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Clinical and mycological predictors of cryptococcosis-associated immune reconstitution inflammatory syndrome

Chang, Christina C.a,b,c,d; Dorasamy, Afton A.e,f; Gosnell, Bernadett I.b; Elliott, Julian H.a; Spelman, Tima,g; Omarjee, Salehac; Naranbhai, Vivekc,h; Coovadia, Yacoobe,f; Ndung’u, Thumbic; Moosa, Mohamed-Yunus S.b; Lewin, Sharon R.a,d; French, Martyn A.i,j

doi: 10.1097/QAD.0b013e3283614a8d
Clinical Science

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.

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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:

Received 18 January, 2013

Revised 15 March, 2013

Accepted 15 March, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.