Clinical and mycological determinants of Cryptococcosis-associated IRIS (C-IRIS) Chang CC, Elliott JE, Gosnell BI, Dorasamy AA, Omarjee S, Naranbhai V, Spelman T, Moosa MY-S, Mahabeer Y, Lim A, Carr W, Coovadia Y, Ndung’u T, Lewin SR, French MA Christina C Chang MB.BS, FRACP, PhD student Department of Infectious Diseases, Alfred Hospital, Monash University, Melbourne HIV Pathogenesis Programme, University of KwaZulu Natal, Durban THSA20: The Rainbow of IRIS in HIV Infection Mini-Symposium XIX International AIDS Conference 2012 – Washington D.C. Thursday 29 July 2012

≥18 years HIV+, cART-naïve First CM W00 W08W04W02W12W16W20W24 cART Clinical assessment Neurological Deterioration Study protocol Ethics approval: UKZN BF 053/09, Monash Uni , UWA RA/4/1/2541 C-IRISNot C-IRISIndeterminate Intensive Ampho 14 d Consolidation 400mg Fluconazole 12 weeks Maintenance 200mg Fluconazole therapy

25.5% of those who commenced cART developed C-IRIS in the first 24 weeks Excluded n=2 Death prior to cART commencement n=19 Patients enrolled n=130 Commenced on cART n=106 Lost to follow-up n=3 Neurological Deterioration n=43 (40.6%) No ND n=63 (59.4%) Any C-IRIS n=27 (25.5%) NDs without C-IRIS n=16 (15.1%)

Predictors of C-IRIS (Cox-regression univariate analysis) No ND n=63 C-IRIS n=27 p- value Hazard ratio (95%CI) Age (years) 33.0 ( ) 34.0 ( ) ( ) CD4 T-cells count (cells/µL) 36 (16-83) 16 (6-53) ( ) HIV Viral Load (log 10 copies/mL) 5.3 ( ) 5.1 ( ) ( ) Seizures4 (6.3%) 5 (18.5%) ( ) Lumbar puncture at CM presentation CSF Protein0.91 ( ) 0.70 ( ) ( ) CSF Polymorphs6 (0-32) 0 (0-2) ( ) CSF Lymphocytes34 (8-144) 10 (0-24) ( ) CSF Quantitative Culture (CFU/mL) 18 (1-910) 1110 ( ) ( ) Lumbar puncture just prior to cART CSF Protein0.94 ( ) 0.57 ( ) ( ) CSF Polymorphs4 (0-10) 4 (0-8) ( ) CSF Lymphocytes32 (8-74) 16 (2-26) ( ) CSF Quantitative Culture (CFU/mL) 0 (0-0) 0.5 (0-2.3) ( ) Crypto culture negative39 (61.9%) 7 (25.9%) ( ) CSF CrAg ≥1:1024 (≥1:1024-≥1:1024 ) ≥1:1024 (≥1:1024-≥1:1024) ( ) Serum CrAg ≥1:1024 (1:512-≥1:1024) ≥1:1024 (≥1:1024-≥1:1024) ( ) Median (interquartile range)

CSF cryptococcal culture negativity pre-cART commencement and increasing CD4 T-cell are significantly associated with decreased rates of C-IRIS  Multivariate analysis p- value Hazard Ratio (95% CI) CSF cryptococcal culture negative pre-cART commencement ( ) CD4 T-cell count ( ) CSF protein just prior to cART commencement ( )

Summary and implications  Lower CD4 + T-cell count, reduced CSF cellularity and CSF protein and higher CSF cryptococcal burden at CM presentation are predictors of C-IRIS  CSF sterility pre-cART is associated with a 74% reduction in the rate of C-IRIS (p=0.002, HR 0.26, 95%CI )  Greater CD4 + T-cell depletion and a higher pathogen load are predictors of C-IRIS on multivariate analysis  Earlier HIV testing and treatment and enhanced cryptococcal management practices to improve attainment of CSF cryptococcal sterility are necessary to reduce rates of C-IRIS

Acknowledgements School of Pathology and Laboratory Medicine, University of Western Australia –Prof MA French, Dr A Lim Dept. of Infectious Diseases, Alfred Hospital, Monash University –Prof SR Lewin, Dr JH Elliott, Dr T Spelman Microbiology Department, NHLS, IALCH –Miss AA Dorasamy, Prof Y Coovadia, Dr Y Mahabeer Dept. of Infectious Diseases, King Edward Hospital, UKZN –Dr BI Gosnell, Prof MY-S Moosa HIV Pathogenesis Programme –Prof T Ndung’u, Dr V Naranbhai, Dr WH Carr, Miss S Omarjee, Miss R Durgiah Dept. of Medicine, medical, nursing, laboratory, radiology, nursing and support staff at KEH and UKZN Laboratory staff at RK Khan and Wentworth hospitals Prof S Levitz, University Massachusetts Mrs L Cockle, Keyboard Training Concepts Study participants and their families REACH initiative grant 2007 Australian Postgraduate Award 2009 Australian NHMRC Postgraduate Scholarship ANZ trustees research grant 2009 Pfizer neuroscience research grant 2010 World AIDS XIX NIAID travel support