Primary prophylaxis for cryptococcal meningitis

Primary prophylaxis with azole antifungals has been shown to be effective in reducing the incidence of cryptococcal meningitis in those with advanced HIV infection [1–3]. Primary prophylaxis for cryptococcal meningitis is not recommended in developed countries because of the lack of evidence of any survival benefit, the cost and the risk of promoting fungal resistance [4]. In resource-poor countries where the prevalence of HIV infection is high [5], the recommendations for primary prophylaxis for cryptococcal meningitis may need to be different. Cryptococcal meningitis is a common opportunistic infection in many countries in which HIV is prevalent. In Thailand, cryptococcal meningitis accounts for 38% of AIDS-defining illnesses amongst HIV hospital admissions [6]. In a semi-rural Ugandan HIV cohort, cryptococcal meningitis has been shown to occur with an incidence of 40.4/1000 person–years and to be associated with 17% of all deaths [7]. Unlike the situation in developed countries, where the availability of intravenous amphotericin has reduced the mortality from cryptococcal meningitis to 12% [8], the mortality in developing countries is depressingly high, with a median survival of 26 days [7,9]. While the cost of highly active antiretroviral therapy is falling, it is still unavailable to the majority of patients in need of treatment. Without the hope of immune reconstitution, prophylaxis against opportunistic infections may be the only means of improving the quality and longevity of patients' lives. To date, little work has been published on the effectiveness of antifungal prophylaxis in resource-poor countries with a high prevalence of HIV [1], although there are studies underway [10]. The study by Chetchotisakd et al. [11], published in this issue of the journal, on the effectiveness of fluconazole prophylaxis in a Thai population with advanced HIV disease is therefore welcome. Patients were randomly assigned to receive either weekly fluconazole (400 mg) or placebo, with weekly fluconazole prophylaxis reducing the overall mortality with a hazard ratio of 4.3. The study involved only a small number of patients and had short follow up, thus limiting the power, and the confidence intervals for the mortality benefit were wide (0.9–19.8). The other primary end point (the prevention of cryptoccoal meningitis) showed a reduction in the rate of cases of cryptococcal meningitis with a hazard ratio of 2.23 but did not reach statistical significance. This study suggests that there may be a mortality benefit of primary fluconazole prophylaxis in this setting. This has not been shown in any previously published work in developed countries [2,3]. If real, this difference might be explained by a higher incidence of cryptococcal meningitis and the fact that the antifungal treatment required to treat this condition [8] is seldom available, hence increasing the attributable mortality from this condition [7]. In addition, this study chose to give fluconazole weekly at a dose of 400 mg rather than at a daily dose of 200 mg. The effectiveness of weekly fluconazole has been suggested elsewhere [12], but not in the resource-poor setting and not with a mortality benefit. The benefits of weekly fluconazole over a daily dosing include a possible reduction in the incidence of fungal azole resistance [13] and a reduction in costs. The cost effectiveness of primary prophylaxis for opportunistic infections has been studied in the developed world setting [14]. Primary prophylaxis for fungal infections has not been shown to be cost effective in the US with an estimated cost of $100 000 per quality adjusted life year (QALY) saved; azole antifungal drugs are expensive (fluconazole costs approximately $12 per 200 mg tablet) and no mortality benefit has been demonstrated. The cost effectiveness of any intervention is even more important in the resource-poor setting. The cost effectiveness of fluconazole prophylaxis has not been addressed in this study. If available at standard pricing, fluconazole prophylaxis at a weekly dose of 400 mg would cost $51.99 per month and would not be a cost-effective intervention for countries with annual health budgets of $10 per capita or less [15]. With the availability of cheaper generic (generic fluconazole is available in Thailand for $0.29 per 200 mg tablet) or donated antifungals [16,17] and evidence of a mortality benefit from weekly fluconazole, the efficiency of this intervention needs to be reassessed. It is important to compare the effectiveness of any prophylactic intervention with that of cheaper antiretroviral drugs that are becoming available. Generic highly active regimens are now available for $17 per month [18]. Immune reconstitution provides protection against a wide range of opportunistic infections and with a proven mortality benefit may be clearly the most cost-effective intervention. The use of fluconazole rather than itraconazole would not provide the same degree of protection against other important fungi endemic in some parts of the world; namely penicilliosis and histoplasmosis [1,3]. Itraconazole has been shown to reduce the incidence of cryptococcal meningitis but has not been shown to provide a mortality benefit [1].