OBJECTIVE:: HIV-infected patients with treated cryptococcal meningitis (CM) are at risk of further neurological deterioration (ND) after commencing combination antiretroviral therapy (cART), mostly due to cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). Identifying predictors of C-IRIS could enable risk stratification strategies. DESIGN:: Prospective, longitudinal cohort study for 24 weeks. SETTING:: Durban, South Africa. SUBJECTS:: 130 HIV-infected patients experiencing first episode of CM. INTERVENTION:: Antifungal therapy (Amphotericin 1 mg/kg median 14 days, followed by consolidation and maintenance fluconazole) and cART (commenced median of 18 days from CM diagnosis). MAIN OUTCOME MEASURE:: Rate of C-IRIS and clinical, blood and CSF markers associated with C-IRIS before and during ART. 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%) ND-not C-IRIS and 63 (59.4%) no-ND. On multivariable analysis, lower CD4+ T-cell increases on cART (Hazard ratio HR 0.99, p = 0.026), persistent CSF cryptococcal growth (HR 0.27, p = 0.026) and lower CSF protein (HR 0.53, p = 0.059) prior to cART initiation were associated with C-IRIS. Using survival analysis, patients with a negative cryptococcal culture pre-cART commencement (n = 51; 48.1%) experienced fewer episodes of ND, C-IRIS and cryptococcal relapse/persistence than patients with a positive CSF culture (n = 55; 51.9%, HR 0.33, 0.33 and 0.12 and p = 0.0003, 0.0042 and, 0.0004, respectively). CONCLUSIONS:: 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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