Prophylactic fluconazole prevented the recurrence of cryptococcal infection after cryptococcal meningitis in AIDS
ACP J Club. 1991 Jul-Aug;115:4. doi:10.7326/ACPJC-1991-115-1-004
Bozzette SA, Larsen RA, Chiu J, et al. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med. 1991 Feb 28;324:580-4. [PubMed ID: 1992319]
To evaluate the effectiveness of maintenance therapy with fluconazole, an antifungal agent, in patients with AIDS who have completed successful primary therapy for cryptococcal meningitis.
Randomized, double-blind, placebo-controlled trial with a mean duration of 140 days (range, 13 to 529 days).
3 university-affiliated medical centers and 1 private medical group in the United States.
Adults with documented HIV infection who had successfully completed a standardized course of amphotericin B therapy or amphotericin B plus flucytosine therapy (within the past 3 weeks) for recently diagnosed cryptococcal meningitis (within the past 4 months) were included. Patients were excluded if they had a history of intolerance to imidazoles, moderate liver function abnormalities, a serum creatinine level > 190 µmol/L; if they were pregnant; or if they were receiving systemic or intrathecal antifungal therapy. Of 84 patients enrolled, 16 were found to be ineligible because of silent, persistent infections. Of the 68 eligible patients randomized, 7 (10%) were lost to follow-up.
During phase I, patients received either 100 mg of oral fluconazole or identical placebo for 3 months. During phase II, patients received either 200 mg of fluconazole or placebo daily.
Main outcome measure
Recurrence of cryptococcal infection at any site.
More patients receiving placebo than those receiving fluconazole had a recurrence of cryptococcal infection (P < 0.001) (Table). 4 of the patients receiving placebo (15%) and none of the patients receiving fluconazole had meningeal recurrence (difference in risk 15%, CI 1% to 28%, P = 0.03). The cumulative risk for recurrence of cryptococcal infection at any site after 1 year was 100% in the placebo group and 5% in the fluconazole group (P < 0.001). The best predictor of recurrence-free survival was fluconazole treatment (P = 0.02). The occurrence of adverse events was similar in the 2 treatment groups (P = 0.80), with gastrointestinal symptoms being reported most frequently.
Treatment with fluconazole at a dosage of 100 to 200 mg/d was effective in preventing recurrence of cryptococcal infection at any site in patients who have completed clinically successful standard therapy for cryptococcal meningitis.
Sources of funding: California University-Wide AIDS Research Program and Pfizer Central Research.
Address for article reprint: Dr. S.A. Bozzette, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, 111N-1, San Diego, CA 92161, USA.
Table. Fluconazole vs placebo for treating patients with AIDS who have had successful primary therapy for cryptococcal meningitis*
|Outcome at mean follow up of 140 d||Fluconazole||Placebo||RRR (95%CI)||NNT (CI)|
|Recurrence of cryptococcal infection||3%||37%||92% (57 to 99)||3 (2 to 6)|
*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
Cryptococcal meningitis was reported to occur in approximately 10% of patients with AIDS and frequently recurs after the primary therapy for meningitis is terminated. A collaborative trial (1) suggested that fluconazole is effective for preventing recurrent cryptococcal disease, which the current report further documents.
The study was well planned and analyzed. The baseline characteristics of the 2 groups were comparable except that patients on placebo received somewhat less flucytosine and had higher cryptococcal antigen titers. These differences, however, were probably not great enough to affect the validity of the conclusions.
Of particular importance is that none of the 34 patients on fluconazole maintenance therapy developed recurrent meningitis, compared with a 15% recurrence rate among patients on placebo. The mortality rates were the same for the 2 groups. However, none of the 7 deaths in the fluconazole group, compared with 2 of the 4 deaths in the placebo group, were attributable to cryptococcal disease.
Fluconazole, 200 mg/d, is well tolerated and should be prescribed to prevent recurrence of cryptococcosis among patients with AIDS who have had successful initial treatment. Although the success of highly active antiretroviral therapy has led to a reassessment of the role of prophylactic therapies, only limited studies have evaluated the safety of stopping secondary prophylaxis for cryptococcal infections in patients who have had an immunologic response to antiretroviral therapy and current guidelines recommend its continuation (2). Although fluconazole taken as primary prophylaxis reduced the frequency of fungal infections in patients with advanced HIV infection (3), its use is not routinely recommended (2).
Tom D.Y. Chin, MD
University of Kansas Medical CenterKansas City, Kansas, USA
3. Powderly WG, Finkelstein DW, Feinberg J, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med. 1995;332:700-5.
Readers should note that fluconazole prevented urinary as well as meningeal recurrence. This is important because the early detection and treatment of persistent and recurrent extraneural disease probably accounted for the unexpectedly low rate of meningeal recurrence in the placebo group. Also, the fact that all meningeal recurrences occurred between monthly visits whereas all urinary recurrences were detected at monthly visits suggests that follow-up urine cultures for fungus may be worth while in this patient group, but that once sterility has been achieved, routine lumbar punctures are not needed.
Samuel A. Bozzette, MD