The Effectiveness of Three Drug Combinations in HIV-Infected Patients Who Have Taken Zidovudine for More Than 12 Weeks

A Phase II Randomized Study of the Virologic and Immunologic Effects of d4T vs Zidovudine Plus d4T vs Zidovudine Plus Ddl in HIV-Infected Patients With CD4 Cell Counts Between 300-600/mm3 and Greater Than 12 Weeks Zidovudine Experience

To compare the effect of stavudine (d4T) alone or with zidovudine (AZT) versus didanosine (ddI) alone or with AZT on CD4 counts, HIV RNA levels, and viral load in HIV-infected patients [AS PER AMENDMENT 3/21/97: To compare the effects of d4T alone versus ddI alone versus AZT plus ddI]. To compare the safety of d4T/AZT. AS PER AMENDMENT 3/21/97: To evaluate the pharmacokinetic interactions of AZT and d4T both at an extracellular and intracellular level.

Although AZT and ddI can delay the advancement of HIV disease, the benefit of either of these drugs has proven to be only temporary. d4T, a new nucleoside analog with a favorable toxicity profile and demonstrated activity against HIV, offers an additional therapeutic option. It is reasonably assumed that the benefit of an antiretroviral agent in terms of delaying clinical disease progression is directly related to its ability to achieve and sustain viral suppression; thus, this study measures effects on viral load and CD4 count.

Although AZT and ddI can delay the advancement of HIV disease, the benefit of either of these drugs has proven to be only temporary. d4T, a new nucleoside analog with a favorable toxicity profile and demonstrated activity against HIV, offers an additional therapeutic option. It is reasonably assumed that the benefit of an antiretroviral agent in terms of delaying clinical disease progression is directly related to its ability to achieve and sustain viral suppression; thus, this study measures effects on viral load and CD4 count.

Patients are randomized in a blinded fashion to receive AZT or placebo in combination with open-label d4T or ddI for up to 48 weeks. AS PER AMENDMENT 3/21/97: The study is now composed of three arms: open-label d4T versus open-label ddI plus blinded AZT placebo versus blinded AZT plus open-label ddI. Patients originally assigned to the d4T + AZT arm, which was closed 10/96, will be given the option of discontinuing AZT and remaining on d4T monotherapy or discontinuing all study drugs. In addition, all study participants will be asked to participate in a pharmacology substudy.

Inclusion Criteria

Concurrent Medication:

Required for patients whose CD4 count falls below 200 cells/mm3:

• PCP prophylaxis with TMP/SMX, aerosolized pentamidine, or dapsone.

Allowed:

• Atovaquone, IV pentamidine, trimethoprim-dapsone, clindamycin-primaquine, trimetrexate, or TMP/SMX for acute PCP.
• Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for mucosal and esophageal candidiasis.
• Itraconazole.
• Amphotericin B.
• Rifabutin.
• Isoniazid.
• Pyrazinamide.
• Clofazimine.
• Clarithromycin.
• Azithromycin.
• Ethambutol.
• Amikacin.
• Ciprofloxacin.
• Ofloxacin.
• Pyrimethamine.
• Sulfadiazine.
• Clindamycin.
• Ganciclovir.
• G-CSF.
• Acyclovir (up to 1000 mg/day).
• Erythropoietin.
• Antibiotics for bacterial infections.
• Antipyretics.
• Analgesics.
• Antiemetics.
• Rifampin.

Concurrent Treatment:

Allowed:

• Local radiation therapy.

Patients must have:

• HIV infection.
• CD4 count 300-600 cells/mm3.
• More than 12 weeks (was 24 weeks, AMENDED 3/31/96) of total prior AZT ( > 500 mg/day without serious adverse event). Subjects must be actively taking ZDV for at least 4 continuous weeks up to the time of study entry.
• No prior or current history of AIDS.
• No active opportunistic infection.
• Life expectancy of at least 2 years.
• Consent of patient and parent or guardian if less than 18 years of age.

NOTE:

• Protocol is approved for prisoner enrollment.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Malignancy requiring systemic cytotoxic chemotherapy.
• Serious underlying medical condition other than HIV that would reduce life expectancy to < 2 years.

Concurrent Medication:

Excluded:

• Antiretrovirals other than study drugs.
• Foscarnet.

Patients with the following prior conditions are excluded:

• Unexplained temperature >= 38.5 C for 7 days or chronic diarrhea (>= three stools daily) for 15 days, if occurring within 30 days prior to study entry.
• History of acute or chronic pancreatitis.
• History of grade 2 or higher peripheral neuropathy.
• History of grade 3 or worse intolerance to 500-600 mg/day AZT.

Prior Medication:

Excluded:

(within 30 days prior to study entry)

• Prior ddI, ddC, 3TC or d4T (more than 2 weeks total).
• Non-nucleoside reverse transcriptase inhibitor or protease inhibitor.
• Biologic response modifiers such as interferon and IL-2.
• Other experimental therapy.