A Controlled, Randomized Phase II Study of the Safety and Efficacy of Combined Therapy With Ganciclovir and Granulocyte-Macrophage Colony Stimulating Factor Versus Ganciclovir Alone for the Treatment of Sight-Threatening Cytomegalovirus Retinitis in AIDS Patients

AMENDED: In ACTG 004, among 11 AIDS patients with CMV infection receiving DHPG maintenance therapy (5 mg/kg, 5x/week) with stable white blood cells (WBC)/absolute neutrophil counts (ANC) 7 (64 percent) required dose reduction or discontinuation of both antiviral medications due to granulocytopenia when AZT (600 mg/day) was added. A mean nadir ANC of 717 cells/ml was reached at a mean of 5 weeks of concomitant DHPG/AZT therapy in these patients. While recovery of depressed ANC occurred following discontinuation of study medications, progressive CMV infection (most commonly retinitis) occurred in 19 of 40 patients and seemed to be associated with DHPG therapy interruption. Only 3 of 40 patients were able to tolerate the complete 16 week study duration of DHPG/AZT. Pharmacokinetic studies of co-administration of DHPG and AZT revealed no significant drug-drug interactions. The study investigators concluded that the main, treatment limiting toxicity of combination DHPG/AZT therapy is granulocytopenia and that many patients treated on this study developed intercurrent OIs or staphylococcal septicemia. In order to determine whether patients receiving maintenance DHPG therapy with or without GM-CSF can tolerate concomitant AZT therapy, extended maintenance therapy with the assigned study regimen in combination with AZT will be incorporated into this protocol. Original design: CMV infection causes inflammation of the retina and can lead to permanent blindness. Treatment for CMV retinitis with DHPG has been shown to be effective in halting the progression of retinal disease. During DHPG treatment, however, about 30 to 55 percent of patients develop decreased white blood cell counts. GM-CSF, a naturally occurring human hormone, stimulates the body's bone marrow to produce more white blood cells. Studies with GM-CSF in AIDS patients have shown that it can significantly increase depressed white blood cell counts in these patients.

AMENDED: Following completion of Phase A, study participants may elect to extend their assigned maintenance therapy (DHPG alone or DHPG/GM-CSF) in combination with AZT therapy (Phase B). GM-CSF dosing will be titrated as above to maintain a target ANC of 2500-5000 cells/mm3. Those patients receiving DHPG/AZT who develop neutropenia (ANC less than 750/ml) on two occasions will begin GM-CSF to maintain a target ANC of 2500-5000 cells/mm3. A similar schedule of clinical, ophthalmologic and laboratory evaluations will be followed in order to determine the efficacy and safety of extended maintenance therapy combined with AZT. Close monitoring of antiviral (CMV, HIV) and immunomodulatory activity will be assessed. This second phase of the study will last for an additional 52 weeks. AMENDED: Extended to 68 weeks. Original design: Patients are hospitalized for a minimum of 7 days to begin treatment for CMV retinitis. They are randomly assigned to one of two groups to receive DHPG either with or without GM-CSF. DHPG is given by intravenous infusion every 12 hours for the first 14 days. DHPG maintenance therapy is then given once a day, 7 days/week for the remaining 14 weeks of the study. For patients in the DHPG with GM-CSF group, the GM-CSF is given by subcutaneous injection for the 16 weeks of the study.