Abstract
Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations. We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800-1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens. Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is "very cost effective" per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease. Please see later in the article for the Editors' Summary.
Highlights
Cryptococcal meningitis (CM) affects an estimated 957,900 people per year, with the overwhelming burden of disease in subSaharan Africa and Southeast Asia, where annual mortality may equal or exceed that for tuberculosis [1,2]
Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is ‘‘very cost effective’’ per World Health Organization criteria and may be a worthy investment for policy-makers seeking costeffective clinical outcomes
The least effective treatment regimen was high-dose (800–1,200 mg/d) fluconazole monotherapy, with a 10-wk mortality of 54.9%
Summary
Cryptococcal meningitis (CM) affects an estimated 957,900 people per year, with the overwhelming burden of disease in subSaharan Africa and Southeast Asia, where annual mortality may equal or exceed that for tuberculosis [1,2]. Where 5FC is not available, combination therapy of amphotericin + fluconazole (800 mg) daily for 2 wk is the preferred regimen over 2 wk of amphotericin alone [3,8] These recommendations do not account for local availability of medications, costs of care, capacity for hospitalization with intensive monitoring, or management of amphotericinrelated toxicities in resource-limited settings, where the prevalence of cryptococcosis remains the highest. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; this is impractical for many resource-limited settings due to cost and intensive monitoring needs. Cryptococcal meningitis, a fungal infection of the membranes around the brain and spinal cord, affects about a million people every year (most of them living in sub-Saharan Africa and Southeast Asia) and kills about 640,000 people annually. Cryptococcal meningitis is treated with antifungal drugs such as amphotericin, fluconazole, and flucytosine (induction therapy); recurrence of the infection is prevented by taking fluconazole daily for life or until the immune system recovers
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