Objective: HIV-infected patients with treated cryptococcal meningitis are at risk for further neurological deterioration after commencing combination antiretroviral therapy (cART), mostly because of cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). Identifying predictors of C-IRIS could enable risk stratification.
Design: Prospective, longitudinal cohort study for 24 weeks.
Setting: Durban, South Africa.
Participants: One hundred and thirty HIV-infected patients with first cryptococcal meningitis episode
Intervention: Antifungal therapy (amphotericin 1 mg/kg median 14 days, followed by consolidation and maintenance fluconazole) and cART (commenced median of 18 days from cryptococcal meningitis diagnosis).
Main outcome measure: Clinical, blood, and cerebrospinal fluid (CSF) markers associated with C-IRIS before and during cART and clinical significance of CSF cryptococcal culture negativity pre-cART commencement.
Results: Of 106 patients commencing cART, 27 (25.5%) developed C-IRIS, 16 (15.1%) neurological deterioration-not C-IRIS, and 63 (59.4%) no neurological deterioration. On multivariable analysis, C-IRIS was associated with persistent CSF cryptococcal growth [hazard ratio (HR) 0.27, P = 0.026] and lower CSF protein (HR 0.53, P = 0.059) prior to cART and lower CD4+ T-cell increases (HR 0.99, P = 0.026) but not change in HIV viral load during cART. Using survival analysis, patients with a negative cryptococcal culture pre-cART commencement (n = 51; 48.1%) experienced fewer episodes of neurological deterioration, C-IRIS, and cryptococcal relapse/persistence than patients with culture positivity (n = 55; 51.9%, HR 0.33, 0.33, and 0.12 and P = 0.0003, 0.0042, and 0.0004, respectively).
Conclusion: Persistent CSF cryptococcal growth at cART initiation and poor CD4+ T-cell increases on cART are strong predictors of C-IRIS. Approaches aimed at achieving CSF culture negativity prior to cART should be evaluated as a strategy to reduce rates of C-IRIS.
aDepartment of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
bDepartment of Infectious Diseases, King Edward VIII Hospital
cHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
dCentre for Virology, Burnet Institute, Melbourne, Australia
eDepartment of Medical Microbiology, National Health Laboratory Services, Inkosi Albert Luthuli Central Hospital Academic Complex
fDepartment of Microbiology and Infection Control, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
gCentre for Population Health, Burnet Institute, Melbourne, Australia
hCentre for the AIDS Programme of Research in South Africa, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
iSchool of Pathology and Laboratory Medicine, University of Western Australia
jDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia.
Correspondence to Professor Martyn A. French, MD, Royal Perth Hospital, Perth, Western Australia, Australia. Tel: +61 8 9224 2899; fax: +61 8 9224 2920; e-mail: Martyn.French@uwa.edu.au
Received 18 January, 2013
Revised 15 March, 2013
Accepted 15 March, 2013
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