1. A randomized trial to estimate efficacy and safety of 2 doses of raltegravir and efavirenz for treatment of HIV-TB co-infected patients : ANRS 12 180 REFLATE TB trial. B. Grinsztejn 1, N. De Castro 2,3, V. Arnold 4, V. Veloso 1, M. Morgado 5, JH. Pilotto 6, C. Brites 7, JV. Madruga 8, N. Barcellos 9, BR Santos 10, C. Vorsatz 1, C. Grondin 4, M. Santini-Oliveira 1, O. Patey 11, C. Delaugerre 2,3, G. Chêne 4, J-M. Molina 2,3 and the ANRS 12 180 Reflate TB study group. 1 Laboratory of Clinical Research on STD/AIDS, IPEC, Fiocruz, Rio de Janeiro, Brazil, 2 University of Paris Diderot, Sorbonne Paris Cité, INSERM U941, 3 Hospital Saint-Louis, AP- HP, France, 4 INSERM U897 and University Bordeaux Segalen, 5 Laboratory of AIDS and Molecular Immunology, Fiocruz, Rio de Janeiro, Brazil, 6 Department of STD/AIDS, Nova Iguacu, Brazil, 7 Laboratory of Research in Infectious Diseases, Salvador de Bahia, Brazil, 8 Research Unit for Treatment of STD/AIDS, Sao Paulo, Brazil, 9 Department of Care and Therapy, Porto Alegre, Brazil, 10 Department of Infectious Diseases, Porto Alegre, Brazil, 11 Department of Internal and Tropical Medicine, Villeneuve St George, France. XIX International AIDS Conference July 26, 2012 Abstract #:THLBB01 CMG-EC ISO 9001:2008 certified for its clinical research activities

2. Background WHO guidelines: efavirenz (EFV)-based regimen 1 st -line therapy for HIV and Tuberculosis (TB) co-infected patients Potential limitations to EFV use –Adverse Events : cutaneous rash, central nervous system toxicity –Transmitted drug resistance to NNRTIs –Teratogenicity Potential interest of Raltegravir (RAL) in HIV-TB co-infection –Favorable safety profile –Not metabolized by CYP450 –Induction by rifampin (RIF): ↓ C trough 61%, ↓AUC 40% in healthy volunteers partially compensated by ↑ RAL 800 mg bid Objective of the ANRS 12180 REFLATE TB trial : estimate the antiviral efficacy of two doses of RAL +TDF+ 3TC, in HIV-1 naive patients co-infected with TB ANRS 12 180

3. Study design Phase II open label randomized multicenter trial W0 W 24 W48 1:1:1 + RAL 800 mg bid TDF245 mg qd + 3TC 300mg qd + EFV 600 mg qd TDF245mg qd + 3TC 300mg qd + RAL 400 mg bid + RAL 400 mg bid ANRS 12 180 Primary endpoint mITT HIV RNA<50copies/mL TB drugs RHZE 2mo followed by RH 4mo HIV RNA>1000 cp/mL ART naïve Confirmed or probable TB RIF containing regimen Sample size : 50 patients/arm, 80% power to show ≥70% success at W24 TDF245 mg qd + 3TC 300 mg qd

4. ANRS 12 180 4 Flow chart Randomized n = 155 Not treated n = 1 RAL 400 n = 51 RAL 800 n = 52 Not treated n = 1 Not included n = 24 Lab abnormality n=9 HIV RNA < 1000cp/ml n=4 ARV treatment n=2 Death n=2 Other n=7 Screened n = 179 France n = 8 Brazil n = 171 EFV n = 52 Disposition at W24 On study drug n = 43 Discontinued study drug n = 8 Adverse event n = 2 Virologic failure n = 4 Lost to follow up n = 0 Withdrawal n = 0 Death n = 2 ANRS 12 180 Not treated n = 0 mITT analysis n = 51 Disposition at W24 On study drug n = 50 Discontinued study drug n = 1 Adverse event n = 0 Virologic failure n = 0 Lost to follow up n = 0 Withdrawal n = 1 Death n = 0 Disposition at W24 On study drug n = 43 Discontinued study drug n = 8 Adverse event n = 3 Virologic failure n = 1 Lost to follow up n = 1 Withdrawal n = 1 Death n = 2

5. Baseline characteristics EFVRAL 400RAL 800 N = 51 Male, n (%)39 (76)35 (69)38 (75) Age in years, median [IQR]35 [29-45]37 [31-44]38 [33-43] Ethnicity, n (%) Black15 (29)14 (27)21 (41) Mixed21 (42) 7 (14) White15 (29)16 (31)23 (45) BMI in kg/m 2, median [IQR]21 [19-23] 20 [17-23] CD4+/mm 3, median [IQR]129 [45-308]115 [50-213]166 [80-367] CD4≤50 /mm 3, n (%)14 (27)12 (24)5 (10) HIV RNA in log 10 cp/ml, median [IQR]5 [4.5-5.5]4.9 [4.4-5.4]4.9 [4.2-5.4] HIV RNA>100,000 cp/ml, n (%)26 (51)20 (39)24 (47) TB location, n (%) Pulmonary only20 (39)24 (47)25 (49) Pulmonary and Extrapulmonary24 (47)19 (37)21 (41) Extrapulmonary only7 (14)8 (16)5 (10) Bacteriologically confirmed TB, n (%)23 (45)26 (51)25 (49) Median time between anti-TB and ART, weeks [IQR]5.7 [4.9-6.9]6.0 [4.9-7.1]5.9 [5-6.7] Hepatitis B or C co-infection, n (%)2 (4)8 (16)6 (12) ANRS 12 180

6. Efficacy outcomes, W24 Primary endpoint : HIV RNA<50 cp/mL at W20 and W24, mITT (M=F, D/C=F) ANRS 12 180 Secondary endpoint : HIV RNA<400 cp/mL at W20 and W24, mITT (M=F, D/C=F) EFV N = 51 RAL 400 N = 51 RAL 800 N = 51 PRIMARY ENDPOINTn% [95% CI]n %[95% CI]n% Success 3263[49-76]3976[65-88]4078[67-90] Failure 1937[24-51]1224[12-35]1122[10-33] Virologic failure 15 124 AE leading to treatment discontinuation 203 Death202 Withdrawal / Lost to Follow-up002 EFV N = 51 RAL 400 N = 51 RAL 800 N = 51 SECONDARY ENDPOINT n%[95% CI]n% n% Success 3976[65-88]4180[69-91]4282[72-93] Failure 1224[12-35]1020[9-31]918[7-28] Virologic failure 8102 AE leading to treatment discontinuation 203 Death202 Withdrawal / Lost to Follow-up002

7. ANRS 12 180 % participants with HIV RNA<50 cp/mL at each visit (M=F, study treatment discontinuation=F)

8. Drug resistance by W24 EFV N = 51 RAL 400 N = 51 RAL 800 N = 51 VF with HIV RNA>50 cp/mL, n (%)15 (29)12 (24)4 (8) VF with HIV RNA>400 cp/mL, n (%)8 (16)10 (20)2 (4) Participants analyzed for resistance, n652 Any INSTI-resistance, n41 N155H2 E92EQ1 Y143R/C11 Any NNRTI-resistance, n4 K103N* 2 V106M1 Y188L1 Any NRTI resistance, n 541 M184V/I541 K65R3 Others (TAMs, K70E)11 ANRS 12 180 * already present at baseline

9. Median CD4 cell count at each visit (available data) ANRS 12 180

10. Adverse events (AE) through W24 EFVRAL 400RAL 800 n = 51 Any AE ≥ grade 2, n (%) 39 (76)37 (73) Grade 3 or 4 clinical AE, n (%) 13 (25)11 (22)12 (22) AE leading to drug discontinuation, n203 Hepatotoxicity*002 Cutaneous rash101 Gynecomastia100 Grade 3 or 4 IRIS 113 AIDS-defining events, n (%) 2 (4)3 (6)0 (0) Death**, n (%)2 (4)0 (0)2 (4) ANRS 12 180 * Both related to TB drugs: fulminant hepatitis with liver transplant in one patient **Causes of death: EFV arm: 1 TB meningitis W4, 1 sepsis related to TB W6 RAL 800 arm : 1 unknown W2, 1 TB meningitis W12

11. ANRS 12 180 EFVRAL 400RAL 800 Laboratory AE of grade 3 or 4, n (%) n = 51 At least one such AE10 (19)13 (25)9 (17) ALT > 5 ULN 3 (6)1 (2) AST > 5ULN 3 (6) PAL > 5ULN 2 (4)0 (0)1 (2) Bilirubin > 5ULN 2 (4)0 (0) Neutrophil count < 750/mm 3 3 (6)5 (10) Platelets < 50 000/mm 3 0 (0)2 (4)1 (2) Haemoglobin < 7g/dl1 (2)2 (4)1 (1) Creatinine > 2.9 ULN 1 (2)0 (0) Glycemia > 16.5mmol/l0 (0)1 (2)0 (0) Laboratory AE (grades 3-4) through W24

12. Conclusion In this phase II study, high rates of success were achieved at week 24 with raltegravir 400 mg bid or 800 mg bid and EFV 600 mg qd in combination with TDF and 3TC, in patients receiving a rifampin-containing TB treatment In the context of HIV and TB co-infection, raltegravir (400 mg bid or 800 mg bid) had a good safety profile Raltegravir seems to be a suitable alternative to EFV for HIV-TB co-infected patients Optimal raltegravir dose yet to be defined based on PK sub- study and W48 follow-up data ANRS 12 180

13. Aknowledgements The patients for their participation and their commitment during the study and the REFLATE TB Study Group: INSERM-ANRS B. Bazin S. Couffin-Cadiergues A. Diallo C. Rekacewicz B. Larouzé (Chair, Brazil site) BRAZILIAN AIDS PROGRAM C. Possas (co-Chair, Brazil site) COORDINATING CTU INSERM U897/ISPED G. Chêne (head) V. Arnold A. Beuscart C. Fagard C. Grondin N. Stival S. Tabuteau INDEPENDANT DATA & SAFETY MONITORING COMMITTEE F. Raffi (chair) JP. Aboulker D. Descamps B. Durovni MERCK SHARPE & DOHME-CHIBRET (donated raltegravir) F. Durand A. De Jacquelot GILEAD (donated tenofovir) A. Jacob P. Pétour V. Tilliet TRIAL STEERING COMMITTEE JM. Molina (Chair) X. Anglaret V. Arnold B. Bazin V. Calvez G. Chêne N. De Castro C. Delaugerre B. Grinsztejn M. Morgado C. Rekacewicz H. Sauvageon AM. Taburet V. Veloso C. Vorsatz CLINICAL CENTERS Rio de Janeiro (B. Grinsztejn) Nova Iguaçu (JH.Pilotto) Salvador (C. Brites) Porto Alegre (N. Barcellos) Porto Alegre (B. Rigel Santos) Sao Paulo (J. Valdez Madruga) Saint-Louis, Paris (JM. Molina) Villeneuve Saint- Georges (O. Patey) LABORATORY, PHARMACY Rio de Janeiro (MC. Lourenço) Rio de Janeiro (E. Wreneck Barroso) Rio de Janeiro (T. Torres) Pitié-Salpêtrière, Paris (G. Carcelain) Saint-Louis, Paris (E. Cambau) Saint-Louis, Paris (I. Madelaine) EVENTS VALIDATION COMMITTEE G. Breton B. Denis S. Wagner BRAZIL CTU LABORATORY OF CLINICAL RESEARCH ON STD/AIDS - FIOCRUZ B. Grinsztejn (head) R. Millan E. Sampaio M. Santini V. Veloso C. Vorsatz CMG-EC ISO 9001:2008 certified for its clinical research activities