Background. Amphotericin-based combination antifungal therapy reduces mortality from human immunodeficiency virus (HIV)-associated cryptococcal meningitis. However, 40%-50% of individuals have positive cerebrospinal fluid (CSF) fungal cultures at completion of 2 weeks of amphotericin induction therapy. Residual CSF culture positivity has historically been associated with poor clinical outcomes. We investigated whether persistent CSF fungemia was associated with detrimental clinical outcomes in a contemporary African cohort. Methods. Human immunodeficiency virus-infected individuals with cryptococcal meningitis in Uganda and South Africa received amphotericin (0.7-1.0 mg/kg per day) plus fluconazole (800 mg/day) for 2 weeks, followed by "enhanced consolidation" therapy with fluconazole 800 mg/day for at least 3 weeks or until cultures were sterile, and then 400 mg/day for 8 weeks. Participants were randomized to receive antiretroviral therapy (ART) either 1-2 or 5 weeks after diagnosis and observed for 6 months. Survivors were classified as having sterile or nonsterile CSF based on 2-week CSF cultures. Mortality, immune reconstitution inflammatory syndrome (IRIS), and culturepositive relapse were compared in those with sterile or nonsterile CSF using Cox regression. Results. Of 132 participants surviving 2 weeks, 57% had sterile CSF at 2 weeks, 23 died within 5 weeks, and 40 died within 6months. Culture positivity was not significantly associated with mortality (adjusted 6-month hazard ratio, 1.2; 95% confidence interval, 0.6-2.3; P = .28). Incidence of IRIS or relapse was also not significantly related to culture positivity. Conclusions. Amongpatients, all treated with enhanced consolidation antifungal therapyandART, residual cryptococcal culture positivity was not found to be associated with poor clinical outcomes.
Bibliographical noteFunding Information:
We thank Drs. Jason Baker, Tihana Bicanic, and Lewis Haddow for serving on the external adjudication committee for clinical events. We thank Dr. Thomas Harrison for input on enhanced consolidation therapy and Dr. Tihana Bicanic for training of laboratory personnel in quantitative culture methodology. We thank Drs. Claudia Muñoz-Zanzi, Alan Lifson, and James Neaton for critical review of the manuscript. We thank the National Institutes of Health support from Drs. Trinh Ly, Chris Lambros, Karen Reese, and Neal Wetherall. We thank institutional support from Drs. Andrew Kambugu, Alex Coutinho, Henry Kajumbula, Aaron Friedman, and the Infectious Diseases Institute DataFax team of Mariam Nama-wejje and Mark Ssennono for data management with support from the National Institute of Allergy and Infectious Diseases Office of Cyberinfras-tructure and Computational Biology, Kevin Newell, and Dr. Steven Reynolds.
Financial support. Financial support for this research was provided by the National Institute of Allergy and Infectious Diseases (grants U01AI089244; K23AI073192; K24AI096925; T32AI055433) and Wellcome Trust (grants 081667, 098316; to G. M.). Potential conflicts of interest. All authors: No reported conflicts.
© The Author 2015.
- Clinical outcome
- Cryptococcal meningitis