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Study Shows Promise of Fluconazole for Treatment of AIDS-Related Cryptococcal Meningitis

Date: January 8, 1992
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

The oral drug fluconazole appears to be an effective alternative to the standard intravenous treatment for initial episodes of a deadly AIDS-related fungal infection of the brain and nervous system, according to a study supported by the National Institute of Allergy and Infectious Diseases (NIAID). The research report, based on a randomized clinical trial of 194 patients, appears in the January 9 The New England Journal of Medicine.

The study investigators found that fluconazole given by mouth is as effective as intravenous doses of the drug amphotericin B as a treatment for AIDS patients with a first outbreak of cryptococcal meningitis. In addition, the patients taking fluconazole had fewer drug-related side effects.

These findings are an important step forward in defining the best approach for treating cryptococcal meningitis in people with AIDS." said Anthony S. Fauci, M.D., NIAID Director.

Cryptococcal meningitis is the most common life-threatening fungal infection seen in persons with AIDS, and accounts for 5 to 8 percent of all AIDS-related opportunistic infections. The disease is an infection of the meninges, the membranes that surround the brain and cord, and it is invariably fatal if untreated. It is caused by a yeast-like fungus, Cryptococcus neoformans, that is found widely in the environment, especially in soil contaminated with bird excrement. Although exposure to C. neoformans is quite common, disease rarely occurs except in persons who have damaged immune systems.

The standard therapy for treating an initial episode of cryptococcal meningitis is intravenous amphotericin B, but the drug's use sometimes is limited because of side effects. Therapy with amphotericin B can result in serious adverse reaction including impairment of kidney function and suppression of bone marrow, as well as milder side effects such as fever and nausea. In this study, patients on fluconazole experienced fewer drug-related side effects, although some patients have drug-associated gastrointestinal symptoms, skin rashes, and, less frequently, elevation of liver enzymes.

The study, known as ACTG 059/MSG 8A, enrolled patients at medical centers affiliated with NIAID's AIDS Clinical Trials Group and Mycoses Study Group, as well as seven independent sites, between April 1988 and November 1989. All patients were infected with HIV and had a diagnosis of cryptococcal meningitis.

Of the 194 patients in the trial, 131 received fluconazole (200 mg./day) and 63 received amphotericin B(0.4-0.5) mg/day per kilogram of body weight). Treatment was successful in 44 of 131 fluconazole recipients (34 percent); and in 25 of the 63 amphotericin B recipients (40 percent).

Rates of death due to cryptococcal meningitis did not differ significantly for the two groups (14 percent for the amphotericin B group vs. 18 percent for the fluconazole group). However, the death rate during the first 2 weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent).

Rates of death due to cryptococcal meningitis did not differ significantly for the two groups (14 percent for the amphotericin B group vs. 18 percent for the fluconazole group). However, the death rate during the first 2 weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent).

Patients tolerated fluconazole much better that amphotericin B: 73 percent of fluconazole recipients reported no adverse effects, as compared with 37 percent of amphotericin B recipients. Severe side effects forced discontinuation of the drug in 8 percent of amphotericin B recipients, as compared with 2 percent of fluconazole recipients.

The study analysis defined patients as either at high risk or at low risk for death while on therapy. This was based on the presence of abnormal mental status, concentration of cryptococcal antigen, and cerebrospinal white blood cell count. Mortality in the low-risk group was 3 percent for amphotericin B and 5 percent for fluconazole. In contrast, the mortality rate in the high-risk group was 33 percent (8 of 24 patients) for patients on amphotericin B, and 40 percent (20 of 50 patients) for those on fluconazole.

"An important goal of future research will be determining the optimal therapy for high-risk patients," said Daniel F. Hoth, M.D., director of the Division of AIDS at NIAID.

The Food and Drug Administration approved fluconazole in January 1990 as an alternative treatment for persons with damaged immune systems and with cryptococcal meningitis or with another fungal infection, candidiasis, which chronically infects the mouths and throats of up to 90 percent of people at advanced stages of AIDS.

Relapse after initial treatment occurs in 50 to 90 percent of persons with cryptococcal meningitis, unless lifelong maintenance therapy is maintained. Other studies have suggested that fluconazole is effective maintenance therapy for patients who have been successfully treated for cryptococcal meningitis, and causes fewer side effects that amphotericin B.

"As people with HIV live longer because of the more widespread use of antiretroviral therapy and treatments for other opportunistic infections, we can expect to see an even greater incidence of cryptococcal disease," said Dr. Hoth. "Therefore, improving treatment, both for acute infection and long-term therapy, and improving prophylaxis, will become increasingly important. Further studies addressing these issues are now under way in the AIDS Clinical Trials Group and Mycoses Study Group."

Collaborators on the study include Michael S. Saag, M.D., Gretchen A. Cloud, M.S., and William E. Dismukes, M.D., University of Alabama at Birmingham School of Medicine; William G. Powderly, M.D., Washington University School of Medicine; Michael H. Grieco, M.D., Columbia University School of Medicine; Patricia K. Sharkey, M.D., University of Texas, San Antonio; Sumner E. Thompson, M.D., Emory University; Alan M. Sugar, M.D., Boston University; Carmelita U. Tuazon, M.D., George Washington University; John F. Fisher, M.D., Medical College of Georgia; Newton Hyslop, M.D., Tulane University; Jeffrey M. Jacobson, M.D., Mount Sinai Medical Center; Richard Hafner, M.D., NIAID; Patrick Robinson, M.D., Pfizer Central Research; and the NIAID Mycoses Study Group and the AIDS Clinical Trials Group.

The AIDS Clinical Trials Group is a nationwide network of medical centers that evaluates promising therapies for AIDS and the opportunistic infections and cancers that characterize the disease. The Mycoses Study Group, another NIAID-sponsored nationwide network of medical centers, conducts clinical research on fungal diseases.

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