Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

Abstract

BACKGROUNDCryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODSWe randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTSA total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.

Short‐course amphotericin B in addition to sertraline and fluconazole for treatment of HIV‐associated cryptococcal meningitis in rural Tanzania

“…Addition of five days of amphotericin B to the fluconazole‐sertraline combination markedly increased the rate of fungal clearance to 0.437 log 10 CFU/mL/day. Our EFA was higher than what was previously observed in a prospective study in Western Uganda (EFA 0.30; 95% CI, 0.26‐0.34 log 10 CFU/mL/day), evaluating 5‐day amphotericin with fluconazole 1200 mg/day, as well as the 0.36 EFA (95% CI, 0.31‐0.41 log 10 CFU/mL/day) observed in the ACTA trial with 7‐day amphotericin + fluconazole . This might be explained by the synergistic effect of sertraline with fluconazole, particularly during the second week of therapy when sertraline would have had probable therapeutic concentrations .…”

“…Key findings of our study are as follows: (a) a two‐fold more rapid CSF fungal clearance rate with sertraline and fluconazole than previously observed with fluconazole 1200 mg/day monotherapy but no improvement in survival; (b) two‐fold further improved CSF clearance and 40% improved 10‐week survival when adding short‐course amphotericin B; and (c) the lack of serious adverse events in this critically ill population. Furthermore with a package of care of: rapid outpatient CrAg LFA diagnosis on blood, rapid referral to hospital, short‐course amphotericin of 5 days and scheduled therapeutic LPs, removing 20 mLs of CSF in the absence of manometers, we achieved 89% two‐week survival in rural Tanzania. This in‐hospital mortality is similar to the 10.5% in‐hospital mortality in the United States from 1997 to 2009 .…”

“…The cerebrospinal fluid (CSF) yeast clearance rate derived from serial CSF quantitative cultures of lumbar punctures over the first 2 weeks, termed early fungicidal activity (EFA), provides a clinically relevant endpoint to explore the antifungal activity of different drug combinations. Fluconazole 1200 mg daily has better CSF Cryptococcus clearance (EFA 0.15 log 10 CFU/mL CSF/day) than lower doses of fluconazole, but fluconazole monotherapy has 4‐fold slower CSF clearance than amphotericin and flucytosine combination therapy . However, amphotericin B is not widely available in low‐income countries, where 1 week of amphotericin increases the total cost of hospitalisation by ~$63, and flucytosine is completely unavailable.…”

Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis

“…More than 90% of the estimated 223,100 annual incident cases of cryptococcal meningitis occur in Sub-Saharan Africa and Asia-Pacific regions (1). The most effective regimen for induction is amphotericin B deoxycholate and flucytosine (2, 3). However, access to these drugs is limited in many regions where the burden of cryptococcal meningitis is greatest (4, 5).…”

Clinical mycology in Latin America and the Caribbean: A snapshot of diagnostic and therapeutic capabilities

“…The situation gets even worse when we track the availability of 5‐FC. 5‐FC is an extremely important drug to treat cryptococcosis: it significantly reduces mortality when added to amphotericin B, and it proved to be effective in an “all‐oral” regimen added to fluconazole . Nevertheless, less than one‐fifth of responders reported access to 5‐FC.…”