1

for the ANRS 12 136 Temprano trial group Higher mortality in HIV-HBV coinfected persons with elevated HBV replication in the Temprano Trial ANRS 12 136 and 12 240 G. Menan Kouamé1, R. Moh1, 4, A. Boyd5, A. Badje1,2, D. Gabillard2, E. Ouattara2, JB Ntakpe1, A. Emième 3, S. Maylin6, S. Eholié1,4, K. Lacombe5, X. Anglaret1, 2, C. Danel1, 2 for the ANRS 12 136 Temprano trial group 1 : Programme PAC-CI, ANRS research site, Abidjan, Côte d’Ivoire 2 : INSERM U897, Université de Bordeaux, France 3 : CeDReS, CHU Treichville, Abidjan, Côte d’Ivoire 4 : Service des Maladies Infectieuses et Tropicale, CHU de Treichville, Abidjan, Côte d’Ivoire 5 : INSERM, UMR S1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France 6 : Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France 2

Background Around 10% of HIV-infected adults are co-infected with hepatitis B virus (HBV) in West African countries. HBV infection diagnosis is often ignored or delayed The impact of HIV-HBV co-infection on mortality is largely unknown, especially among patients in West African countries with higher CD4 cell counts. =>We aim to analyze the association between HBV replication and mortality during long-term follow-up in the Temprano trial ANRS 12136, a randomized controlled trial to assess the benefits and risks of early ART and 6 months IPT (Isoniazid Prophylaxis Therapy) on HIV infected adults in 9 centers, Abidjan Côte d’Ivoire 3

TEMPRANO* trial design Main outcome Death of any cause or severe morbidity (AIDS, not AIDS, invasive bacterial diseases cancers) Main inclusion criteria - CD4 <800/mm3 - no reason to start HAART according to WHO - No tuberculosis ART by WHO criteria ART by WHO criteria 6 months INH ART TDF-FTC EFV or TDF FTC r/LPV Immediate ART 6 months INH Immediate ART N= 2076 (519 per arm) Temprano (followed up to 30 months) 4 * Temprano study group, N Engl J Med. 2015;373:808-22

Long-term follow-up Temprano long-term follow-up Temprano 1ary Outcome Death ART by WHO criteria ART by WHO criteria 6 months INH Immediate ART 6 months INH Immediate ART N= 2076 (519/arm) Temprano (followed up to 30 months) Temprano long-term follow-up (until last participant reached 30 months) * Temprano study group, N Engl J Med. 2015;373:808-22 5

Methods Hepatitis B : Hepatitis B surface Antigen at inclusion in the trial for all the patients (Mini Vidas®, Biomérieux) for HBsAg-positive patients: Hepatitis B « e » antigen and antibody (n=125; Elecsys Assay, Roche) HBV DNA (PCR technique1 ) Analysis for this sub-study: Cox multivariate models adjusted on CD4, HIV viral load, Isoniazid prophylaxis, ARVs and Gender Main variable of interest: HBV DNA viral load, cut of choose by Youden index Primary endpoint : All-cause mortality 1Boyd A et al., Antiviral Ther, 2015. 6

Temprano Trial, patients analyzed n=2052* Flow Chart Temprano Trial, patients analyzed n=2052* Positive HBs Ag, n=190 (9%) LTFU n= 23 (12%) Death n= 12 (6%) Long term follow up, n=155 Negative HbS Ag, n= 1862(91%) LTFU n= 183 (10%) Death n=74 (4%) Long term follow up, n=1605 *as the 2076 patients enrolled, HIV 2 (n= 15), negative HIV test (n=4) , ART+ (1) Missing HBV DNA measures (n=4) 7

Baseline characteristics according to HBs status   HBsAg serology p-value Positive Négative N (%) 190 (9%) 1862 (91%) Male sex, N(%) 57 (29%) 385 (20%) 0,004 CD4, cells/mm3 , median 456 465 0,70 HIV viral load Log10/ml, median 4.8 4.6 0,08 Early ART, N (%) 103 (53%) 930 (50%) 0,36 IPT, N (%) 102 (53%) 928 (50%) 0,42 TGP > N , UI/ml, N (%) 29 (15%) 129 (7%) <0,01 Ag Hbe Positive 17 (14%) - HBV DNA, copies/ml, Médian (IQR) 523 (<12-11420) HBV DNA , copies/ml < 7000 139 (73 %) > 7000 51 (27%) 8

Survival 0.96 0.78 p=0.02 9

Associated factors with mortality Multivariable analysis TAR Deaths Incidence mortality µ aHR* [CI 95%] p AgHBS Negative 8528 74 0.87 - AgHBS Positive 867 12 1.38 1.48 [0.80- 2.74] 0.20 AgHBS+ <7000 copies/ml and Ag HBs- 9166 80 Ag HBS+ >7000 copies/ml 228 6 2.63 2.51 [1.09- 5.80] 0.03 TAR: time at risk (years) µ /100 Person years *2 models, adjusted on early ART, IPT, HIV Viral Load (<5 vs >5) and CD4 at inclusion (>500 vs <500) and gender 10

Discussion There is a 2.5-times higher mortality in patients with HBV DNA greater than 7000 copies/ml enrolled in the Temprano trial Early ART needs to be provided to all HIV infected-patients and especially to coinfected patients with high HBV replication 11

Site ANRS de Côte d’Ivoire THANKS All individuals who agreed to be included and followed in the Temprano trial and all the teams of CEPREF, CMSDS, CIRBA, La Pierre Angulaire, Hôpital Nord d’Abobo, Centre El Rapha, FSU Anonkoua Koute, USAC, SMIT. Programme PAC-CI Site ANRS de Côte d’Ivoire 12 Thanks to MSD, and Gilead for providing Efavirenz and Truvada for the 2076 patients

FULLY FUND THE GLOBAL FUND 13