Factors associated with conversion or reversion of QuantiFERON ® -TB Gold after 12 months of follow up with or without ART and with or without INH prophylaxis in HIV infected adults in sub- Saharan Africa (ANRS 12224) Sub study of Temprano Trial, ANRS ICASA, Addis Abeba, 3 au 8 décembre 2011 C. Danel, M. Kabran, A. Inwoley, JL Herrmann, R. Moh, A. Badje, D. Gabillard, JB Ntakpe, S. Eholie, X. Anglaret 1

Background - Objective Background: –Tuberculosis and HIV infection are both endemic in sub-Saharan Africa. –QuantiFERON®-TB Gold is more specific than tuberculin skin test for the diagnosis of Tuberculosis infection. –There are few data on the evolution of interferon gamma test in patients receiving antiretroviral therapy (ART) or INH prophylaxis. –The Temprano trial assess the benefits and risks of early ART (<800 CD4/mm 3 ) and 6 months INH prophylaxis in HIV1-infected adults in Côte d’Ivoire, West Africa Objective : –To describe the incidence and factors associated with 12-month conversion and reversion of the QuantiFERON®-TB Gold test in HIV-infected adults on/off ART and on/off INH prophylaxis 2

Methods (1) QuantiFERON-TB Gold The QuantiFERON®-TB Gold In-Tube is an interferon gamma release assay (Cellestis, GmbH Darmstadt, Germany). The test is : – Positive: IFN > 0.35 UI/ml – Negative: IFN < 0.35 UI/ml – Indeterminate: mitogene 8 UI/ml Definitions –Conversions : IFN 0.35 UI/ml at M12 –Reversions : IFN > 0.35 UI/ml at baseline and IFN < 0.35 UI/ml at M12 Statistical analyses : –Univariate and multivariate logistic regression –Baseline and follow up characteristics included in analysis : Baseline : age, sex, WHO clinical stage, CD4 count, plasma HIV-1 RNA, Hemoglobin, HBs Antigen, Between baseline and Month-12: INH, ART, CD4 count evolution 3

Temprano ANRS Study design N= 2000 Methods (2) Patients 4

Temprano Trial – QuantiFERON Study N=1000 At inclusion N=450 At M12 N= 2000 QTF Study Methods (2) Patients 5

Patients with QTF-TBG test at baseline and at Month-12: Baseline and follow up characteristics Women, n (%) 340 (79 %) Baseline age (years), median (IQR) 36 (30-42) Baseline CD4/mm 3, median (IQR) 379 ( ) Month-12 CD4 /mm 3, median (IQR)479 ( ) Baseline WHO stage 1262 (61%) 2114 (27%) Baseline Plasma HIV-1 RNA, log 10 copies/mL, median (IQR) 4,6 (3,9-5,2) Baseline QuantiFERON-TB Gold test Positive > 0,35/ml 166 (39 %) Negative < 0,35UI/ml262 (61 %) Patients on ART between baseline and Month-12, n (%) 276 (64%) 6-month INH between baseline and Month-12, n (%) 170 (40 %) Active Tuberculosis at baseline, n (%)7 (2%) Active Tuberculosis between baseline and Month-12, n (%)10 (2%) N=430 Results (1) 6

7 Conversion and reversion between baseline and month-12 QuantiFERON-TB Gold Month-12 N (%) QuantiFERON-TB Gold Baseline Negative b Positive a Indeterminate c Overall Negative b 237 (91%)24 (14%)1 (50%)262 Positive a 23 (9%)142 (85%)1 (50%)166 Indeterminate c 1 (0%)1 (1%)0 (0%)2 Overall a positive: ≥0,35 UI/ml ; b négative <0,35UI/ml ; c indeterminate N= 430

Conversion and reversion between inclusion and Month-12, by definitions Conversion N%IC 95% BaselineMonth-12 <0,35 UI/ml > 0,35 UI/ml 249.2( ) <0,35 UI/ml >0,7 UI/ml 166.1( ) <0,35 UI/ml >0,35 UI/ml and increase > 35% 249.2( ) <0,35 UI/ml > 0,35 UI/ml and increase >30 UI/ml 218.0( ) Reversion BaselineMonth-12 >=0.35 UI/ml <0,35UI/ml ( ) >=0.70 UI/ml <0,35UI/ml ( ) >=0.35 UI/ml 30 % ( ) >=0.35 UI/ml 0,35 UI/ml ( ) 8

9 Factors associated with conversion Odds Ratio 95% CIp Baseline characteristics Sex (men vs. women) 0,9 (0,3-2,5) 0,8 Age (18-40 y vs. > 40 y) 0,8 (0,3-1,9) 0,7 WHO stage (3 vs.1 or 2) 1,1 (0.3-4,1) 0,8 Hemoglogin ( 10g/dl) 1,3 (0,5-3,3) 0,5 CD4 ( 500/mm 3 ) 0,4 (0,2-1,1) 0,1 HIV-1 RNA ( 5.0 log10/ml) 1,5 (0,6-3,9) 0,4 HBs Antigen (positive vs.negative) 0,9 (0,2-4,0) 0,8 M0-M12 characteristics ART (yes vs.no) 0,9 (0,4-2,2) 0,9 6-month INH (yes vs.no) 0,8 (0,3-1,9) 0,7 ΔCD4 Month12- baseline <0 (yes vs.no) 1,2 (0,5-1,1) 0,1

UnivariateMultivariate OR95CI%pOR95CI%p Baseline characteristics Sex (men vs. women) 1.6 ( ) Age (18-40 y vs. > 40 y) 7.0 ( ) (1.3 – 28.0) 0.01 WHO stage (3 vs.1 or 2) 0.5 ( ) Hemoglogin ( 10g/dl) 0.6 ( ) CD4 ( 500/mm 3 ) 0.8 ( ) HIV-1 RNA ( 5.0 log10/ml) 1.5 ( ) HBs Antigen (positive vs.negative) 0.7 ( ) M0-M12 characteristics ART (yes vs.no) 0.2 (0,1-0.5) month INH (yes vs.no) 1.5 ( ) ΔCD4 Month12- baseline <0 (yes vs.no) 3.2 ( ) ( ) 0.03 Factors associated with reversion 10

First study on12-month QuantiFERON-TB gold conversion and reversion in HIV infected-adults with or without ART and with or without INH in sub-Saharan Africa ART was not associated with conversion, but was associated with reversion in univariate analysis. In multivariate analysis, the association with ART appeared to be mainly driven by the CD4 count evolution INH was associated neither with conversion nor with reversion Younger people had higher risks of reversion than older ones Discussion 11

Aknowledgements A tous les patients qui participent à l’essai Aux investigateurs et équipes: – SMIT: S Eholie (IP), G Nzunettu, D Rabe, B Sidibé, S Tuo, R Gbê, M Abanou, E Bissagnene – CIRBA:, H Chenal, O Ba-Gomis, Daligou, D Hawerlander, F Kouamé, A Douhouré, L Bombo, J Oupoh – CNTS: A Minga, A Yao, L Dohoun, K Martin, E Amon, K N’Dri, MJ N’dri, I Bohouo – USAC: S Koulé, A Adou, I Adou, J Djobi, F Dembélé, V Kouadio, J Séri, C Guéhi, A Ani – CePReF: E Messou, A Anzian, P Gouesse, A Kati-Coulibaly, J Gnokoro, MC Kassi, A Tchehy – HG Abobo nord: E Kouamé, D Koua, A Kouamé, S Amon, L Beugré, A Yapo, Y N’zué, Y N’dri – FSU Anonkoua kouté: O Makaïla, M Oyébi, S Sodenougbo, G Kouamé, K Christian, M Gbaguidji, N Mbakop – La pierre angulaire: M Kadio-Morokro, AC Kouadio, S Gountodji, E Yédjédji, P Kouadio, MJ Kouakou – El Rapha : Babatounde N, Babatounde C, Bleoué G, Tchountedjem M, Kouassi C – CeDReS: H Menan, A Emieme, A Inwoley, T Ouassa, TA Toni, M Kabran – Equipes de coordination, de monitorage et administrative: X Anglaret (IP), C Danel, R Moh, A Badjé, JB N’takpé, E Ouattara, J Lecarrou, D Gabillard, R Konan, S Konan, B Siloué, C Kouamé, C N’Chot, H Djetouan, G Kouamé, E Yao, A Kouakou, B Kouadio Conseil Scientifique: JM Massumbuko, E Bissagnene, G Chêne, K Domoua, M Dosso, PM Girard, V Jarlier, C Perronne, C Rouzioux, PS Sow. Observateurs : A de Jacquelot, A Jacob, C Rekacewicz Comité indépendant : B Autran, X Blanc, D Costagliola, O Doumbo,S Mboup, Y Yazdanpanah; Représentants du promoteur (ANRS): JF Delfraissy, B Bazin, A N’Diaye, C Canon, C Rekacewicz, C Lallemand Comité d’éthique de Côte d’Ivoire Gilead Sciences pour le don de Truvada ®: A Jacob, P Petour, V Tillier Merck Sharp & Dohme pour le don de Stocrin®: A Aslan, A de Jacquelot 12