Randomized, Phase I/II, Dose-Ranging, Open-Label Trial of the Anti-HIV Activity of Delavirdine Mesylate (DLV; U-90,152S)

PRIMARY: To study the safety and tolerance of delavirdine mesylate ( U-90152 ) monotherapy. To compare the anti-HIV activity of three blood concentration levels of this agent with nucleoside analog monotherapy, either zidovudine ( AZT ) or didanosine ( ddI ), based on the reduction of HIV viral burden.

SECONDARY: To use pharmacokinetic parameters to assess the relationship between daily drug exposure and antiviral activity and toxicity of the U-90152, AZT, and ddI monotherapy. To assess anti-HIV activity using other disease markers.

Data suggest that bisheteroarylpiperazines (BHAPs) such as delavirdine mesylate are potent and safe anti-HIV agents and may have different biological behavior than other currently available non-nucleoside RT inhibitors.

Data suggest that bisheteroarylpiperazines (BHAPs) such as delavirdine mesylate are potent and safe anti-HIV agents and may have different biological behavior than other currently available non-nucleoside RT inhibitors.

Patients are randomized to receive U-90152 at one of three doses (treatment arms I through III) or either AZT or ddI (treatment arm IV). Patients on arm IV who are AZT-naive receive AZT; those who are AZT-experienced receive ddI. Treatment continues for 24 weeks.

PER 12/22/94 AMENDMENT: All patients receiving U-90152 have the same starting dose, to attain one of three target trough levels.

Eligibility Criteria:
Inclusion Criteria

Concurrent Medication:

Allowed:

* PCP prophylaxis.
* Topical antifungal agents, clotrimazole troches, nystatin oral suspension, topical ketoconazole, and oral fluconazole.
* Acyclovir (\<= 1000 mg/day) as maintenance therapy for herpes simplex virus.
* Recombinant erythropoietin and G-CSF.
* Antibiotics for bacterial infections, unless specifically excluded.
* Symptomatic treatment such as antipyretics, analgesics, nonsteroidal anti-inflammatory agents, and antiemetics.
* Antacids.

Patients must have:

* HIV-1 infection.
* CD4 count 200 - 500 cells/mm3.
* Either no prior antiretroviral therapy or discontinued AZT monotherapy 3 or more weeks prior to study entry.

NOTE:

* Half of patients should be antiretroviral naive.

Prior Medication:

Allowed:

* Prior AZT.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Malignancy other than minimal Kaposi's sarcoma.

Concurrent Medication:

Excluded:

* Rifabutin.
* Rifampin.
* Terfenadine.
* Astemizole.
* Loratadine.
* Trifluoperazine.
* Piperazine citrate.
* Any acute or chronic therapy for CMV, MAC, toxoplasmosis, or disseminated fungal infection.
* Non-study antiretroviral therapies, interferons, biologic response modifiers, and HIV vaccines.
* 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 pancreatitis (in patients who received prior AZT).
* History of grade 2 or worse peripheral neuropathy (in patients who received prior AZT).
* History of hypersensitivity to BHAP compounds (e.g., trifluoperazine - Stelazine, piperazine citrate - Antepar).

Prior Medication:

Excluded within 30 days prior to study entry:

* Any investigational medication.
* Interferon.
* Interleukin.
* Rifabutin.
* Rifampin.
* Terfenadine.
* Astemizole.
* Loratadine.
* Trifluoperazine.
* Piperazine citrate.

Excluded at any time:

* Prior ddI, ddC, d4T, or 3TC.
* Prior foscarnet.
* Prior BHAP compound or other non-nucleoside RT inhibitor.

Active substance abuse interfering with compliance.