1. Long-term clinical and viro-immunologic outcomes of post-treatment controllers (PTCs) in the ANRS-VISCONTI study Laurent HOCQUELOUX, MD Orléans’ Regional Hospital (France) For the ANRS EP47 VISCONTI study group ANRS satellite symposium at Kuala Lumpur – 2 July 2013

2. Reports of PTCs (published) Lisziewicz J. et al, NEJM 1999 Lafeuillade A. et al, J Infect Dis 2003 Steingrover R. et al, AIDS 2008 Hocqueloux L. et al, AIDS 2010 Salgado M. et al, Retrovirology 2011 Goujard C. et al, Antiv Therapy 2012 Lodi S. et al, Arch Intern Med 2012 Sáez-Cirión A. et al, PLoS Pathogens 2013 N=1 N=2 N=5 N=1 N=14 N=11 N=14

3. Lafeuillade A. et al, J Infect Dis 2003 Hocqueloux L. et al, AIDS 2010 Goujard C. et al, Antiv Therapy 2012 Sáez-Cirión A. et al, PLoS Pathogens 2013

4. Viro-Immunologic Sustained CONtrol after Treatment Interruption French nationwide study including patients with: cART initiation within 10 weeks after acute infection cART for (at least) one year Undetectable VL while on treatment VL remaining <400 cp/mL for (at least) 12 months after treatment interruption

5. Inclusions on June 2013 18 patients diagnosed at primary HIV-infection (PHI) Median year of diagnosis: 2000 (IQR: 1998-2001) Median age at PHI: 33y (IQR: 31-39) Sex male = 76% / white ethnicity = 73% / MSM: 56% Symptomatic at PHI = 88% – AIDS-related events = 1/18 (5%) First cART: – Dual / triple / quadruple: 7% / 73%/ 20% – PI-based: 80% Median duration of cART = 2.4 years (IQR: 1.7-4.7)

6. Viro-immunologic characteristics before TI Median (IQR) At PHIAt TI CD4/mm 3 544 (416-781) 915 (742-1050) Ratio CD4/CD80.80 (0.41-1.05) 1.51 (0.98-1.96) Viral load, Log cp/mL5.1 (4.3-6.0) <1.7 ADN-VIH, Log cp/10 6 PBMC3.4* (3.1-3.6) 2.15* (1.9-2.6) * n=7 (data from the PRIMO cohort)

7. PTCs often achieved a normal CD4 count during cART % of patients achieving CD4 ≥ 900 CD4/mm 3 Since CHI 1, n=283 Since PHI 1, n=36 Pre-PTC, n=18 P < 0.0001, Log-rank test Time under suppressive cART, y 1 Hocqueloux et al., JAC 2013 P = 0.047, Log-rank test

8. Clinical outcomes Median duration since TI = 9.3 years (IQR: 8.4-10 – range: 4.5-12.5) Median age = 48y (IQR: 43-53) No AIDS-defining illness since TI Treatment resumed in 1/18 patient (5%) – 1 patient experienced a cancer (non-AIDS defining) – VL <40 cp/mL at treatment resumption – Complete remission of cancer at 2 years After one decade without antiretroviral therapy, PTC are going well

9. Virologic outcomes Only 3/18 patients (16%) “rebounded” just after TI (VL = 86, 1976, 4900 cp/ml) No patients resumed cART due to viral failure Overall, 338 VL were measured after TI – 287/338 (85%) were <50 cp/mL – 45/338 (13%) were >50 and <400 cp/mL – 6/338 (2%) were >400 cp/mL Low viral reservoir (PBMC, gut 1 ) – Still decreasing since TI in some of them 2 1 Avettand-Fènoël V, AIDS 2008 2 Rouzioux C, ANRS symposium

10. Virologic outcomes Median (IQR) or %No residual viremia (n=13) Residual viremia + (n=5) P-value Residual viremia is defined by 2 consecutive VL >50 cp/mL

11. Virologic outcomes Median (IQR) or %No residual viremia (n=13) Residual viremia + (n=5) P-value VL after TI, n (%) <50 cp/mL 50 to 400 cp/mL >400 cp/mL 199 (100%) 197 (99%) 2 (1%) 0 (0%)

12. Virologic outcomes Median (IQR) or %No residual viremia (n=13) Residual viremia + (n=5) P-value VL after TI, n (%) <50 cp/mL 50 to 400 cp/mL >400 cp/mL 199 (100%) 197 (99%) 2 (1%) 0 (0%) 139 (100%) 90 (65%) 43 (31%) 6 (4%) <0.0001

13. Virologic outcomes Median (IQR) or %No residual viremia (n=13) Residual viremia + (n=5) P-value VL after TI, n (%) <50 cp/mL 50 to 400 cp/mL >400 cp/mL 199 (100%) 197 (99%) 2 (1%) 0 (0%) 139 (100%) 90 (65%) 43 (31%) 6 (4%) <0.0001 Ultrasensitive VL, cp/mL5 (3-5)45 (12-89)0.014

14. Virologic outcomes Median (IQR) or %No residual viremia (n=13) Residual viremia + (n=5) P-value VL before at PHI, cp/mL5.6 (4.7-6.9)4.3 (3.3-4.9)0.04 VL after TI, n (%) <50 cp/mL 50 to 400 cp/mL >400 cp/mL 199 (100%) 197 (99%) 2 (1%) 0 (0%) 139 (100%) 90 (65%) 43 (31%) 6 (4%) <0.0001 Ultrasensitive VL, cp/mL5 (3-5)45 (12-89)0.014

15. Virologic outcomes Median (IQR) or %No residual viremia (n=13) Residual viremia + (n=5) P-value VL before at PHI, cp/mL5.6 (4.7-6.9)4.3 (3.3-4.9)0.04 VL after TI, n (%) <50 cp/mL 50 to 400 cp/mL >400 cp/mL 199 (100%) 197 (99%) 2 (1%) 0 (0%) 139 (100%) 90 (65%) 43 (31%) 6 (4%) <0.0001 Ultrasensitive VL, cp/mL5 (3-5)45 (12-89)0.014 HLA B*27 or B57, n (%)0/10 (0%)3/5 (60%)0.022

16. Immunologic outcomes (all) MedianAll PTC (n=18) CD4/mm 3 544 Ratio CD4/mm 3 915 Ratio CD4/mm 3 855 Ratio At PHI At TI At last visit P=0.001 P=0.5

17. Immunologic outcomes (all) MedianAll PTC (n=18) CD4/mm 3 Ratio0.80 CD4/mm 3 Ratio1.51 CD4/mm 3 Ratio1.48 At PHI At TI At last visit P=0.003 P=0.8

18. Immunologic outcomes (RV-) MedianRV- (n=13) CD4/mm 3 502 Ratio CD4/mm 3 954 Ratio CD4/mm 3 983 Ratio At PHI At TI At last visit P=0.001 P=0.9

19. Immunologic outcomes (RV-) MedianRV- (n=13) CD4/mm 3 Ratio0.75 CD4/mm 3 Ratio1.75 CD4/mm 3 Ratio2.10 At PHI At TI At last visit P=0.013 P=0.7

20. Immunologic outcomes (RV+) MedianRV- (n=13)RV+ (n=5) CD4/mm 3 593 Ratio CD4/mm 3 583 Ratio CD4/mm 3 530 Ratio At PHI At TI At last visit P=0.3 P=0.6

21. Immunologic outcomes (RV+) MedianRV- (n=13)RV+ (n=5) CD4/mm 3 Ratio0.65 CD4/mm 3 Ratio1.35 CD4/mm 3 Ratio0.88 At PHI At TI At last visit P=0.3 P=0.12

22. Immunologic outcomes (RV- vs RV+) MedianRV- (n=13)RV+ (n=5)P-value CD4/mm 3 5025930.6 Ratio CD4/mm 3 9545830.14 Ratio CD4/mm 3 9835300.003 Ratio At PHI At TI At last visit

23. Immunologic outcomes (RV- vs RV+) MedianRV- (n=13)RV+ (n=5)P-value CD4/mm 3 Ratio0.750.650.4 CD4/mm 3 Ratio1.751.350.17 CD4/mm 3 Ratio2.100.880.02 At PHI At TI At last visit

24. Summary Overall, patients included in VISCONTI study: – Show a sustained viral control – Have stable CD4 count and CD4/CD8 ratio – Are going well Two different groups ? – Most of PTC show a complete viral suppression and keep a ‘normal’ CD4 count – For one third of cases, a residual (and intermittent) viremia is associated with lower CD4 count and ratio after TI

25. Summary Overall, patients included in VISCONTI study: – Show a sustained viral control – Have stable CD4 count and CD4/CD8 ratio – Are going well Two different groups ? – A majority of PTCs show a complete viral suppression and keep a ‘normal’ CD4 count and ratio – Whereas in some an intermittent residual viremia is associated with poorer immunologic outcomes after TI

26. Ackowledgments All patients who accepted to participate in the study Special thanks to: – Christine Rouzioux, V. Avettand-Fènoël (Necker Hospital) – Asier Sáez-Cirión, G. Pancino (Pasteur Institute, Paris) – Physicians in charge of the patients: T. Prazuck, A. Lafeuillade, J.P. Viard, B. Cardon, L. Cotte, P. Miailhes, C. Brochier, C. Merle de Boever, C. Lascoux-Combes, L. Crevon, F. Bastides, J. Derouineau, G. Le Moal and all investigators of the PRIMO cohort – CHR d’Orléans – La Source (sponsor) – The ANRS’ AC32 and PRIMO / CODEX cohorts