0 and 4 (median decrease 231 ×
106 cells/l; P <
0.001); there was no such tendency in the GM-CSF group (P =
non-significant when comparing CD4 cell counts at weeks 0 and 4).
The median CD4 cell AUC (area under the curve) from week 0
to week 12 was higher in the GM-CSF group (9166 cells.week) than
in patients without GM-CSF (7257), P = 0.02.
GM-CSF
produced local reactions in 88% of patients, and generalized symptoms
such as fever, back pain or headache in 82% of patients. Seventy-six
percent of patients completed the planned course of 12 injections.
The administration of GM-CSF blunted the viral rebound following
interruption of HAART, and largely prevented a decrease of CD4
cell counts during a 12-weeks-treatment interruption.
This pilot study showed that GM-CSF had a favorable effect
on CD4 cell counts during treatment interruption which was evident
during and shortly after its administration during weeks 1-4 of
STI, but appeared to wane by week 12.
Regarding viral load, results also tended to favor the GM-CSF
group. However, the study was small, and not all results reached
statistical significance.
It is uncertain whether the favorable influence of GM-CSF on
HIV surrogate markers can be translated into clinical benefit.
A better understanding of the underlying mechanism(s) may help
to identify synergistic treatment targets and improved administration
protocols to enhance control of chronic HIV infection.
07/04/03
Source
C
Fagard and others (for the Swiss cohort study). A controlled trial
of granulocyte macrophage-colony stimulating factor during interruption
of HAART. AIDS 17(10): 1487-1492. July 4, 2003.
Selected
References
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B
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JAMA 1999, 282:2220-2226.
F
Lori and others. Control
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HIV Clinical Trials 2002, 3:115-124.
A
Oxenius and others. Impact
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A
Oxenius and others. Viral
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G
Skowron and others. The
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Journal of Infectious Diseases 2002, 180:1064-1071.
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