The Effectiveness of GM-CSF in HIV-Positive Patients Who Are Also Receiving Anti-HIV Therapy

The purpose of this study is to see how HIV-positive patients who are taking anti-HIV drugs and have a viral load (level of HIV in the blood) of 1,500 copies/ml or more respond to GM-CSF (granulocyte-macrophage colony-stimulating factor).

GM-CSF is a medication that is being tested in HIV-positive patients to see if it can improve their immune systems or if it can lower the level of HIV in their blood. GM-CSF is often given to patients with leukemia or patients who have received bone marrow transplants to increase their white blood cells and to improve their immune systems. Doctors believe that GM-CSF can increase CD4 counts in HIV-positive patients, but this study will also look at how GM-CSF affects viral load.

GM-CSF promotes the differentiation and activation of granulocytes, monocytes, macrophages, and dendritic cells and enhances the function of these cells. The various cellular responses (i.e., division, maturation, activation) are induced when GM-CSF binds to specific receptors expressed on the surface of target cells. At higher doses, such as the dose used in this protocol, GM-CSF may result in a rapid rise in white blood cell count. However, further research is necessary to determine the potential antiviral effect of GM-CSF in a potent ART-treated population. It is hoped that GM-CSF can decrease the extent of ongoing HIV replication via alteration of macrophage activation and chemokine receptor expression and that this effect can result in reduction of the pool of latently infected T cells.

Patients are stratified at study entry according to screening CD4 count (below 200 cells/mm3 versus 200 cells/mm3 or higher) and screening HIV-1 RNA copy number (between 1,500 and 10,000 versus 10,000 copies/ml or higher). Then, patients are randomized to receive GM-CSF or GM-CSF placebo subcutaneously 3 times per week for 16 weeks. All patients remain on their current stable potent ART (not provided by this study). During Step 2, all patients receive open-label study treatment, consisting of current potent ART plus GM-CSF subcutaneously 3 times per week for 32 additional weeks. HIV-1 RNA, CD4 counts, and clinical and safety parameters are monitored for all patients periodically until Week 52. Patients who experience an increase in HIV-1 RNA of greater than 1 log 10 from baseline on 2 consecutive determinations or a greater than 50% decrease in CD4 count from baseline (a drop of at least 50 cells) on 2 consecutive determinations at any time during Step 1 or 2 must discontinue all study treatment. Patients who discontinue study treatment for any reason prior to Week 16 continue following the study visit schedule through Week 16.

Additional laboratory samples are performed on patients participating in the immunology substudy (ACTG A5042s) in order to further evaluate the effects of GM-CSF on immune function.

• Drug: Indinavir sulfate
• Drug: Sargramostim

Inclusion Criteria

Patients may be eligible for this study if they:

• Are HIV-positive.
• Have a stable viral load of at least 1,500 copies/ml within 30 days of study entry.
• Are on stable aggressive anti-HIV therapy for at least 8 weeks before study entry and intend to remain on this therapy during the study.
• Agree to learn how to give themselves the GM-CSF shots.
• Agree to practice acceptable barrier methods of birth control (such as condoms) during the study and for at least 12 weeks after treatment ends.
• Are at least 18 years old.

Exclusion Criteria

Patients will not be eligible for this study if they:

• Have an infection or other illness within 14 days of study entry.
• Have certain types of hepatitis within 30 days of study entry.
• Have a fever or chronic diarrhea within 30 days of study entry.
• Have cancer (except for certain types of Kaposi's sarcoma).
• Have heart disease.
• Are allergic to GM-CSF.
• Have received certain medications.
• Are pregnant or breast-feeding.