The Safety and Effectiveness of Ganciclovir Used Alone or in Combination With Granulocyte-Macrophage Colony Stimulating Factor in the Treatment of Cytomegalovirus (CMV) of the Eye in Patients With AIDS
Condition: Cytomegalovirus Retinitis; HIV Infections
MeSH terms: Cytomegalovirus Retinitis; Retinitis
Study type: Interventional

Summary: 
      AMENDED: To evaluate the effect of sargramostim ( GM-CSF ) on modulating the granulocytopenia
      associated with concomitant DHPG and AZT therapy ( Phase B ), in terms of time to development
      of granulocytopenia as defined by an absolute neutrophil count ( ANC ) less than or equal to
      750 cells/mm3.

      Original design: To determine if granulocyte-macrophage colony-stimulating factor ( GM-CSF )
      is helpful in preventing the decreased numbers of white blood cells (infection-fighting
      cells) associated with ganciclovir ( DHPG ) therapy and to determine if GM-CSF can be safely
      used in AIDS patients with cytomegalovirus ( CMV ) retinitis.

      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.
    

Detailed description: 
      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.
    

Intervention name(s): Zidovudine; Sargramostim; Ganciclovir
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Zidovudine; Ganciclovir; Ganciclovir triphosphate; Sargramostim
Intervention model: Parallel Assignment
Primary purpose: Treatment
Keywords: Retinitis; Ganciclovir; Drug Evaluation; Drug Therapy, Combination; Cytomegalovirus Infections; Acquired Immunodeficiency Syndrome; Zidovudine