To determine the effects of fluconazole and either rifabutin or clarithromycin, alone and in combination, on the pharmacokinetics of first sulfamethoxazole-trimethoprim and then dapsone in HIV-infected patients. Although prophylaxis for more than one opportunistic infection is emerging as a common clinical practice in patients with advanced HIV disease, little is known about possible adverse drug interactions. The need exists to define pharmacokinetics and pharmacodynamic adverse interactions of the many combination prophylactic regimens that may be prescribed.

Condition	Treatment or Intervention	Phase
Bacterial Infections Mycoses HIV Infections	Drug: Clarithromycin  Drug: Rifabutin  Drug: Sulfamethoxazole-Trimethoprim  Drug: Dapsone  Drug: Fluconazole	Phase I

Further Study Details: 

Expected Total Enrollment:  48

Although prophylaxis for more than one opportunistic infection is emerging as a common clinical practice in patients with advanced HIV disease, little is known about possible adverse drug interactions. The need exists to define pharmacokinetics and pharmacodynamic adverse interactions of the many combination prophylactic regimens that may be prescribed.

In Part A, patients receive sulfamethoxazole-trimethoprim (SMX/TMP) alone for 2 weeks, then in combination with fluconazole, rifabutin, or both drugs, each over 2-week periods in a randomly assigned order. Patients in Part B receive the same regimens except with clarithromycin substituted for rifabutin. In Part C, patients receive dapsone alone for 2 weeks, then in combination with fluconazole, rifabutin, or both drugs in the same manner as in Part A. Part D patients receive the same regimen as those in Part C, except with clarithromycin substituted for rifabutin. Patients are followed every 2 weeks.

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Concurrent Medication: Allowed:

• Antiretroviral therapy provided patient has been on a stable dose for at least 4 weeks prior to study entry.
• Methadone for drug abuse programs provided patient has been on a stable dose for at least 4 weeks prior to the study.

Patients must have:

• HIV infection.
• CD4 count >= 200 cells/mm3.
• No active opportunistic infection.

Prior Medication: Allowed:

• Antiretroviral therapy.
• Methadone for drug abuse therapy.

Exclusion Criteria

Co-existing Condition: Patients with the following symptoms or conditions are excluded:

• Suspicion of gastrointestinal malabsorption problems (at discretion of investigator).
• Known hypersensitivity to dapsone, SMX, or other sulfonamides, trimethoprim, clarithromycin, rifabutin or other rifamycins, fluconazole, or other azoles.
• G-6-PD deficiency or methemoglobinemia (in Part C and D patients only). Concurrent Medication: Excluded:
• Cytolytic agents.
• Amiodarone.
• Anesthetics, general.
• Astemizole.
• Azithromycin.
• Barbiturates.
• Carbamazepine.
• Cimetidine.
• Ciprofloxacin.
• Cisapride.
• Clarithromycin (except as required on study).
• Clotrimazole.
• Dexamethasone.
• Disulfiram.
• Erythromycin.
• Fluoroquinolones.
• Fluoxetine.
• Gestodene.
• Hydrochlorothiazide.
• Hypoglycemics, oral.
• Isoniazid.
• Itraconazole.
• Ketoconazole.
• Levomepromazine.
• Loratadine.
• MAO inhibitors.
• Methoxsalen.
• Miconazole.
• Nafcillin.
• Narcotic analgesics.
• Naringenin.
• Nifedipine.
• Norethindrone.
• Pentazocine.
• Phenothiazines.
• Phenytoin.
• Protease inhibitors.
• Quinidine.
• Ranitidine.
• Rifabutin (except as required on study).
• Rifampin.
• Sedative hypnotics.
• Sulfaphenazole.
• Terfenadine.
• Tranquilizers (unless allowed by investigator).
• Tricyclic and tetracyclic antidepressants.
• Troleandomycin.
• Warfarin.

Concurrent Treatment: Excluded:

• Radiation therapy.

Prior Medication: Excluded:

• Cytolytic agents within 5 years prior to study entry.
• Rifabutin and/or rifampin within 4 weeks prior to study entry.
• Fluconazoles or other azoles within 4 weeks prior to study entry.
• Glutathione, glutathione precursors, or related prodrugs within 2 weeks prior to study entry.

Excluded within 72 hours prior to study entry:

• Amiodarone.
• Anesthetics, general.
• Astemizole.
• Azithromycin.
• Cimetidine.
• Ciprofloxacin.
• Cisapride.
• Clarithromycin.
• Dexamethasone.
• Disulfiram.
• Erythromycin.
• Fluoroquinolones.
• Fluoxetine.
• Hydrochlorothiazide.
• Hypoglycemics, oral.
• Isoniazid.
• Levomepromazine.
• Loratadine.
• MAO inhibitors.
• Methoxsalen.
• Nafcillin.
• Narcotic analgesics.
• Naringenin.
• Nifedipine.
• Norethindrone.
• Pentazocine.
• Phenothiazines.
• Phenytoin.
• Protease inhibitors.
• Quinidine.
• Ranitidine.
• Sedative hypnotics.
• Sulfaphenazole.
• Terfenadine.
• Tranquilizers (unless allowed by investigator).
• Troleandomycin.
• Warfarin.

Excluded within 4 weeks prior to study entry:

• Barbiturates.
• Carbamazepine.
• Clotrimazole.
• Gestodene.
• Itraconazole.
• Ketoconazole.
• Miconazole.
• Omeprazole.
• Rifabutin.
• Rifampin.
• Tricyclic and tetracyclic antidepressants.

Prior Treatment: Excluded:

• Blood transfusion within 1 week prior to study entry.
• Radiation therapy within 5 years prior to study entry.

Active drug or alcohol abuse or dependence that would preclude completion of study.

California
      San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States
District of Columbia
      Georgetown Univ Med Ctr, Washington,  District of Columbia,  20007,  United States
Tennessee
      Meharry Med College, Nashville,  Tennessee,  37203,  United States
Washington
      Univ of Washington, Seattle,  Washington,  981224304,  United States

Study chairs or principal investigators

Unadkat J,  Study Chair
Trapnell CB,  Study Chair

Study ID Numbers:  ACTG 283
Record last reviewed:  February 2003
Last Updated:  December 6, 2004
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000826
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08