1. 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

2. ≥18 years HIV+, cART-naïve First CM W00 W08W04W02W12W16W20W24 cART Clinical assessment Neurological Deterioration Study protocol Ethics approval: UKZN BF 053/09, Monash Uni 2009001224, UWA RA/4/1/2541 C-IRISNot C-IRISIndeterminate Intensive Ampho 14 d Consolidation 400mg Fluconazole 12 weeks Maintenance 200mg Fluconazole therapy

3. 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%)

4. 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 (28.0-40.0) 34.0 (27.0-42.0) 0.7041.09 (0.70-1.71) CD4 T-cells count (cells/µL) 36 (16-83) 16 (6-53) 0.0150.71 (0.54-0.94) HIV Viral Load (log 10 copies/mL) 5.3 (4.9-5.7) 5.1 (4.4-5.6) 0.322 1.00 (1.00-1.00) Seizures4 (6.3%) 5 (18.5%) 0.0282.98 (1.12-7.87) Lumbar puncture at CM presentation CSF Protein0.91 (0.61-1.54) 0.70 (0.49-0.82) 0.0130.44 (0.24-0.84) CSF Polymorphs6 (0-32) 0 (0-2) 0.0180.53 (0.31-0.90) CSF Lymphocytes34 (8-144) 10 (0-24) 0.0060.64 (0.46-0.88) CSF Quantitative Culture (CFU/mL) 18 (1-910) 1110 (61-1110) 0.0041.26 (1.08-1.48) Lumbar puncture just prior to cART CSF Protein0.94 (0.69-1.45) 0.57 (0.36-0.80) 0.0030.69 (0.20-0.73) CSF Polymorphs4 (0-10) 4 (0-8) 0.6650.99 (0.96-1.02) CSF Lymphocytes32 (8-74) 16 (2-26) 0.3511.00 (1.00-1.00) CSF Quantitative Culture (CFU/mL) 0 (0-0) 0.5 (0-2.3) 0.3971.08 (0.91-1.27) Crypto culture negative39 (61.9%) 7 (25.9%) 0.0020.26 (0.11-0.62) CSF CrAg ≥1:1024 (≥1:1024-≥1:1024 ) ≥1:1024 (≥1:1024-≥1:1024) 0.9471.00 (1.00-1.00) Serum CrAg ≥1:1024 (1:512-≥1:1024) ≥1:1024 (≥1:1024-≥1:1024) 0.7561.00 (1.00-1.00) Median (interquartile range)

5. 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 0.0100.269 (0.099-0.734) CD4 T-cell count0.0260.990 (0.980-0.999) CSF protein just prior to cART commencement 0.0590.528 (0.273-1.023)

6. 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 0.11-0.62)  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

7. 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 2010-2012 ANZ trustees research grant 2009 Pfizer neuroscience research grant 2010 World AIDS XIX 2012 - NIAID travel support