Comparison of Three Anti-HIV Drug Combinations in HIV-Infected Patients With No Symptoms of the Disease

A Double-Blinded, Randomized Trial Comparing Zidovudine (AZT) Versus AZT Plus Didanosine (ddI) Versus AZT Plus ddI Plus Nevirapine in Asymptomatic Patients on AZT Monotherapy Who Develop a Mutation at Codon 215 of HIV Reverse Transcriptase in Serum/Plasma Viral RNA

To validate that the alteration of codon 215 of reverse transcriptase in plasma virus precedes the increase in viral burden as measured in the peripheral blood and the decline in CD4 count that have been observed in association with clinical failure on zidovudine (AZT). To determine whether alternative regimens of antiretroviral agents alter the course of viral burden as measured in the peripheral blood and CD4 changes in patients with HIV infection. To obtain further data on the safety and immunologic and virologic response to AZT/didanosine/nevirapine.

Of the HIV-1 mutations reported to be associated with zidovudine resistance, the mutation at codon 215 of the reverse transcriptase gene is the most commonly occurring and has the greatest impact on susceptibility. When this mutation appears, a change in drugs may prevent further immunologic and virologic deterioration.

Of the HIV-1 mutations reported to be associated with zidovudine resistance, the mutation at codon 215 of the reverse transcriptase gene is the most commonly occurring and has the greatest impact on susceptibility. When this mutation appears, a change in drugs may prevent further immunologic and virologic deterioration.

Initially, all patients receive AZT alone. After detection of a 215 mutation in plasma RNA, patients are randomized to one of three treatment arms: AZT alone, AZT plus ddI, or AZT/ddI plus nevirapine. Patients are followed every 8 weeks and receive treatment for up to 4 years.

AS PER AMENDMENT 5/9/96: All AZT monotherapy options have been eliminated. Patients will be randomized to either Arm II or Arm III, regardless of their codon 215 status. All patients who were randomized to Arm I following a mutation at codon 215 will be rerandomized to Arm II or Arm III. All patients who were randomized to either Arm II or Arm III following a mutation at codon 215 will remain on their initial randomized assignment.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Chemoprophylaxis for Pneumocystis carinii pneumonia.
• Antibiotics, antifungals, and antiviral medications, as clinically indicated.
• Regularly prescribed medication such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, or any other medications deemed appropriate by the primary care provider.

Concurrent Treatment:

Allowed:

• Limited localized radiation therapy to the skin.

Prior Medication: Required:

• AZT (minimum 300 mg/day) for at least 1 month (uninterrupted) but no more than 2 years immediately prior to study entry.

Patients must have:

• Asymptomatic HIV infection.
• CD4 count 300-600 cells/mm3.
• No plasma/serum PCR for codon 215 mutation at screening.
• Prior AZT monotherapy.

NOTE:

• All Department of Defense (DOD)-eligible patients must be at least 18 years of age. Enrollment of women is encouraged.

AS PER AMENDMENT 04/03/95:

• DOD female patients must have a negative pregnancy test within 48 hours prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Symptomatic grade 2 or worse peripheral neuropathy.
• Unable to swallow capsules and tablets.
• Other medical condition that contraindicates study participation.

Concurrent Medication:

Excluded:

• Systemic cytotoxic chemotherapy.
• Biologic response modifiers (such as interferon, ampligen, or PEG-IL2).
• Anti-HIV agents other than study drugs.
• Other investigational agents.
• Foscarnet unless clinically indicated for unresponsive herpes virus infection.
• Chronic antacid or H-2 blocker use.
• Rifampin or rifamycin class agents.
• Antibiotics containing clavulanic acid.

Concurrent Treatment:

Excluded:

• Radiation therapy other than limited localized therapy to skin.

Patients with the following prior condition are excluded:

• History of pancreatitis.

Prior Medication:

Excluded:

• Prior therapy with nucleoside or non-nucleoside antiretroviral agents other than AZT.
• Immune modulating therapies (e.g., IFN-alpha, gp160) within 60 days prior to screening.

Prior Treatment:

Excluded:

• Blood transfusion within the preceding 2 weeks.

Illicit drug or alcohol abuse.