Important note: Information in this article was accurate in June 2000. The state of the art may have changed since the publication date.
Although potent anti-HIV therapy can reduce viral load and increase CD4+ and CD8+ cell counts, complete restoration of immune function does not occur. To remedy this situation, doctors are conducting experiments with different products to try and enhance the function and activity of the immune systems's cells. One such product is GM-CSF (granulocyte-macrophage colony-stimulating factor) or sargramostim. Results from a recent North American double-blind, placebo-controlled study in more than 300 HIV-positive subjects suggest that the drug raises CD4+ cell counts, reduces the risk of infections in some PHAs and appears to help suppress viral load when used with anti-HIV drugs.
Researchers in Canada and the United States enrolled 309 HIV-positive subjects (10% female, 90% male) for this study. All subjects were taking anti-HIV therapy and were randomly assigned to receive either of the following products for six months:
At the end of six months, subjects could choose to remain in the study for a further 20 months. At the time they entered the study, subjects had the following profile:
Subjects receiving GM-CSF had increased numbers of lymphocytes and, as a result, more CD4+ cells than those who received placebo. By the sixth month of the study, the increased numbers of CD4+ cells seen in each group was, on average, as follows:
This difference between the two groups was statistically significant. The researchers did not report any changes in CD8+ cells, so it would appear they did not change significantly.
Over the course of the study there was a general trend for the viral load to decline in both the GM-CSF and placebo groups. When the researchers analysed data from subjects who entered the study with fewer than 30,000 copies, however, they found that subjects given GM-CSF were more likely than subjects given placebo to maintain low viral loads throughout the study.
Overall, there was no statistically significant difference in the number of life-threatening infections, specific AIDS-associated complications or deaths seen in either group during the study.
Among subjects who never had a life-threatening infection before entering the trial, the risk of developing such an infection was three times higher in subjects given placebo than in subjects given GM-CSF. This difference was not statistically significant but had the trial been larger it might have become so.
Subjects given GM-CSF took significantly longer to develop their first infection or to die during the study (97 days) compared with those given placebo (56 days). This difference was statistically significant.
According to the study doctors, the drug was "well tolerated," although subjects given GM-CSF were more likely to lose 5% or more of their body weight than subjects given placebo. The proportion of subjects in each group who experienced this complication was as follows:
This difference was statistically significant, that is, not likely due to chance alone.
Taking GM-CSF three times weekly for six months was associated with increased CD4+ cell counts and longer viral load suppression compared to placebo. This effect of GM-CSF on viral load occurred in those subjects who entered the study with fewer than 30,000 copies. How GM-CSF might help suppress viral load is not clear. Those subjects who did not have life-threatening infections before entering the study and who received GM-CSF were much less likely to develop such infections.
Weight loss of 5% or more of body weight, particularly in the form of muscle, may be difficult for PHAs to regain. The fact that nearly twice as many people who received GM-CSF lost this amount of weight compared to those on placebo is troubling and deserves further investigation. This apparent effect of GM-CSF needs to be taken into account before PHAs use the drug.
1. Angel JB, High K, Rhame F, Brand D, et al. Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. AIDS 2000;14(4):387-395.
2. Skowron G, Stein D, Drusano G, et al. The safety and efficacy of granulocyte-macrophage colony-stimulating factor (Sargramostim) added to indinavir- or ritonavir-based antiretroviral therapy: a randomized double-blind, placebo-controlled trial. Journal of Infectious Diseases 1999;180(4):1064-71.
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