A Comparative Study of a Combination of Zidovudine, Didanosine, and Double-Blinded Nevirapine Versus a Combination of Zidovudine and Didanosine

A Comparative Study of a Combination of Zidovudine, Didanosine, and Double-Blinded Nevirapine Versus a Combination of Zidovudine and Didanosine

To assess the safety and toxicity of zidovudine (AZT)/didanosine (ddI) versus AZT/ddI combined with nevirapine in HIV-infected patients, and to obtain preliminary anti-HIV activity data using immunologic and virologic markers.

Previous in vitro studies suggest that HIV that has already developed resistance to AZT and ddI is less able to develop resistance to nevirapine, a non-nucleoside reverse transcriptase inhibitor. Thus, convergent combination therapy with these three drugs in HIV-infected patients may prove more effective.

Previous in vitro studies suggest that HIV that has already developed resistance to AZT and ddI is less able to develop resistance to nevirapine, a non-nucleoside reverse transcriptase inhibitor. Thus, convergent combination therapy with these three drugs in HIV-infected patients may prove more effective.

Patients are randomized to receive AZT/ddI plus either nevirapine or placebo daily for 48 weeks, with possible extension for at least 12 weeks. At eight participating sites, ACTG 808 and 809 will be conducted as virologic and pharmacokinetic substudies.

Inclusion Criteria

Concurrent Medication:

Required:

• PCP prophylaxis for patients with CD4 count < 200 cells/mm3 or a prior history of PCP.

Allowed:

• Trimethoprim with sulfamethoxazole or dapsone, intravenous pentamidine, atovaquone, primaquine-clindamycin or trimetrexate for acute PCP.
• Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for treatment of mucosal and esophageal candidiasis.
• Prophylaxis or therapy for opportunistic infections, as indicated, with other medications such as itraconazole, isoniazid, pyrazinamide, clofazimine, clarithromycin, azithromycin, ethambutol, amikacin, ciprofloxacin, ofloxacin, pyrimethamine, sulfadiazine, and clindamycin.
• Maintenance therapy for opportunistic infections as long as patients have been on a stable dosage regimen for 1 month prior to study entry.
• Ganciclovir for CMV retinitis or gastrointestinal disease as long as patients have been on a stable dose for at least 1 month prior to study entry with no grade 3 or 4 neutropenia or dependence on G-CSF.
• Acyclovir (<= 1000 mg/day) for maintenance of herpes simplex virus infections.
• Erythropoietin or G-CSF if clinically indicated.
• Antibiotics for bacterial infections unless specifically excluded.
• Rifampin or rifabutin.
• Symptomatic treatments such as antipyretics, analgesics, and antiemetics.

Concurrent Treatment:

Allowed:

• Local radiation therapy.

Prior Medication: Required:

• At least 6 months of prior cumulative nucleoside therapy with AZT, ddI, or ddC, given as monotherapy or in combination.

Patients must have:

• Prior or current documentation of HIV seropositivity by ELISA confirmed by Western blot, positive HIV antigen, or positive HIV culture, or a second antibody test by a method other than ELISA.
• CD4 count <= 350 cells/mm3.
• Prior cumulative nucleoside therapy of >= 6 months.
• Consent of parent or guardian if less than 18 years of age.

Exclusion Criteria

Concurrent Medication:

Excluded:

• Antiretroviral therapies other than study medications.
• Systemic corticosteroids given consecutively for > 21 days.
• Induction or maintenance with foscarnet.
• Systemic cytotoxic chemotherapy for a malignancy.
• Erythromycin.
• Coumadin/warfarin.
• Phenytoin or phenobarbital.
• Amoxicillin/clavulanate acid (Augmentin) or ticarcillin/clavulanate acid (Timentin).

Patients with the following prior conditions are excluded:

• History of pancreatitis.
• History of intolerance to 500 or 600 mg/day AZT or to 400 mg/day ddI tablets or 500 mg/day ddI sachets.
• History of grade 2 or worse peripheral neuropathy.

Prior Medication:

Excluded at any time:

Prior non-nucleoside reverse transcriptase inhibitors (NVP; L697,611; TIBO; atevirdine).

Excluded within 14 days prior to study entry:

• Acute treatment for a serious infection or any opportunistic infection.
• Biologic response modifiers such as interferon and IL-2.
• Erythromycin.
• Coumadin/warfarin.
• Phenytoin or phenobarbital.
• Ticarcillin/clavulanate acid (Timentin) or amoxicillin/clavulanate acid (Augmentin).