Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group.
OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM-CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA, and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III randomized, double-blind, placebo-controlled trial enrolled subjects with CD4 cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 microg or placebo three times per week for 24 weeks. Subjects were permitted to continue on blinded drug for up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three-hundred and nine subjects received at least one dose of study drug, 70% completed 24 weeks of therapy. Groups were well matched at baseline. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. GM-CSF significantly reduced the incidence of overall infections (78% placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative opportunistic infections was observed between groups; however, among subjects without an opportunistic infection prior to study, the GM-CSF group demonstrated a trend towards fewer subjects with an opportunistic infection on study (26% placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA levels below the limit of detection at baseline, more GM-CSF patients maintained an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02). GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell count and decreased virological breakthrough and overall infection rate in subjects with advanced HIV disease.