Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression

Objective: To evaluate the effect of adjuvant granulocyte-macrophage colony -stimulating factor (CM-CSF) (sargramostim, yeast-derived recombinant human CM-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 less than or equal to 50 x 10(6)/l o r less than or equal to 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RN A level (greater than or equal to or < 30 000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 mu g or placebo three times p er week for 24 weeks. Subjects were permitted to continue on blinded drug f or up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and surviva l. Results: Three-hundred and nine subjects received at least one dose of stud y drug, 70% completed 24 weeks of therapy. Groups were well matched at base line. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. CM-CSF significantly reduced th e 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 CM-CSF ; P = 0.04). No statistical difference in cumulative opportunistic infectio ns was observed between groups; however, among subjects without an opportun istic infection prior to study, the GM-CSF group demonstrated a trend towar ds fewer subjects with an opportunistic infection on study (26% placebo ver sus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline vira l load < 30 000 copies/ml had changes in antiretroviral therapy for increas ed viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with H IV-RNA levels below the limit of detection at baseline, more GM-CSF patient s maintained an undetectable viral load at 24 weeks (54% placebo versus 83% CM-CSF; P = 0.02). GM-CSF was well tolerated. Conclusions: GM-CSF significantly increased CD4 cell count and decreased vi rological breakthrough and overall infection rate in subjects with advanced HIV disease. (C) 2000 Lippincott Williams & Wilkins.