Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV

Infection with the human immunodeficiency virus (HIV) leads to progressive destruction and weakening of the body's immune system. Patients with advanced HIV disease are vulnerable to various diseases, called opportunistic infections (OIs), which most people with normal immune systems are protected against. One of these OIs, a fungal disease called cryptococcosis, causes meningitis (an inflammation of the membrane surrounding the brain) and pneumonia and is lethal when untreated. This study looked at two medications, itraconazole and fluconazole, which could be taken by patients with advanced HIV disease, to prevent this fungal infection from ever occurring. This study found that both were effective drugs for preventing cryptococcal disease. However, these drugs were not found to be effective in decreasing the overall death rates from HIV. More studies of these medications are needed to further evaluate their cost-effectiveness and benefits in decreasing death rates in groups of patients with HIV.

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.

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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/µl, and the majority of patients had CD4 cell counts <150 cells/µl. 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).