Safety and Efficacy of Liposomal Amphotericin B Compared with Conventional Amphotericin B for Induction Therapy of Histoplasmosis in Patients with AIDS

Safety and Efficacy of Liposomal Amphotericin B Compared with Conventional Amphotericin B for Induction Therapy of Histoplasmosis in Patients with AIDS

Philip C. Johnson, MD;
L. Joseph Wheat, MD;
Gretchen A. Cloud, MS;
Mitchell Goldman, MD;
Dan Lancaster, MD;
David M. Bamberger, MD;
William G. Powderly, MD;
Richard Hafner, MD;
Carol A. Kauffman, MD;
William E. Dismukes, MD; and
for the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group*

From the University of Texas–Houston Medical School, Houston, Texas; Indiana University School of Medicine and Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; University of Alabama at Birmingham, Birmingham, Alabama; Methodist Hospital, Memphis, Tennessee; University of Missouri–Kansas City, Kansas City, and Washington University School of Medicine, St. Louis, Missouri; National Institute of Allergy and Infectious Diseases Mycoses Study Group, National Institutes of Health, Bethesda, Maryland; and Veterans Affairs Medical Center and University of Michigan Medical School, Ann Arbor, Michigan.

Abstract

Background: In patients with moderate to severe histoplasmosis associated with AIDS, the preferred treatment has been the deoxycholate formulation of amphotericin B. However, serious side effects are associated with use of amphotericin B.

Objective: To compare amphotericin B with liposomal amphotericin B for induction therapy of moderate to severe disseminated histoplasmosis in patients with AIDS.

Design: Randomized, double-blind, multicenter clinical trial.

Setting: 21 sites of the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group.

Patients: 81 patients with AIDS and moderate to severe disseminated histoplasmosis.

Measurements: Clinical success, conversion of baseline blood cultures to negative, and acute toxicities that necessitated discontinuation of treatment.

Results: Clinical success was achieved in 14 of 22 patients (64%) treated with amphotericin B compared with 45 of 51 patients (88%) receiving liposomal amphotericin B (difference, 24 percentage points [95% CI, 1 to 52 percentage points]). Culture conversion rates were similar. Three patients treated with amphotericin B and one treated with liposomal amphotericin B died during induction (P = 0.04). Infusion-related side effects were greater with amphotericin B (63%) than with liposomal amphotericin B (25%) (P = 0.002). Nephrotoxicity occurred in 37% of patients treated with amphotericin B and 9% of patients treated with liposomal amphotericin B (P = 0.003).

Conclusion: Liposomal amphotericin B seems to be a less toxic alternative to amphotericin B and is associated with improved survival.

*For a list of study investigators and numbers of patients enrolled, see Appendix.

Article and Author Information

Note: This work was presented in part at the 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, California, 31 January 2000.
Acknowledgments: The authors thank Deanne Fuller, Dr. Tom Davis, and Ann LeMonte for laboratory work; Estella C. Wheatley for preparation of the manuscript; and Cynthia R. Flanigan for help with the management of the data over the course of the clinical trial.
Grant Support: In part by a grant from the National Institute of Allergy and Infectious Diseases to the Mycoses Study Group (contract NO1-A1-15802) and by a grant from the National Center for Research Resources, General Clinical Research Center (contract MO1-RR02558) to participating centers, and by Gilead Sciences, Inc. (formerly NeXstar Pharmaceuticals).
Requests for Single Reprints: Philip C. Johnson, MD, University of Texas–Houston Medical School, Division of General Medicine, 6431 Fannin, MSB 1.122, Houston, TX 77030; e-mail, Philip.C.Johnson{at}uth.tmc.edu.
Current Author Addresses: Dr. Johnson: Division of General Medicine, University of Texas–Houston Medical School, 6431 Fannin, MSB 1.122, Houston, TX 77030.
Dr. Wheat: Indiana University School of Medicine, OPW 430, 1001 West 10th Street, Indianapolis, IN 46202-2879.
Ms. Cloud: University of Alabama at Birmingham, Liberty National Building, LNB 1078, Suite 1078, 2001 Third Avenue South, Birmingham, AL 35233.
Dr. Goldman: Wishard Memorial Hospital, 430 OPW, 1001 West 10th Street, Indianapolis, IN 46202.
Dr. Lancaster: Methodist Hospital, One Tower 1265 Union Avenue, Memphis, TN 38104.
Dr. Bamberger: University of Missouri–Kansas City, School of Medicine, Division of Infectious Diseases, Red 4 Unit, 2411 Holmes Street, Kansas City, MO 64108-2792.
Dr. Powderly: Washington University School of Medicine, Division of Infectious Diseases, Campus Box 8051, 660 South Euclid, St. Louis, MO 63110.
Dr. Hafner: National Institute of Allergy and Infectious Diseases, Division of AIDS, National Institutes of Health, 6700-B Rockledge Drive, MSC 7624, Room 5107, Bethesda, MD 20817.
Dr. Kauffman: VA Medical Center, Infectious Diseases Section, 2215 Fuller Road, Ann Arbor, MI 48105.
Dr. Dismukes: University of Alabama School of Medicine at Birmingham, Department of Medicine and Division of Infectious Diseases, THT 229-1900 University Boulevard, Birmingham, AL 35294-0006.
Author Contributions: Conception and design: P.C. Johnson, L.J. Wheat, G.A. Cloud, B.M. Bamberger, W.G. Powderly, R. Hafner, C.A. Kauffman, W. Dismukes.
Analysis and interpretation of the data: P.C. Johnson, L.J. Wheat, G.A. Cloud, M. Goldman, D.M. Bamberger, W.G. Powderly, C.A. Kauffman, W.E. Dismukes.
Drafting of the article: P.C. Johnson, L.J. Wheat, G.A. Cloud, W. Dismukes.
Critical revision of the article for important intellectual content: P.C. Johnson, L.J. Wheat, G.A. Cloud, M. Goldman, D. Lancaster, D.M. Bamberger, W.G. Powderly, R. Hafner, C.A. Kauffman, W. Dismukes.
Final approval of the article: P.C. Johnson, L.J. Wheat, G.A. Cloud, M. Goldman, D. Lancaster, D.M. Bamberger, W.G. Powderly, R. Hafner, C.A. Kauffman, W. Dismukes.
Provision of study materials or patients: P.C. Johnson, L.J. Wheat, G.A. Cloud, M. Goldman, D. Lancaster, D.M. Bamberger, W.G. Powderly.
Statistical expertise: G.A. Cloud.
Obtaining of funding: W.E. Dismukes.
Administrative, technical, or logistic support: G.A. Cloud, R. Hafner, C.A. Kauffman, W.E. Dismukes.
Collection and assembly of data: G.A. Cloud, D.M. Bamberger.