A Study of Itraconazole in the Treatment and Prevention of Histoplasmosis, a Fungal Infection, in Patients With AIDS
A Study of Itraconazole in the Treatment and Prevention of Histoplasmosis, a Fungal Infection, in Patients With AIDS
To evaluate the feasibility of itraconazole as (1) primary therapy in histoplasmosis and (2)
 maintenance therapy after completion of primary therapy. To evaluate the effect of therapy of
 CNS histoplasmosis. To determine if resistance to drug occurs in patients who fail therapy.

 Histoplasmosis is a serious opportunistic infection in patients with AIDS. Although the
 clinical response to amphotericin B treatment in the AIDS patients is generally good,
 administration difficulties and toxicity detract from its usefulness. Oral treatment with
 ketoconazole overcomes these limitations of amphotericin B, but does not appear to be
 effective for primary treatment in patients with AIDS. Itraconazole is a triazole compound in
 which preclinical studies have demonstrated activity against Histoplasmosis capsulatum.
 Preclinical studies have also shown that itraconazole appears effective in the treatment of
 histoplasmosis. The frequency of adverse reactions to itraconazole has been low in several
 studies. Central nervous system (CNS) involvement occurs in up to 20 percent of patients with
 histoplasmosis, and appears to have a poor response to amphotericin B treatment. Itraconazole
 has been used successfully in a small number of patients with cryptococcal meningitis,
 supporting a study of its use in CNS histoplasmosis.
Histoplasmosis is a serious opportunistic infection in patients with AIDS. Although the
 clinical response to amphotericin B treatment in the AIDS patients is generally good,
 administration difficulties and toxicity detract from its usefulness. Oral treatment with
 ketoconazole overcomes these limitations of amphotericin B, but does not appear to be
 effective for primary treatment in patients with AIDS. Itraconazole is a triazole compound in
 which preclinical studies have demonstrated activity against Histoplasmosis capsulatum.
 Preclinical studies have also shown that itraconazole appears effective in the treatment of
 histoplasmosis. The frequency of adverse reactions to itraconazole has been low in several
 studies. Central nervous system (CNS) involvement occurs in up to 20 percent of patients with
 histoplasmosis, and appears to have a poor response to amphotericin B treatment. Itraconazole
 has been used successfully in a small number of patients with cryptococcal meningitis,
 supporting a study of its use in CNS histoplasmosis.

 At least 30 patients with AIDS and an initial episode of disseminated histoplasmosis are
 selected for this study. Up to 5 patients will have a diagnosis of CNS histoplasmosis.
 Therapy with all other systemic antifungal agents must be halted before study entry. Patients
 receive itraconazole for 3 days followed by daily oral doses for a total of 12 weeks.
 Patients who are doing well clinically, 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. Patients who are being treated for CNS histoplasmosis will
 continue to receive itraconazole.
Inclusion Criteria

 Concurrent Medication:

 Allowed:

 -  Vincristine, vinblastine, bleomycin, or interferon for Kaposi's sarcoma.

 -  Erythropoietin.

 -  Didanosine by exemption for 10 patients.

 -  Barbiturates.

 -  Coumarin-type anticoagulants.

 -  Oral contraceptives.

 -  Digoxin.

 -  Methadone.

 -  Narcotics.

 -  Acyclovir.

 -  Acetaminophen.

 -  Sulfonamides.

 -  Trimethoprim / sulfamethoxazole.

 -  Pentamidine for Pneumocystis carinii pneumonia (PCP) or PCP prophylaxis.

 -  Topical antifungals.

 -  Pyrimethamine.

 -  Ganciclovir.

 -  AZT.

 -  Stress doses of steroids in patients with adrenal insufficiency.

 Concurrent Treatment:

 Allowed:

 -  Dose reduction or interruption of myelosuppressive therapy and transfusion to maintain
 hemoglobin of 7 or more g/dl.

 -  Radiation therapy.

 Patient must:

 -  Show laboratory evidence of HIV infection and disseminated histoplasmosis.

 -  Be oriented to person, place, and time.

 -  Be able to give written informed consent (appropriate consent must be obtained from a
 parent or legal guardian for patients under 18 years of age).

 Allowed:

 -  Abnormal liver function tests in Grade 3 toxicity range if liver biopsy shows evidence
 that histoplasmosis caused these abnormalities.

 -  Mucocutaneous candidiasis.

 Prior Medication:

 Allowed:

 -  Amphotericin B or ketoconazole for pulmonary histoplasmosis at least 3 months prior to
 study entry.

 -  Azidothymidine (AZT).

 -  Vincristine, vinblastine, bleomycin, or interferon for mucocutaneous Kaposi's sarcoma.

 -  Prophylaxis for Pneumocystis carinii pneumonia (PCP).

 Exclusion Criteria

 Co-existing Condition:

 Patients with the following conditions or symptoms are excluded:

 -  Severely ill, or at risk of dying from histoplasmosis within the first week of
 treatment, as indicated by systolic blood pressure less than 90 mm Hg , or PO2 less
 than 60.

 -  Active CNS lesions, malignancies, or infections other than MAI.

 -  Severe malabsorption syndrome (persistent diarrhea more than 4 weeks duration with at
 least 4 loose stools per day accompanied by a 10 percent or greater weight loss).

 -  Requiring cytotoxic therapy for malignancies.

 -  Any systemic fungal infection other than histoplasmosis.

 -  Systemic Mycobacterium avium intracellulare.

 -  Receiving treatment for other acute opportunistic infections whose signs and symptoms
 have not yet resolved or stabilized.

 -  History of allergy to or intolerance of imidazoles or azoles.

 Concurrent Medication:

 Excluded:

 -  All other systemic antifungal agents.

 -  Investigational drugs not specifically allowed.

 -  Oral hypoglycemics.

 -  Rifamycins.

 -  Phenytoin.

 -  Carbamazepine.

 -  Steroids in excess of physiologic replacement doses not specifically allowed.

 -  Cytotoxic chemotherapy.

 -  Discouraged:

 -  Antacids.

 -  Sucralfate.

 -  H2 blockers.

 Patients with the following are excluded:

 -  Severely ill, or at risk of dying from histoplasmosis within the first week of
 treatment.

 -  Active CNS infections, malignancies or lesions not documented to be caused by
 histoplasmosis, which would interfere with assessment of response.

 -  Unable to take oral medications reliably.

 -  Severe malabsorption syndrome.

 -  Requiring cytotoxic therapy for malignancies.

 -  Any systemic fungal infection other than histoplasmosis.

 -  Systemic Mycobacterium avium intracellulare.

 -  Receiving treatment for other acute opportunistic infections whose signs and symptoms
 have not yet resolved or stabilized.

 Prior Medication:

 Excluded for greater than 1 week within the last 3 months:

 -  Fluconazole.

 -  Itraconazole.

 -  SCH 39304.

 -  Amphotericin B greater than 1.5 mg/kg, or any other antifungal for this episode of
 disseminated histoplasmosis.

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