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Prevention of Relapse of Histoplasmosis with Itraconazole in Patients with the Acquired Immunodeficiency Syndrome

Joseph Wheat, MD; Richard Hafner, MD; Michael Wulfsohn, MD, MS; Patricia Spencer, MD; Kathleen Squires, MD; William Powderly, MD; Brian Wong, MD; Michael Rinaldi, PhD; Michael Saag, MD; Richard Hamill, MD; Robert Murphy, MD; Patricia Connolly-Stringfield, BS; Necia Briggs, BS; Susan Owens, MSN, National Institute of Allergy and Infectious Diseases Clinical Trials and Mycoses Study Group Collaborators*
[+] Article, Author, and Disclosure Information

From Indiana University School of Medicine and Richard L. Roudebush Veterans Affairs Hospital, Indianapolis, Indiana; National Institutes of Health, Bethesda, Maryland; Harvard School of Public Health, Newton, Massachusetts; Cornell University, New York, New York; Washington University, St. Louis, Missouri; University of Cincinnati College of Medicine, Cincinnati, Ohio; University of Texas Health Science Center, San Antonio, Texas; Department of Veterans Affairs Medical Center, Birmingham, Alabama; Department of Veterans Affairs Medical Center, Houston, Texas; Northwestern University Medical School, Chicago, Illinois; Frontier Science and Technical Research Foundation, Amherst, New York. Requests for Reprints: Joseph Wheat, MD, Indiana University School of Medicine, Wishard Memorial Hospital, Room OPW430, 1001 West Tenth Street, Indianapolis, IN 46202-2879. Grant Support: In part by the Division of AIDS of the National Institutes of Allergy and Infectious Diseases; National Institutes of Allergy and Infectious Diseases Mycoses Study Group contract 1-AI-15082; and the Department of Veterans Affairs.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;118(8):610-616. doi:10.7326/0003-4819-118-8-199304150-00006
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Objective: To assess the efficacy and safety of itraconazole in preventing relapse of histoplasmosis after induction therapy with amphotericin B in patients with the acquired immunodeficiency syndrome (AIDS) and disseminated histoplasmosis.

Design: A prospective, multicenter, open-label clinical trial, with follow-up for at least 52 weeks.

Setting: Tertiary care hospitals participating in a clinical investigation sponsored by the National Institutes of Allergy and Infectious Diseases (AIDS Clinical Trial Group and Mycoses Study Group).

Patients: Forty-two patients with AIDS who had successfully completed induction therapy for disseminated histoplasmosis amphotericin B, at least 15 mg/kg body weight given over 4 to 12 weeks.

Interventions: Itraconazole, 200 mg given orally twice daily.

Main Outcome Measures: Response to therapy, specifically prevention of histoplasmosis relapse, was the main outcome measure. Secondary end points were survival and the effect of therapy on Histoplasma capsulatum variety capsulatum antigen levels in urine and serum. Plasma itraconazole concentrations were measured to document drug absorption and compliance with therapy.

Results: The median follow-up was 109 weeks, and median survival was 98 weeks. Two relapses occurred (5%; 95% CI, 0.5% to 16%), one in a patient withdrawn from the study 18 weeks earlier and one in a patient who did not comply with the study therapy. Patients with elevated antigen levels at study entry showed clearance of antigen from urine and serum; urine specimens became negative in 43% of patients (CI, 26% to 59%), and serum specimens became negative in 75% of patients (CI, 56% to 94%). Only one patient discontinued treatment because of itraconazole toxicity (hypokalemia).

Conclusions: Itraconazole, 200 mg twice daily, is safe and effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. Antigen clearance from blood and urine correlates with clinical efficacy.

* For a list of other contributors to the study, see end the Appendix.


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Figure 1.
Kaplan-Meier estimates of survival and relapse.

The numbers in parentheses along the x-axis refer to number of patients still taking the study drug at that week of follow-up. Twenty-one patients were still living at the time of the analysis, and 17 were still receiving study medication.

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Figure 2.
Histoplasma capsulatum var. capsulatum in serum and urine.

Initial antigen levels and final levels after 1 year of treatment (or at withdrawal from study if sooner) are shown for individual patients. The number of patients with negative results at enrollment and at follow-up is represented by the thick bar at the bottom of the figure.

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Figure 3.
Plasma itraconazole concentrations as a function of time after drug administration.

The analysis is based on 254 observations in patients receiving itraconazole, 200 mg twice daily. The horizontal lines through the bars represent the median concentrations; the upper and lower ends of the bars represent the 5th and 95th percentile, respectively; and the vertical lines extend to 1.5 times the interquartile range of concentrations. The number at the bottom of the bar represents the number of observations at that time after administration.

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