Amphotericin-based combination antifungal therapy reduces mortality from HIV-associated cryptococcal meningitis. However, 40-50% of individuals have positive cerebrospinal fluid (CSF) fungal cultures at completion of amphotericin induction therapy. Residual CSF culture-positivity is associated with poor clinical outcomes using standard consolidation therapy with fluconazole 400mg/day for 8 weeks.
A prospective cohort of 138 HIV-infected Ugandan adults with first episode of culture-positive cryptococcal meningitis received amphotericin (0.7-1.0 mg/kg/day) plus fluconazole (800 mg/day) and sertraline (100-400mg/day) for 2 weeks. Survivors were classified as having sterile or non-sterile CSF based on 2-week CSF cultures. “Enhanced” consolidation therapy started thereafter, which consisted of 1) fluconazole 800 mg/day for at least 3 weeks depending on CSF culture status, then 400 mg/day to complete 10-week consolidation phase, and 2) sertraline 200mg/day for 10 weeks. All-cause mortality, as well as culture-positive relapse and cryptococcal-related immune reconstitution inflammatory syndrome (IRIS) during follow-up, were compared by culture positivity using Cox regression.
Of 100 participants surviving two weeks, 68% (68/100) had sterile CSF at 2 weeks. 21 deaths occurred between 2 and 12 weeks. CSF Culture positivity at two-weeks was not significantly associated with mortality (hazard ratio: 1.0, Figure; P=0.9). Incidence of culture-positive relapse (n=0) or possible paradoxical IRIS (n=4) were low. Enhanced consolidation therapy was well tolerated.
Among patients treated with “enhanced” consolidation using extended durations of high dose fluconazole plus sertraline 200 mg/day, residual cryptococcal culture positivity was not associated with poor clinical outcomes, including death, unlike historical experiences with fluconazole 400mg/day consolidation therapy.
Figure. Kaplan-Meier Survival Plot stratified 2-week CSF sterility status following cryptococcal meningitis during consolidation therapy.
B. Morawski, None
K. H. Hullsiek, None
L. Tugume, None
H. Nabeta, None
R. Kiggundu, None
A. Akampurira, None
D. Williams, None
D. Meya, None
D. Boulware, None