1. Time to HAART Resume after Structured Treatment Interruption is Strongly Associated with HIV DNA Level in PBMC at Interruption: Results of the ANRS 116 SALTO trial C. Piketty 1, L. Weiss 1, S. Bachir-Cherif 2, L. Assoumou 2, M. Burgard 3, J-M. Ragnaut 4, M. Bentata 5, P-M. Girard 6, C. Rouzioux 3, D. Costagliola 2 and The ANRS 116 SALTO study group 1 Georges Pompidou hosp and Univ Paris 5, Paris; 2 INSERM U720 and Univ Pierre et Marie Curie, Paris; 3 Necker hosp and Univ Paris 5; 4 Pellegrin hosp, Bordeaux; 5 Avicenne hosp, Bobigny; 6 Saint-Antoine hosp, Paris, France.

2. Background Patients who started HAART under previous more aggressive treatment guidelines may wish to discontinue HAART Predictors of outcome in these patients would allow clinicians to make recommendations for these patients Measurable virologic and immune markers may reflect clinical stability after treatment interruption (TI)

3. Primary hypothesis A subset of patients who started HAART early based on previous guidelines (1996-1997) could safely discontinue HAART without significant risk of disease progression

4. Objectives The aim of the study was to evaluate the safety and efficacy of TI in chronically HIV- infected patients who started treatment based on earlier guidelines and to assess the predictive factors of the duration of TI including HIV DNA level in PBMCs at TI

5. Methods A prospective, open-label, multicentre trial of TI in patients who have been treated –with CD4 cell count >350 x10 6 /L and plasma HIV-RNA (VL)<50,000 copies/ml, –who have CD4 cell count >450 x10 6 /L and stable VL <5000 copies/ml and, –Stable HAART treatment within 6 months prior to inclusion and, – who experienced no more than one prior treatment failure. Criteria to resume HAART were a decrease in CD4 cell count to < 300 x10 6 /L or the occurrence of a B or C defining event.

6. Baseline demographics N = 99 Gender : male63 (64%) Age (years) median (range) 39.5 (24.8 – 79.6) Transmission group Homo/bisexual men Heterosexuals IVDUs 50 (51%) 38 (38%) 8 (8%) Prior AIDS event3 (3%)

7. Baseline laboratory values CD4 count (x 10 6 /L), median (IQR)809 (696 – 949) HIV RNA (log/mL), median (IQR) < 400 copies / mL 2.6 (2.6 – 2.6) 95 (96%) Nadir CD4, median (IQR) < 300 cells / mm3 300- 500 cells / mm3 > 500 cells / mm3 382 (340 – 492) 12 (12%) 66 (67%) 21 (21%) Pre HAART VL, median (IQR) HIV DNA in PBMCs at inclusion 4.2 (3.9 – 4.5) 2.3 (1.9 – 2.8)

8. HAART history Time on HAART (y), median (IQR)5.3 (3.4 – 5.9) Triple Nucleoside based regimen37 (37%) NNRTI based regimen40 (41%) PI based regimen20 (20%) PI / NNRTI combination2 (2%)

9. Change in CD4 cell count Nbr pts 98 969997919388 81807265 61

10. Change in HIV viral load Nb pts99 95% 94 56% 98 19% 97 9% 93 9% 92 10% 87 8% 89 7% 82 7% 78 9% 73 10% 60 3% 58 5% VL < 400

11. Change in HIV DNA in PBMC Nbr pts96907975

12. Results: Primary End Point To month 12 –2 patients CD4 < 300/mm 3 –1 severe thrombocytopenia –No CDC C events –5 reinitiated HAART for other reasons Month 12 – Month 24 –7 additional patients CD4 < 300/mm 3 –1 additional severe thrombocytopenia –1 CDC C event (cutaneous KS with CD4=364/mm 3 ) –7 reinitiated HAART for other reasons From Month 24 –11 additional patients CD4 < 300/mm 3 (total 20) –No CDC B event (total 2) –1 additional CDC C event (cutaneous KS with CD4=648/mm 3 ) (total 2) –7 reinitiated HAART for other reasons (total 19)

13. Proportion of patient who did not meet the criteria to resume HAART Intent to treat*Observed data M1296.9% (91.2 – 98.9)91.9% (84.8 – 95.8) M2486.6% (78.0 – 92.2)75.4% (65.9 – 82.9) M3669.3% (58.0 – 78.7)52.7% (42.2 – 62.9) *CD4 < 300 or CDC B or C event

14. Predictors of time to CD4 < 300 or CDC B or C event (24/99) VariablesRelative Risk (CI 95); p HIV DNA (log10) > 2.56 CD4 nadir (log2) Pre HAART CD4 (log2) CD4 at inclusion (log2) Pre HAART VL (log10) Prior AIDS event Gender (female =1) Age (year) Transmission Group Duration of HAART 3.22 (1.38 – 7.54); 0.007 0.09 (0.02 – 0.38); <0.001 0.12 (0.02 – 0.89); 0.038 0.33 (0.08 – 1.36); 0.125 1.30 (0.51 – 3.32); 0.58 9.34 (2.01 – 43.36); 0.004 1.37 (0.59 – 3.16); 0.46 0.98 (0.94 – 1.04); 0.58 1.00 (0.43 – 2.31); 0.99 0.98 (0.74 – 1.29); 0.89

15. Predictors of time to CD4 < 300 or CDC event by month 36 multivariate analysis VariablesRelative Risk (CI 95); p HIV DNA (log10) > 2.56 CD4 nadir (log2) Prior AIDS event 2.49 (1.03 - 6.01); 0.043 0.18 (0.04 – 0.81); 0.025 5.61 (1.18 – 26.78); 0.030

16. Cardiovascular events 232.3 person-years of follow-up 4 cardiovascular events including one death –2 validated –2 validation pending –1.7/100 P-Y No renal or hepatic event

17. Discussion Single treatment interruption resulted in low progression rate at 36 months in this selected population –31% resume therapy for CD4 <300 or B/C CDC event –Few CDC C clinical events 2 cutaneous KS with CD4 > 350/mm 3 0.9 /100 P-Y Rapid initial CD4 cell loss after stopping HAART then gradual loss Predictors of month 36 outcome –HIV DNA in PBMCs at entry > 2.56 log –Nadir CD4 –Prior AIDS events

18. Conclusion In patients who started HAART based on earlier guidelines, long term treatment interruption resulted in a low absolute risk of AIDS defining events or cardiovascular events In addition to CD4 nadir, HIV-DNA level is a useful tool to select patients at risk of disease progression if they undergo a prolonged treatment interruption

19. Acknowledgements ANRS 116 SALTO study group –Hôpital Avicenne, Bobigny (M. Bentata); Hôpital Européen Georges Pompidou, Paris (M. Kazatchkine, L. Weiss, C. Piketty, M. Karaman); Hôpital Saint Antoine, Paris (P-M Girard, J-L Meynard ); Hôpital Pitié Salpétrière, Paris (C. Katlama, R. Tubiana, A. Simon); Hôpital Bicêtre (J-F Delfraissy, C. Gougard); Hôpital Henri Mondor, Creteil (Y. Levy, ); Hôpital Tenon, Paris (G. Pialoux); Hôpital Necker, Paris (J-P Viard); Hôpital Saint Jacques, Besançon (B. Hoen); Hôpital Bichat, Paris (P. Yeni, R. Landman); Hôpital Sainte Marguerite, Marseille (JA. Gastaut, I. Poizot-Martin); Hôpital Pellegrin, Bordeaux (JM Ragnaut); Hôpital Saint Jacques, Bordeaux (P. Morlat); Hôpital Brabois, Nancy (T. May); CHU de Caen (C. Bazin); CHU Strasbourg (JM. Lang); Hôpital Purpan, Toulouse (P. Massip); Hôpital de l’Archet, Nice (JP. Cassuto); Hôpital Edouard Herriot, Lyon; Hôpital Bretonneau, Tours (P. Choutet) ANRS 116 SALTO Scientific committee –C. Piketty, L. Weiss, D. Costagliola, C. Rouzioux, M. Burgard, C. Goujard, J- P Viard, Y. Levy, G. Pialoux, J-L Meynard, S. Bachir Cherif, L. Assoumou, MJ. Commoy ANRS 116 SALTO DSMB –JL. Pellegrin, C. Fagard, L. Morand-Joubert, J. Gilquin THE PATIENTS ENROLLED IN THE ANRS 116 SALTO STUDY