1. 1 Efficacy and safety of switching from boosted Lopinavir (LPV/r) to boosted Atazanavir (ATV/r) in patients with virologic suppression receiving a LPV/r containing HAART: The ATAZIP study Mallolas J. 1, Podzamczer D. 2, Domingo P. 3, Clotet B. 4, Ribera E. 5, Gutierrez F. 6, Knobel H. 7, Cosin J. 8, Ferrer E. 2, Arranz J.A. 9, Roca V. 10, Vidal F. 13, Murillas J. 14, Pedrol E. 15, Llibre J.M. 16, Dalmau D. 17, Garcia I. 18, Aranda M. 19, Pich J. 11, de Lazzari E. 12, Gatell J.M. 1, for the ATAZIP study group 1Hospital Clinic Universitari, Infectious Diseases, Barcelona, Spain, 2Bellvitge, Infectious Diseases, Barcelona, Spain, 3Hospital Sant Pau, Medicina Interna, Barcelona, Spain, 4Fundacio IrsiCaixa, HIV, Barcelona, Spain, 5Hospital Vall d´Hebron, Infectious Diseases, Barcelona, Spain, 6Hospital de Elche, Medicine, Elche, Spain, 7Hospital del Mar, Infectious Diseases, Barcelona, Spain, 8Gregorio Marañon, Medicina, Madrid, Spain, 9Hospital Principe de Asturias, Medicina, Madrid, Spain, 10Clinico San Carlos, Medicina, Madrid, Spain, 11Hospital Clinic Universitari, Pharmacology, Barcelona, Spain, 12Hospital Clinic Universitari, Biostatistics, Barcelona, Spain 13 Hospital Joan XXIII, Tarragona 14 Hospital Son Dureta. Palma de Mallorca. 15 Hospital de Granollers. 16 Hospital de Calella.17 Mutua de Tarrasa. 18 Hospital de Hospitalet. 19 Consorci Sanitari de Tarrasa. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention Sydney, Australia, July 22-26, 2007 WEPEB117LB

2. 2 Background  ATV is a potent, well-tolerated, once-daily (QD) protease inhibitor (PI) extensively studied in treatment-naive and - experienced patients  The SWAN study (BMS 097) 1 demonstrated that switching from PI ± RTV-containing regimens to an unboosted ATV- containing regimen maintained virologic suppression with improvement in plasma lipids through 48 weeks in patients without previous failures to PI contaning regimens  However, there are limited data available on the utility of switching virologically suppressed patients from LPV/r- based regimens to a different boosted PI such as ATV/r including those with previous failures to PI containing regimens or PI associated mutations 1 Gatell et al. Clin Infect Dis 2007

3. 3 Objective  To assess the safety and efficacy of ATV/r based HAART in virologically suppressed patients receiving a LPV/r contaning regimen including patients with previous failures (< 3) to PI regimens or history of having PI associated mutations (< 5) prior to starting the LPV/r-based regimen.

4. 4 Final Analysis, Week 96 Switch to ATV/r QD † (N = 121) Baseline Continue LPV/r BID* (N = 127) * LPV/r 400/100 mg BID capsules then tablets when available + unchanged NRTI backbone. † ATV/r 300/100 mg QD + unchanged NRTI backbone. Study Population (N = 265)  Stable LPV/r-based Regimen for > 6 months (VL < 200)  < 3 Previous Virologic Failures While on PI-based HAART and < 5 PI-associated mutations  The study was conducted in Spain Primary Analysis, Week 48 1:1 Randomization Study Design

5. 5 Primary end-point – The proportion of patients with treatment failure for any reason through Week 48 Includes virologic rebound (> 200 cp/mL), discontinuation of study therapy or lost to follow- up, progression to a new CDC event or death. Non-inferiority study. Upper limit of 95% CI of estimated difference < 12.5%.

6. 6 Secondary end-points – The proportion of patients with virologic rebound at or prior to Week 48 Confirmed on-study HIV RNA ≥ 200 copies/mL or last on-study HIV RNA ≥ 200 copies/mL followed by discontinuation – Time to treatment failure and to virologic failure – Safety – Evolution of fasting plasma lipids

7. 7

8. 8 General ATV/rLPV/r N = 121N = 127 Median Age, y4243 Gender, N (%) Male97 (80)100 (79) Risk group, N (%) Heterosexual trans.45(37)40(31) MSM27(22) 41 (32) IDUs39 (32)37 (29) Other10 (8)9 (7) AIDS, N (%)48 (40)74 (57) CD4 < 200, cell/ mm 3 9(8)12 (10) Median CD4, cells/mm 3 472435 Baseline Characteristics

9. 9 Laboratory ATV/rLPV/r N = 121N = 127 Total chol > 240 mg/dl, N (%)28 (23%)26 (20%) TG > 500 mg/dl, N (%)4 (3%) 13 (10%)* LDL-c > 130 mg/dl, N (%)24 (20%)25 (20%) HDL-c < 40 mg/dl, N (%)19 (16%)27 (21%) ALT > 40, N (%)28 (24%) 22 (18%) AST > 40, N (%)20 (21%)24 (23%) ALT or AST > 40, N (%)34 (28%)33 (26%) Baseline Characteristics * P=0.023

10. 10 ARV Therapy ATV/rLPV/r N = 121N = 127 ARV exposure, yr.5.15.4 1st. ARV regimen, N (%)17 (14)19 (15) 1st. ARV regimen with PI, N (%)36 (30)42 (33) Previous mono/bi therapy, N (%)47 (39)48 (38) Current ZDV+3TC, N (%)12 (10)20 (16) Current TDF+3TC, N (%)24 (20)22 (17) Current TDF+ddI, N (%)21 (17)12 (9) Current ddI+3TC, N (%)8 (7)9 (7) Previous PI failures (>=1), N (%)25 (21)25 (20) History of Previous PI mutations >=1, N (%)43 (36)41 (32) >=1 major, N (%)17 (14)13 (10) None, N (%)3 (1)9 (7) Not tested, N (%)75 (63)77 (61) Baseline Characteristics

11. 11 Patient Disposition at month 12 Pacientes enrolled (n=265) Assigned to continue with LPV/r (n=127) # Assigned to switch to ATV/r (n=121) # Continuing assigned therapy 109 † (86%) Discontinued 18 (14%) Adverse events 6 Death 1 * Virological failure 1 Lost to follow-up 6 Patient decission 2 Other 2 Continuing assigned therapy 105 † (86%) Discontinued 17 (14%) Adverse events 6 Death 0 Virological failure 1 Lost to follow-up 7 Patient decission 0 Other 2 † 5 subjects with virological failure † 7 subjects with virological failure * Hepatic encephalopaty # 11 additional patients not eligible# 6 additional patients not eligible

12. 12 Virologic Failure (≥ 200 c/mL) Treatment Failure ATV/rLPV/r 0 5 10 15 20 25 30 p = NS 17% 20% 21/12125/127 Difference Estimate (95% CI) -2.3% (–12%, 8%) –1.3% (–7.7%, 4.8%) Treatment Failure and Virologic Failure (≥ 200 c/mL) through month 12 0 5 10 15 20 25 30 p = NS 5% 6% 6/1218/127 Proportion of patients

13. 13 Time to treatment failure

14. 14 Time to virological failure p=0.609, long rank test P=0.5

15. 15 ATV/r (n=121) LPV/r (127) N 6 8 Previous PI failures 2 4 Previous PI mutations 6 1 Previous PI major mutations 2 1 High baseline risk (*) 5 5 Reported lack of adherence 0 4 Continue with same cART 5 7 Virological response at 12 mo. 3 4 * Previous >= 1 PI failure or >= 3 PI mutations or >= 1 major PI mutation Virological failures through month 12

16. 16 CD4 Changes  Median changes from baseline in CD4 cell count were similar beteween groups: +26 cells/mm 3 (ATV/r) and +51 cells/mm 3 (LPV/r) at month 12 (p=0.2)

17. 17 Adverse Events through month 12. Adverse Events leading to discontinuation ATV/rLPV/r N = 121 N (%) N = 127 N (%) Total6 (5) GI-related1 (1)2 (2) CNS1 (1)0 (0) Liver1 (1) #0 (0) Metabolic-related1 (1)4 (4) Hyperbilirubin/Jaundice2 (2)0 (0) * Hepatic encephalopaty; # ALT 113, AST 90 Death0 (0)1 (1) * Any AE74 (58)63 (52)

18. 18 LAB Abnormalities Liver Function Abnormalities (ALT/AST > 200; bilirrubin > 5) ATV/r N = 121 LPV/r N = 127 ALT2% 1% AST 2 % ALT or AST4% 2% Total bilirubin5% 2% Liver Function Abnormalities (ALT/AST > 200 ) when ALT or AST were > 40 at baseline ATV/r N = 34 LPV/r N = 33 ALT 9 % 6% AST9 % 6% ALT or AST12% 6%

19. 19 Fasting LIPIDS. Median values and Changes From Baseline in Lipid Parameters at month 12 Fasting Lipids ATV/rLPV/r P value BLm12 Change  mg/dL BLm12 Change  mg/dL TG, mg/dL181145-51 (-29%)191202-3 (-1%)<0.0001 Total Chol, mg/dL202193-19 (-9%)205207-4 (-2%)<0.0001 LDL-c, mg/dL107111-8 (-7%)111 -2 (-3%)0.163 HDL-c, mg/dL5046-3 (-6%)4946-2 (-3%)0.375

20. 20

21. 21 LIPIDS. Percentage above NCEP treatment recommendations at baseline and through month 12. ATV/r N=121 LPV/r N=127 BLMo 12ChangeBLMo 12Change TG m12 > 500 mg/dL 3%4%+1%10%17%+7% Total Chol > 240 mg/dL 23%20%-3%20%26%+6% LDL > 130 mg/dL 20%25%+5%20%30%+10% HDL < 40 mg/dL 16%32%+16%21%29%+8% No significant changes were obseved in Lipid Lowering Agents (LLA) usage during the follow-up in both arms.

22. 22 Conclusions  Switching to ATV/r in virologically suppressed patients who were receiving a LPV/r containing HAART provided comparable efficacy and safety profile with improved lipid parameters.

23. 23 ATAZIP Study Group HOSPITAL CLINIC BARCELONA J. Mallolas J.M. Gatell J. Pich E. de Lazzari E. Martínez A. Milinkovic A. Cruceta H. Agell J.A. Arnaiz HOSPITAL BELLVITGE HOSPITALET D. Podzamczer E. Ferrer G. Leibenger HOSPITAL SANT PAU BARCELONA P. Domingo M. Gutiérrezerrer G. Mateo HOSPITAL GERMANS TRIAS I PUJOL BADALONA B. Clotet P. Echeverria C. Alcalde HOSPITAL VALL D’HEBRÓN BARCELONA E. Ribera S. Villar HOSPITAL ELCHE ALICANTE F. Gutiérrez M. Masiá E. Bernal HOSPITAL MAR BARCELONA H. Knobel A. González G. Mestre HOSPITAL GREGORIO MARAÑÓN MADRID J. Cosín M. Sánchez M. Ramírez I. Gutiérrez HOSPITAL PRINCIPE ASTURIAS MADRID J.A. Arranz J. Sanz E. Casas HOSPITAL CLÍNICO SAN CARLOS MADRID V. Roca J. Vergas M.J. Téllez HOSPITAL JOAN XXIII TARRAGONA F. Vidal J. Peraire M. Saumoy HOSPITAL SON DURETA PALMA MALLORCA M. Peñaranda J. Murillas HOSPITAL GRANOLLERS GRANOLLERS E. Pedrol E. Deig HOSPITAL CALELLA CALELLA J.M. Llibre S. Valero HOSPITAL MUTUA TERRASSA TERRASSA D. Dalmau M. Cairó HOSPITAL L’HOSPITALET HOSPITALET I. García HOSPITAL TERRASSA TERRASSA M. Aranda