A Phase II Double-Blind Study of Delavirdine Mesylate ( U-90152 ) in Combination With Zidovudine ( AZT ) and/or Didanosine ( ddI ) Versus AZT and ddI Combination Therapy

A Phase II Double-Blind Study of Delavirdine Mesylate ( U-90152 ) in Combination With Zidovudine ( AZT ) and/or Didanosine ( ddI ) Versus AZT and ddI Combination Therapy

To determine the safety and anti-HIV activity of delavirdine mesylate ( U-90152 ) in combination with zidovudine ( AZT ) and/or didanosine ( ddI ) versus AZT/ddI combination.

U-90152 has demonstrated anti-HIV activity. Since the combination of this drug with either AZT or ddI has synergistic inhibitory activity against HIV-1 in vitro, and triple therapy appears to have greater inhibitory activity against HIV-1 in vitro than dual therapy, the use of U-90152 in combination with AZT and/or ddI may improve the benefits of these drugs in persons with HIV disease.

U-90152 has demonstrated anti-HIV activity. Since the combination of this drug with either AZT or ddI has synergistic inhibitory activity against HIV-1 in vitro, and triple therapy appears to have greater inhibitory activity against HIV-1 in vitro than dual therapy, the use of U-90152 in combination with AZT and/or ddI may improve the benefits of these drugs in persons with HIV disease.

Patients are randomized to receive U-90152/AZT/ddI, U-90152/AZT, U-90152/ddI, or AZT/ddI for 48 weeks.

Inclusion Criteria

Concurrent Medication:

Required:

• PCP prophylaxis for patients with CD4 count <= 200 cells/mm3.

Allowed:

• Topical antifungal agents.
• Oral ketoconazole, fluconazole, and itraconazole for candidiasis or disseminated fungal infections.
• Isoniazid, ethambutol, pyrazinamide, clofazimine, ciprofloxacin, and clarithromycin for acute or maintenance therapy for mycobacterial disease (also clarithromycin for MAC prophylaxis).
• Acute or maintenance therapy for toxoplasmosis.
• Acute or maintenance therapy with acyclovir (no more than 1000 mg/day) for herpes simplex virus infection.
• rEPO and rG-CSF.
• Antibiotics for bacterial infections (except rifampin and rifabutin).
• Antipyretics, analgesics, nonsteroidal anti-inflammatory agents, antiemetics, and methadone.

Concurrent Treatment:

Allowed for cutaneous Kaposi's sarcoma:

• Localized radiation therapy.
• Limited intralesional therapy.

Patients must have:

• HIV infection.
• CD4 count 100 - 500 cells/mm3.
• Prior cumulative monotherapy of <= 6 months (may have taken either AZT or ddI, but not both) OR no prior antiretroviral therapy.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Malignancy (other than basal or squamous cell carcinoma of the skin, Stage 1 or 2 cervical intraepithelial neoplasia, or minimal Kaposi's sarcoma).
• Considered to be unlikely to comply with study requirements.

Concurrent Medication:

Excluded:

• Antiretroviral therapies and biologic response modifiers (except for study medications, rEPO, and rG-CSF).
• Rifampin.
• Rifabutin.
• Terfenadine.
• Astemizole.
• Loratadine.
• Quinidine.
• Digitoxin.
• Systemic corticosteroids for more than 21 consecutive days.
• Foscarnet.
• Systemic cytotoxic chemotherapy for a malignancy.

Patients with the following prior conditions are excluded:

• History of intolerance to AZT at <= 600 mg/day or ddI at <= 400 mg/day or discontinuation of either drug for toxicity.
• History of intolerance to trifluoperazine or piperazine citrate (per amendment).
• History of pancreatitis.
• History of grade 2 or worse peripheral neuropathy.
• Unexplained temperature >= 38.5 C on any 7 days within the past 30 days.
• Chronic diarrhea on any 15 days during the past 30 days.

Prior Medication:

Excluded:

• Prior foscarnet as induction or maintenance therapy.
• Prior U-90152.
• Prior ddC or d4T.
• Prior AZT/ddI in combination or taken separately at different times.
• Prior non-nucleoside reverse transcriptase inhibitors (nevirapine, atevirdine, etc.).
• Prior protease inhibitors (although patients from ACTG 282 are eligible).
• HIV-1 vaccine within the past 21 days.
• Acute treatment for a serious infection or for any opportunistic infection within the past 14 days.

Excluded within the past 30 days:

• Interferon or interleukin.
• Rifampin.
• Rifabutin.
• Terfenadine.
• Astemizole.
• Loratadine.
• Recombinant EPO or G-CSF.
• Hydroxyurea.
• SPV-30.
• Any other investigational drug.

Active drug or alcohol use.