Pilot Study to Determine the Feasibility of Fluconazole for Induction Treatment and Suppression of Relapse of Histoplasmosis in Patients With the Acquired Immunodeficiency Syndrome

To evaluate the use of fluconazole as (1) induction therapy in histoplasmosis, (2) maintenance therapy to prevent relapse of histoplasmosis.

Histoplasmosis is a serious opportunistic infection in patients with AIDS. Fluconazole is a triazole antifungal agent that has been used successfully in the treatment of experimental histoplasmosis in animals, but has not been completely evaluated in patients for this use. It has been approved by the Food and Drug Administration for certain other fungal infections. Nevertheless, physicians are prescribing it to their patients with histoplasmosis. This is a pilot study to examine the role of fluconazole for treating histoplasmosis in AIDS patients.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Histoplasmosis
• Intervention / Treatment: Drug: Fluconazole

Detailed Description

Histoplasmosis is a serious opportunistic infection in patients with AIDS. Fluconazole is a triazole antifungal agent that has been used successfully in the treatment of experimental histoplasmosis in animals, but has not been completely evaluated in patients for this use. It has been approved by the Food and Drug Administration for certain other fungal infections. Nevertheless, physicians are prescribing it to their patients with histoplasmosis. This is a pilot study to examine the role of fluconazole for treating histoplasmosis in AIDS patients.

At least 40 patients with AIDS and an initial episode of disseminated histoplasmosis are selected for the study. Patients receive fluconazole for a total of 12 weeks. Patients who are unable to take the drug orally may receive it intravenously until oral administration is possible. Patients are evaluated at weeks 0, 1, 2, 4, 8, and 12. Patients who are doing well without evidence of clinical failure or dose-limiting toxicity are permitted to continue maintenance therapy to prevent relapse at a reduced dose for an additional 12 months; those who relapse on the reduced dose are permitted to receive re-induction with a higher dose.

• Study Type: Interventional
• Enrollment: 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 900331079
      • Univ of Southern California / LA County USC Med Ctr
    • San Francisco, California, United States, 94121
      • San Francisco Veterans Administration Med Ctr
  • Indiana
    • Indianapolis, Indiana, United States, 462025250
      • Indiana Univ Hosp
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hosp of Indiana / Life Care Clinic
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Med Ctr of Springfield
    • Worcester, Massachusetts, United States, 01605
      • Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial
  • Missouri
    • Kansas City, Missouri, United States, 641082792
      • Univ of Missouri at Kansas City School of Medicine
    • Kansas City, Missouri, United States, 64132
      • Infectious Diseases Association / Research Med Ctr
    • Saint Louis, Missouri, United States, 63112
      • St Louis Regional Hosp / St Louis Regional Med Ctr
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Med Ctr / Bronx Municipal Hosp
    • Bronx, New York, United States, 10461
      • Montefiore Drug Treatment Ctr / Bronx Municipal Hosp
    • Bronx, New York, United States, 10461
      • Montefiore Family Health Ctr / Bronx Municipal Hosp
    • Bronx, New York, United States, 10461
      • Samaritan Village Inc / Bronx Municipal Hosp
    • Bronx, New York, United States, 10467
      • North Central Bronx Hosp / Bronx Municipal Hosp
    • New York, New York, United States, 10003
      • Beth Israel Med Ctr
    • New York, New York, United States, 10021
      • Cornell Univ Med Ctr
    • New York, New York, United States, 10025
      • Saint Luke's - Roosevelt Hosp Ctr
    • New York, New York, United States, 10029
      • Mount Sinai Med Ctr
  • Ohio
    • Columbus, Ohio, United States, 432101228
      • Ohio State Univ Hosp Clinic
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Julio Arroyo
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Veterans Administration Med Ctr
    • Houston, Texas, United States, 77030
      • Univ TX Health Science Ctr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

• Corticosteroids for up to 21 days at doses no greater than 20 mg/day prednisone (higher doses may be given for shorter durations, if clinically indicated).
• Zidovudine, oral contraceptives, methadone, narcotics, acyclovir, acetaminophen, sulfonamides, trimethoprim/sulfamethoxazole, pentamidine for Pneumocystis carinii pneumonia (PCP) or PCP prophylaxis, topical antifungals, pyrimethamine, ganciclovir.
• Didanosine (ddI), dideoxycytidine (ddC), foscarnet, or other investigational drugs considered to be essential for patient management.

Concurrent Treatment:

Allowed:

• Transfusion.

Patients must have the following:

• HIV infection.
• Histoplasmosis.
• Appropriate consent must be obtained from a parent or legal guardian for patients less than 18 years of age.

Allowed:

• Hematologic and/or renal laboratory abnormalities.
• Concurrent malignancies.
• Concurrent infection with Mycobacteria.
• Patients with severe manifestations of histoplasmosis who are thought to be at risk of dying within one week should receive up to 250 mg amphotericin B for up to seven days prior to enrollment and then be re-evaluated. Patients who are still severely ill and do not meet eligibility criteria may not enter the study.

Specific criteria defining life-threatening histoplasmosis include:

• Systolic blood pressure < 90 mm Hg without other cause; arterial pO2 < 60 torr without other cause; and SGOT > 10 x upper limit of normal or bilirubin > 3 x upper limit of normal. Any other cases not meeting this definition must be reviewed with the protocol chair.

Prior Medication:

Allowed:

• Amphotericin B (up to 250 mg) over 7 days in patients with severe histoplasmosis.

Risk Behavior:

Allowed:

• Patients with a history of high-risk behavior for HIV infection (bisexual or homosexual men, intravenous drug abusers, recipients of blood or blood products prior to May 1985, or sexual partners of any of the foregoing).

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

• Allergy to, or intolerance of, imidazoles or azoles.
• Active hepatitis (viral, drug induced, or other).
• Fungal infections for which the study drug is not indicated (e.g., aspergillosis, mucormycosis).
• CNS/CSF culture positive for pathogens other than H. capsulatum. If C. neoformans is subsequently identified and the patient is improving, the patient may be allowed to remain on study with the permission of the protocol chair.

Concurrent Medication:

Excluded:

• Corticosteroid use for > 21 days at > 20 mg/day of prednisone.
• Systemic antifungals.

Prior Medication:

Excluded:

• Amphotericin B at > 2.5 mg/kg for the current episode of histoplasmosis within 7 days prior to enrollment.
• Suppressive treatment for histoplasmosis or other fungal infections with > 200 mg/day of ketoconazole, fluconazole, or itraconazole, or more than 50 mg amphotericin B twice weekly.

Risk Behavior:

Excluded:

• Patients who the investigator feels would be undependable with regard to adherence to the protocol.

Patients may not have the following prior conditions:

• History of allergy to, or intolerance of, imidazoles or azoles.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Pfizer
• Investigators: Study Chair: Wheat LJ

Publications and helpful links

General Publications

• Wheat J, Vanden Bossche H, Marichal P. Mechanism for resistance of Histoplasma capsulatum to fluconazole. Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:157
• Wheat J, MaWhinney S, Hafner R, McKinsey D, Chen D, Korzun A, Shakan KJ, Johnson P, Hamill R, Bamberger D, Pappas P, Stansell J, Koletar S, Squires K, Larsen RA, Cheung T, Hyslop N, Lai KK, Schneider D, Kauffman C, Saag M, Dismukes W, Powderly W. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group. Am J Med. 1997 Sep;103(3):223-32. doi: 10.1016/s0002-9343(97)00151-4.

Study record dates

Study Major Dates

• Study Completion (Actual): November 1, 1994

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 26, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Fluconazole; Recurrence; Acquired Immunodeficiency Syndrome; Drug Evaluation; Pilot Projects; Histoplasmosis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Bacterial Infections and Mycoses; Mycoses; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Histoplasmosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fluconazole
• Other Study ID Numbers: ACTG 174; R-0245; 11149 (DAIDS ES Registry Number)