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JID 2000;182 (November)
groups (21% for placebo and 32% for GM-CSF; P p .20). Ad-
mission diagnoses included infections (8 for placebo and 9 for
GM-CSF), adverse events (5 for placebo and 7 for GM-CSF),
and other (2 for placebo and 2 for GM-CSF).
Two deaths (1 suicide and 1 disease progression) occurred
during the 6 months on study, both in the GM-CSF group.
Survival for both groups was also similar at 1 year (36 [69%]
of 52 placebo vs. 36 [68%] of 53 GM-CSF). Kaplan-Meier
analysis demonstrated no differences in survival between
groups.
Safety. No difference was observed in the incidence of
fever; hematologic, hepatic, or renal function toxicities; or with-
drawals because of adverse events (table 3). Flulike syndrome
(15% vs. 4%) and injection site reactions (30% vs. 2%) were
more frequent with GM-CSF, though nearly all were mild
(grade 1–2).
Subject withdrawal was similar between groups (13/52 pla-
cebo and 15/53 GM-CSF). Adverse events accounted for only
7 subject withdrawals: 2 in the placebo group (1 anemia and
1 thrombocytopenia) and 5 in the GM-CSF group (1 confusion
and 4 anemia). The remaining subjects were withdrawn because
of disease progression or death (4 per group), noncompliance
(3 per group), loss to follow-up (2 per group), and reasons listed
as “other” (2 placebo and 1 GM-CSF).
azido-nucleoside active metabolites and thus augment the an-
tiviral activity of zidovudine and stavudine [5, 6]. Second, mac-
rophages activated with GM-CSF, but not M-CSF or G-CSF,
have been shown to resist infection with macrophage-tropic
strains of virus both by down-regulating of CCR5 and CXCR4
chemokine receptor expression on monocyte-derived macro-
phages and by inducing the monocyte/macrophages to secrete
b-chemokines that competitively inhibit HIV entry in bystander
CD4 T cells [7–9]. Finally, GM-CSF has been shown to aug-
ment host defenses. Further studies are needed to determine
the mechanism by which GM-CSF exerts an antiviral effect.
Although the incidence of OIs and survival at 6 months and
1 year were similar between groups, it is important to note that
the GM-CSF group had a greater risk of infections and mor-
tality based on baseline CD4 cell count, proportion of subjects
with CD4 cell counts !50 cells/mL, and history of OIs before
the study. In fact, GM-CSF subjects who did not have a history
of OIs before the study did not develop OIs during the study,
unlike placebo subjects.
This study demonstrates that GM-CSF may be a novel bio-
logical agent for treating HIV disease. Studies are needed to
evaluate GM-CSF in combination with HAART and longer
courses of therapy and to determine the effects of GM-CSF
on viral reservoirs and immune recovery.
Acknowledgments
Discussion
We thank N. McDonnell, J. Enzweiler, and A. Mongillo (Immunex
Corporation, Seattle), for countless hours of assistance in data collec-
tion and analysis and manuscript preparation, and Robert Schooley
(University of Colorado, Health Science Center, Denver), for reviewing
the manuscript. We are also indebted to all staff members of the Uni-
dade Docente de Infectogia, Universidade Federal da Bahia/Brazil, for
assistance with subjects, as well as Miriam Carvalho, from Curitiba,
Brazil.
This is the first clinical study to demonstrate conclusively
that GM-CSF can significantly suppress plasma viremia in
adults with AIDS receiving nucleoside analogues. Virus load
fell to !500 copies/mL in a greater number of GM-CSF-treated
subjects, which suggests that the reduction in virus load with
GM-CSF may be clinically significant. Also, significantly fewer
zidovudine-resistant mutations developed during treatment,
which suggests that GM-CSF may extend the effectiveness of
antiretroviral therapy by delaying viral breakthrough. This ef-
fect is likely a direct consequence of the greater decrease in
virus load observed in the treatment group.
References
1. Cohen OJ, Fauci AS. Transmission of multidrug-resistant human immuno-
deficiency virus: the wake-up call. N Engl J Med 1998;339:341–3.
2. Esser R, Glienke W, Andreesen R, et al. Individual cell analysis of the cytokine
repertoire in human immunodeficiency virus–1-infected monocytes/mac-
rophages by a combination of immunocytochemistry and in situ hybrid-
ization. Blood 1998;91:4752–60.
3. Barbaro G, Di Lorenzo G, Grisorio B, Soldini M, Barbarini G. Effect of
recombinant human granulocyte-macrophage colony-stimulating factor
on HIV-related leukopenia: a randomized, controlled clinical study. AIDS
1997;11:1453–61.
4. Bernstein ZP, Brooks S, Hayes FA, Gould M, Jacob S, Tomasi TB. A pilot
study in the use of GM-CSF in human immunodeficiency virus infected
individuals. Blood 1997;90(Suppl 1):133a [abstract 584].
5. Perno CF, Yarchoan R, Cooney DA, et al. Replication of human immu-
nodeficiency virus in monocytes: granulocyte-macrophage colony-stimu-
lating factor (GM-CSF) potentiates viral production yet enhances the
antiviral effect mediated by 3’-azido-2’3’-dideoxythymidine (AZT) and
The anti-HIV effect of GM-CSF may be distinct from anti-
retroviral agents. Typically, antiretroviral agents produce a
rapid fall in virus load during the first 3–10 weeks of therapy,
followed by an increase in plasma viral RNA due to the de-
velopment of resistant phenotypes or difficulty in regimen ad-
herence [14–17]. In contrast, GM-CSF therapy produced a
steady decline in virus load that did not appear to have reached
a plateau by 6 months of treatment. These data raise the pos-
sibility that longer courses of therapy may produce further de-
creases in viral burden or permit reductions in antiretroviral
therapy.
In vitro studies have demonstrated several mechanisms by
which GM-CSF may reduce virus production. First, GM-CSF
has been reported to increase the intracellular concentration of
Naito
