1. Glomerular lesions in HIV-1-infected patients: evolution from 1996 to 2007 on 88 consecutive renal biopsies. Clara Flateau, François-Xavier Lescure, Emmanuelle Plaisier, Patrice Callard, Jérôme Pacanowski, Pierre-Marie Girard, Pierre Ronco, Gilles Pialoux, for the ANAVIR study group.

2. Background 1984 : First description of HIV-associated nephropathy (HIVAN) Establishment of the direct pathogenic role of HIV-1 in HIVAN Identification of genetic suceptibility locus for HIVAN in Blacks (MYH9) (Kopp et al. 2008) HAART 1 : o Dramatic improvement of survival o Reduction in HIVAN incidence o Mild decrease in incidence of ESRD related to HIV HAART 2: o Nephrotoxicity of ARV agents o Comorbid conditions : diabetes, hypertension, aging, dyslipidemia = Risk factors for Chronic Kidney Diseases Lucas et al, AIDS, 2004

3. Method Aims – Describe the typological changes of glomerular disease in HIV-infected patients over study period (1996-2007) – Identify discriminant variables for HIVAN Design – Retrospective pathological study Data source – Pathology laboratory, Tenon Hospital, APHP – Departments of Infectious Diseases, Tenon and Saint Antoine Hospitals, APHP

4. Method Population – Consecutive adult HIV-infected patients with or without antiretroviral treatment – Kidney biopsies from 1995 to 2007 with diagnosis of glomerular disease Variables – Demographic variables – Hypertension, diabetes, dyslipidemia, history of cardiovascular events, and history of intravenous drug use. – Clinical data on HIV-infection, co-infections, CDC staging, history of opportunistic infections, ART history – Renal data including treatment, nephrotoxic drugs – Laboratory measurements at the time of biopsy

5. Method Kidney biopsies were analysed according to standard protocols Glomerular lesions were classified according to established criteria Glom Tub HIVAN Classical Focal and Segmental Glomerulosclerosis (FSGS)

6. Features of patients Total N= 88 1995-2000 N=27 2001-2003 N=29 2004-2007 N=32 p Median age, years [IQR]43 [34-50]38 [32-47]44 [34-53]46 [41-51]0.06 Men, n (%)69 (78.4)18 (66.7)21 (72.4)30 (93.8)0.03 Weight, kg [IQR]65 [58-72]63 [56-70]60 [53-67]72 [65-77]<0.01 Black, n (%)49 (71.0)18 (85.7)17 (77.3)14 (53.8)0.04 Undetectable HIV viral load, n (%)27 (37)6 (40)6 (21.4)15 (50)0.08 AIDS, n (%)45 (51.1)17 (63.0)15 (51.7)13 (40.6)0.23 ART, n (%)63 (71.6)17 (63.0)19 (65.5)27 (84.4)0.13 Hepatitis B, n (%)7 (8.9)1 (4.2)4 (15.4)2 (6.9)0.17 Hepatitis C, n (%)22 (26.2)7 (29.2)4 (14.3)11 (34.4)0.15 IDU n (%)9 (17.0)2 (22.2)3 (12.5)4 (20.0)0.72 Time HIV infection, months [IQR]84 [36-156]48 [24-114]108 [36-162]114 [36-171]0.04 CD4 count, cells/µL [IQR]217 [69-373]180 [15-354]211 [80-294]234 [143-449]0.18 GFR, ml/mn/1.73 m 2 [IQR]40 [12-63]20 [9-71]27 [11-52]55 [38-74]0.05 Proteinuria, mg/mmol [IQR]218 [114-508]406 [217-709]170 [108-400]160 [70-390]0.65

7. Features of patients Total N= 88 1995-2000 N=27 2001-2003 N=29 2004-2007 N=32 p Median age, years [IQR]43 [34-50]38 [32-47]44 [34-53]46 [41-51]0.06 Men, n (%)69 (78.4)18 (66.7)21 (72.4)30 (93.8)0.03 Weight, kg [IQR]65 [58-72]63 [56-70]60 [53-67]72 [65-77]<0.01 Black, n (%)49 (71.0)18 (85.7)17 (77.3)14 (53.8)0.04 Undetectable HIV viral load, n (%)27 (37)6 (40)6 (21.4)15 (50)0.08 AIDS, n (%)45 (51.1)17 (63.0)15 (51.7)13 (40.6)0.23 ART, n (%)63 (71.6)17 (63.0)19 (65.5)27 (84.4)0.13 Hepatitis B, n (%)7 (8.9)1 (4.2)4 (15.4)2 (6.9)0.17 Hepatitis C, n (%)22 (26.2)7 (29.2)4 (14.3)11 (34.4)0.15 IDU n (%)9 (17.0)2 (22.2)3 (12.5)4 (20.0)0.72 Time HIV infection, months [IQR]84 [36-156]48 [24-114]108 [36-162]114 [36-171]0.04 CD4 count, cells/µL [IQR]217 [69-373]180 [15-354]211 [80-294]234 [143-449]0.18 GFR, ml/mn/1.73 m 2 [IQR]40 [12-63]20 [9-71]27 [11-52]55 [38-74]0.05 Proteinuria, mg/mmol [IQR]218 [114-508]406 [217-709]170 [108-400]160 [70-390]0.65

8. History of patients Total N= 88 1995-2000 N=27 2001-2003 N=29 2004-2007 N=32 p ARV with potential nephrotoxicity Indinavir19 (22.4)3 (12.0)8 (27.6)8 (25.8)0.33 Atazanavir6 (7.1)006 (19.4)0.01 Lopinavir11 (13.9)04 (14.3)7 (28.0)0.01 Abacavir18 (22.8)1 (3.8)6 (21.4)11 (44.0)<0.01 Tenofovir15 (17.6)06 (20.7)9 (29.0)0.02 Hypertension, n (%)29 (33.0)8 (29.6)11 (37.9)10 (31.3)0.79 Diabetes mellitus, n (%)11 (12.6)4 (14.8)4 (13.8)3 (9.7)0.82 Dyslipidemia n (%)21 (24.1)4 (14.8)6 (21.4)11 (34.4)0.12 Lipodystrophy, n (%)6 (7.5%)03 (11.1%)3 (9.7%)0.28 History of cardiovascular events, n (%)6 (6.8)2 (7.4)2 (6.9)2 (6.3)0.98 ACE-I therapy n (%)14 (16.5)4 (16.0)3 (10.7)7 (21.9)0.51 ARBs therapy n (%)5 (6.0)02 (7.4)3 (9.4)0.31

9. History of patients Total N= 88 1995-2000 N=27 2001-2003 N=29 2004-2007 N=32 p ARV with potential nephrotoxicity Indinavir19 (22.4)3 (12.0)8 (27.6)8 (25.8)0.33 Atazanavir6 (7.1)006 (19.4)0.01 Lopinavir11 (13.9)04 (14.3)7 (28.0)0.01 Abacavir18 (22.8)1 (3.8)6 (21.4)11 (44.0)<0.01 Tenofovir15 (17.6)06 (20.7)9 (29.0)0.02 Hypertension, n (%)29 (33.0)8 (29.6)11 (37.9)10 (31.3)0.79 Diabetes mellitus, n (%)11 (12.6)4 (14.8)4 (13.8)3 (9.7)0.82 Dyslipidemia n (%)21 (24.1)4 (14.8)6 (21.4)11 (34.4)0.12 Lipodystrophy, n (%)6 (7.5%)03 (11.1%)3 (9.7%)0.28 History of cardiovascular events, n (%)6 (6.8)2 (7.4)2 (6.9)2 (6.3)0.98 ACE-I therapy n (%)14 (16.5)4 (16.0)3 (10.7)7 (21.9)0.51 ARBs therapy n (%)5 (6.0)02 (7.4)3 (9.4)0.31

10. Histologic glomerular lesions

14. Patients’ characteristics according to the type of FSGS HIVAN N=26 (%) Classical FSGS N=23 (%) OR (CI, 95%)p Mean age, years [IQR]40 [34-46]46 [38-53]/0.06 Men, n (%)20 (76.9)18 (78.3)1.1 (0.28-4.15)1.0 African American, n (%)22 (88.0)13 (68.4)0.3 (0.06-1.4)0.11 Time HIV infection, months [IQR]42 [8-96]108 [36-156]/0.03 CD4 count, cells/mm 3 [IQR]74 [22-185]367 [179-516]/<0.01 CD4<200/µL, n (%)21 (80.8)5 (23.8)0.07 (0.02-0.3)<0.01 Undetectable HIV viral load, n (%)4 (20.0)13 (61.9)6.5 (1.6-26.5)0.01 AIDS, n (%)11 (42)12 (52)0.5 (0.16-1.8)0.49 HAART, n (%)13 (50.0)21 (91.3)0.1 (0.02-0.5)<0.01 Hepatitis B, n (%)1 (4.3)1 (4.8)1.1 (0.06-18.8)0.75 Hepatitis C, n (%)2 (8.7)7 (31.8)4.9 (0.9-26.9)0.06

15. Patients’ characteristics according to the type of FSGS HIVAN N=26 (%) Classical FSGS N=23 (%) OR (CI, 95%)p Hypertension3 (12)11 (48)7.02 (1.6-30.1)<0.01 Dyslipidemia, n (%)3 (12)9 (39)4.7 (1.1-20.5)0.04 Diabetes mellitus, n (%)2 (8)2 (9)1.2 (0.15-9.3)0.86 Lipodystrophy, n (%)0 (0)3 (13.6)/0.09 GFR, ml/mn/1.73 m 2 [IQR]10 [7-26]52 [36-71]/<0.01 GFR<30 ml/mn/1.73 m2, n (%)24 (92.3)4 (17.4)0.02 (0.003-0.1)<0.01 Proteinuria, mg/mmol [IQR]215 [120-964]138 [104-420]/0.07

16. Risk factors associated with HIVAN Univariate analysisMultivariate analysis Risk factorsHIVAN n=26 Others n=62 OR (95% CI)p p African-Americans, n (%)22 (88)27 (61)4.6 (1.2-17.8)0.023.2 [0.5-21.6]0.2 CD4<200/mm 3, n (%)21 (81)18 (32)9.1 (3.0-28.0)<0.017.5 [1.4-39.7]0.02 GFR<30ml/mn/1.73m 2, n (%)24 (92)14 (23)41.1 (8.6-196)<0.0120.4 [3.5-120.3]<0.01 Absence of ARV, n (%)13 (50)12 (19)4.2 (1.5-11.3)<0.012.7 [0.6-12.8]0.2

17. HIVAN scale VariablesScore African-American origin3 points CD4<200/mm 3 8 points GFR<30ml/min/1.73m 2 20 points Absence of ARV3 points 1-specificity Sensitivity HIVAN scale > 21 points Sensitivity = 92% Specificity = 81% Positive predictive value = 67% Negative predictive value = 96% Area Under Curve = 0.93 (p<0.001) HIVAN scale > 21 points Sensitivity = 92% Specificity = 81% Positive predictive value = 67% Negative predictive value = 96% Area Under Curve = 0.93 (p<0.001) ROC curve

18. Discussion Less Blacks and HCV-coinfected patients than in prior African-American studies Indications for kidney biopsies could have changed between the 3 periods (under biopsy of HIVAN profile patients) A real switch of FSGS types over time Classical FSGS associated with long term infection, cardiovascular risk factors and lipodystrophy A discriminant clinical and biological scale for identification of HIVAN

19. Conclusion The emergence of one glomerular disease among treated HIV-infected patients: the classical FSGS A particular susceptibility for Black population concerning both main types of glomerular diseases in HIV infection, as previously shown in genetic linkage studies An HIVAN scale ≤ 21 points coud lead to perform the kidney biospy