BACKGROUND: Cryptococcal disease is an opportunistic infection that causes 
significant morbidity and mortality in adults with HIV. Primary prophylaxis with 
antifungal interventions may decrease cryptococcal disease incidence and 
associated mortality.
OBJECTIVES: To assess the efficacy of antifungal interventions for the primary 
prevention of cryptococcal disease in adults with HIV.
SEARCH STRATEGY: We searched the following databases: MEDLINE, EMBASE, 
Cumulative Index to Nursing and Allied Health Literature (CINAHL), 
ClinicalTrials.gov, Database of Abstracts of Reviews of Effectiveness (DARE), 
Latin American and Caribbean Literature on the Health Sciences (LILACS), and the 
Cochrane Controlled Trials Register (CCTR). We reviewed abstracts from the 
following relevant conferences: International AIDS Conference, International 
AIDS Society Conference on HIV Pathogenesis and Treatment, and Conference on 
Retroviruses and Opportunistic Infections. We searched reference lists for all 
primary and other pertinent articles identified. We attempted to contact experts 
in the field, particularly primary authors of included studies, to better ensure 
completeness of included studies. We also approached pharmaceutical companies 
for any available and relevant unpublished data. The time period searched was 
from 1980 to August 2004. We placed no language restrictions on the search. Key 
words used include: meningitis, cryptococcal, cryptococcus, cryptococcosis, 
acquired immunodeficiency syndrome, human immunodeficiency virus, prophylaxis, 
chemoprevention, antifungal agents, and the Cochrane screen for randomized 
controlled trials.
SELECTION CRITERIA: Randomized controlled trials using antifungal interventions 
for the primary prevention of cryptococcal disease in adults with HIV were 
selected.
DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial 
eligibility and quality. Trial authors, experts, and pharmaceutical companies 
were contacted for additional and/or missing information. Data were abstracted 
by two reviewers. Data were pooled, where appropriate, to yield summary 
estimates.
MAIN RESULTS: Five studies (N=1316) were identified. All study patients had CD4 
cell counts <300 cells/microl, and the majority of patients had CD4 cell counts 
<150 cells/microl. When all five studies are analyzed as a single group 
(N=1316), the incidence of cryptococcal disease was decreased in those taking 
primary prophylaxis (RR 0.21, 95% CI 0.09, 0.46) compared to those taking 
placebo. However, there was no significant difference in overall mortality 
observed (RR 1.01, 95% CI 0.71, 1.44). When the three studies using itraconazole 
as the intervention were analyzed together (N=798), the incidence of 
cryptococcal disease was decreased in those taking itraconazole for primary 
prophylaxis (RR 0.12, 95% CI 0.03, 0.51) compared to those taking placebo; 
however, there was no significant difference in overall mortality (RR 1.12, 95% 
CI 0.70, 1.80). When the two studies using fluconazole as the intervention were 
analyzed together (N=518), the incidence of cryptococcal disease was decreased 
in those taking fluconazole for primary prophylaxis (RR 0.25, 95% CI 0.07, 0.87) 
compared to those taking placebo; however, there was no significant difference 
in overall mortality (RR 0.59, 95% CI 0.14, 2.62).
AUTHORS' CONCLUSIONS: Antifungal primary prophylaxis with either itraconazole or 
fluconazole is effective in reducing the incidence of cryptococcal disease in 
adults with advanced HIV disease. However, neither of these interventions has a 
clear effect on overall mortality. Further research is needed to better 
understand these interventions and the populations in which they may be most 
effective.