The Safety and Effectiveness of Lamivudine Plus Stavudine or Zidovudine in HIV-Infected Patients Who Have Taken Zidovudine

A Randomized Double-Blind Study of Safety, Virologic and Immunological Effects of Stavudine Plus Lamivudine (3TC) Versus Zidovudine Plus Lamivudine in HIV-Infected Subjects Following At Least Six Months of Zidovudine Therapy

To compare the magnitude and durability of the reduction in plasma HIV RNA in the two treatment groups over the first 12 weeks of treatment. To determine the safety of each of the two treatment groups.

Patients will be randomized to either Stavudine (d4T) + Lamivudine (3TC) + Zidovudine placebo or Zidovudine (ZDV) + Lamivudine + Stavudine placebo. Patients whose plasma HIV RNA levels remain >= 500 copies/ml after 8 weeks of blinded double combination therapy will have indinavir added to their treatment regimen at the week 12 visit.

Inclusion Criteria

Patients must have:

• At least six months of prior cumulative ZDV therapy.
• Qualifying plasma HIV RNA count of >= 4 log10 copies/ml obtained within 2 weeks of randomization.

Exclusion Criteria

Co-existing Condition:

Patients with any of the following symptoms or conditions are excluded:

• Presence of newly diagnosed AIDS defining opportunistic infection requiring acute therapy at time of enrollment.
• Intractable diarrhea (>= 6 loose stools/day for >= 7 consecutive days).
• Signs and symptoms of bilateral peripheral neuropathy >= grade 2 at the time of screening.
• Inability to tolerate oral medication.
• Any other clinical conditions that in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.

Concurrent Medication:

Excluded:

• Therapy with agents with systemic myelosuppressive, neurotoxic pancreatotoxic, hepatotoxic or cytotoxic potential.
• Therapy with rifampin, rifabutin, terfenadine, astemizole, cisapride, triazolam, midazolam and ketoconazole at any time while on indinavir therapy.

Patients with any of the following prior conditions or symptoms are excluded:

• History of acute or chronic pancreatitis.
• Prior history of bilateral peripheral neuropathy.
• Intractable diarrhea (>= 6 loose stools/day for >= 7 consecutive days) within 30 days prior to study entry.

Prior Medication:

Excluded:

• Any prior antiretroviral therapy except for ddI, ddC, 3TC or ZDV (for ZDV, as specified in inclusion criteria).
• Previous therapy with agents with significant systemic myelosuppressive, neurotoxic pancreatotoxic, hepatotoxic or cytotoxic potential within 3 months of study start.
• Therapy with rifampin, rifabutin, terfenadine, astemizole, cisapride, triazolam, midazolam and ketoconazole within 2 weeks prior to starting indinavir.
• Any other prior therapy that, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing regimen.

Risk Behavior:

Excluded:

• Active alcohol abuse, sufficient in the investigator's opinion, to prevent compliance with study therapy or to increase the risk of developing pancreatitis.

Required:

At least 6 months of prior cumulative ZDV therapy.