1. 02-15 INFC-1022464-0001 Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: The SPIRAL study* 1 Date of preparation: February 2013 Prescribing information can be found on the final slide. *Supported in part by a research grant from MSD 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

2. 02-15 INFC-1022464-0001 Background PI/r-based cART is an effective therapy for HIV-infected patients, but it has been associated with a higher risk of cardiovascular disease due at least in part to lipid effects. Raltegravir-based cART may show a better lipid profile while being as effective as PI/r-based cART in selected patients. 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

3. 02-15 INFC-1022464-0001 Objective To demonstrate the non-inferiority of raltegravir vs. PI/r-based cART when administered for 48 weeks to HIV-1 seropositive patients with virologic suppression. 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

4. 02-15 INFC-1022464-0001 Study design * Raltegravir 400mg BID (maintaining other antiretrovirals unchanged). Switch to Raltegravir * (N = 139) Baseline Continue with boosted PI (N = 134) Study Population (N = 273) Patients on current PI/r + at least 2 ARV for > 6 months VL<50 cp/mL within 180 days Analysis, Week 48 1:1 Randomisation Stratified by presence or not of lipid lowering agents 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

5. 02-15 INFC-1022464-0001 Primary end-point The proportion of patients free of treatment failure for any reason through Week 48 (ITT, S=F) –Includes virologic rebound (two consecutive > 50 cp/mL), discontinuation of study therapy or lost to follow-up, progression to a new CDC event or death. –Non-inferiority study of Raltegravir vs. boosted PI. Lower limit of 95% CI of estimated difference ≥ 12.5%. 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

6. 02-15 INFC-1022464-0001 Secondary end-points The proportion of patients with virologic failure at or prior to Week 48 (confirmed virological failure defined as the first of two consecutive HIV RNA ≥ 50 cp/mL at least 2 weeks apart) (OT). Change in CD4+ cells. Time to treatment and virologic failure. Safety (adverse events leading to drug discontinuation and serious adverse events). Evolution of fasting plasma lipids. 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

7. 02-15 INFC-1022464-0001 Baseline characteristics (I) Characteristics RaltegravirPI/r N = 139N = 134 Age, median (IQR); years 44 (41-50)45 (40-50) Gender, N (%) 26 (19)37 (28) Female Risk group, N (%) Heterosexual transmission 42 (30)46 (34) Male Homosexuality 46 (33)44 (33) IDUs 39 (28)32 (24) Other12 (9) AIDS, N (%)63 (38)65 (39) CD4 cell count, median (IQR); cells/mm 3 529 (377-780)509 (369-726) TG, median (IQR); mg/dL 168 (117-270)174 (114-236) Total cholesterol, median (IQR); mg/dL 198 (171-226)198 (171-223) HDL- cholesterol, median (IQR); mg/dL44 (35-54)43 (37-51) LDL- cholesterol, median (IQR); mg/dL121 (97-141)122 (97-147) Lipid-lowering therapy at entry, N (%)27 (19)28 (21) 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

8. 02-15 INFC-1022464-0001 Baseline characteristics (II) RaltegravirPI/r N = 139N = 134 TG > 200 mg/dl, N (%) 57 (41)51 (38) Cholesterol > 240 mg/dl, N (%) 21 (15)20 (15) LDL > 160 mg/dl, N (%) 17 (12)16 (12) HDL < 40 mg/dl, N (%) 53 (38)44 (33) 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

9. 02-15 INFC-1022464-0001 Baseline characteristics (III) RaltegravirPI/r N = 139N = 134 ARV exposure, median (range); years11 (5-13)10 (6-12) Nº of regimens before study entry, median (IQR); years5 (2-8)5 (3-7) History of previous virological failure, N (%) History of previous virological failure with PI, N (%) 55 (40) 33 (24) 48 (36) 25 (19) Previous suboptimal ARV therapy, N (%)57 (41)47 (35) 1st. ARV regimen with PI, N (%)16 (12)14 (10) PI exposure, median (IQR); months31 (20-47)31 (18-22) PI at entry, N (%) Lopinavir60 (43)60 (45) Atazanavir52 (37)44 (33) Other27 (19)30 (22) NRTI at entry, N (%) TDF + 3TC/FTC, N (%)81 (58)74 (55) ABC + 3TC/FTC, N (%)27 (19)27 (20) Other, N (%)31 (22)33 (25) 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

10. 02-15 INFC-1022464-0001 Patient disposition at week 48 † 2 subjects with virological failure * 4 subjects with virological failure Patients assessed for eligibility (n=339) Continuing assigned therapy 126 † (91%) Discontinued 13 (9%) Adverse events 3 Virological failure 2 Lost to follow-up 1 Patient decission 5 Other 2 Assigned to Raltegravir (n=142) Excluded: 3 Valid cases: 139 Continuing assigned therapy 120* (90%) Discontinued 14 (10%) Adverse events 3 Virological failure 2 Lost to follow-up 4 Patient decission 4 Other 1 Assigned to PI/r (n=140) Excluded: 6 Valid cases: 134 Patients enrolled (n=282) 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

11. 02-15 INFC-1022464-0001 Patients free of treatment failure and virologic failure (≥ 50 cp/mL) through Week 48 Free of virologic failure (≥ 50 cp/mL) (OT)Free of treatment failure (ITT, S=F) RALTEGRAVIRPI/r Difference Estimate (95% CI) 2.6% (–5.2%, 10.6%) 89% 87% 97% 96% Difference Estimate (95% CI) 1.8% (–3.5%, 7.5%) 97% 95% 124/128116/122 89% 87% 124/139116/134 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

12. 02-15 INFC-1022464-0001 Time to virological failure 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

13. 02-15 INFC-1022464-0001 Time to virological failure 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

14. 02-15 INFC-1022464-0001 Patients with virological failure Raltegravir (n=4)PI/r (n=6) Failure at week16,16,16,4816,16,16,48,48,48 VL at failure71,260,1278,1000097,111,206,870,49000, 500000 Prior virological failure 1/4 (25%)3/6 (50%) Prior suboptimal ART 2/4 (50%)3/6 (50%) Resist. test at failure 14 Major mutations0/1 (RT gene) 3/4 (protease & RT genes) 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

15. 02-15 INFC-1022464-0001 CD4 changes Median changes in CD4 cell count were: +46 cells/mm3 (Raltegravir arm) and +44 cells/mm3 (PI/r arm) through Week 48 (p=0.33) 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

16. 02-15 INFC-1022464-0001 Adverse events (I) Characteristic RaltegravirPI/r N = 142 N (%) N = 140 N (%) Patients with a least one AE78 (55)79 (56) Patients with grade 3 or 4 side effects Any16 (11)18 (13) AEs Clinical7 (5) Description of clinical grade 3 or 4 AE Neuropsychiatric32 Respiratory13 Digestive21 Genitourinary11 Osteomuscular01 Cardiovascular10 Hepatic01 AEs Laboratory9 (6)12 (9) Description of lab grade 3 or 4 AE Triglycerides34 Total cholesterol15 Transaminases53 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

17. 02-15 INFC-1022464-0001 Adverse events (II) Characteristic RaltegravirPI/r N = 142 N (%) N = 140 N (%) Patients with AE leading to study drug discontinuation 3 (2) Neuropsychiatric21 Hepatic01 Digestive01 Respiratory10 Patients with Serious Adverse Event6 (4)5 (4) Among adverse events leading to study drug discontinuation and serious adverse events, those considered to be drug related are specified in the brackets. 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

18. 02-15 INFC-1022464-0001 LIPIDS: Change in mean fasting lipid parameters through week 48 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

19. 02-15 INFC-1022464-0001 LIPIDS: Percentage above NCEP treatment recommendations at baseline and through week 48 Variable Raltegravir % patients PI/r % patients BaselineWeek 48BaselineWeek 48Significance TG > 200 mg/dl41153829P=0.0068 Cholesterol > 240 mg/dl 154 17P=0.0004 HDL < 40 mg/dl 38423334P=0.1644 LDL > 160 mg/dl 123 8P=0.0997 Lipid lowering agents 19122124P=0.0104 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707.

20. 02-15 INFC-1022464-0001 SWITCHMRK-1 and -2 Efficacy at 24 weeks; Proportion of patients with viral RNA <50 Copies/mL a,b CI = confidence interval; LPV/r = lopinavir/ritonavir; RAL = raltegravir. a Error bars represent 95% confidence intervals. b All patients who did not complete the study were regarded as failures. Number of patients RAL group174 166 169173172 LPV/r group174171171171174 Weeks RAL LPV/r 481224 HIV RNA level <50 copies/mL (%) Difference between groups at week 24 −6.6% (95% CI −14.4 to 1.2) SWITCHMRK-1 Weeks RAL LPV/r 481224 HIV RNA level <50 copies/mL (%) Difference between groups at week 24 −5.8% (95% CI −12.2 to 0.2) SWITCHMRK-2 Number of patients RAL group176 176 176176175 LPV/r group 178178177177178 87.4% 80.8% 93.8% 88.0% 2. Eron JJ et al. Lancet. 2010; Vol. 375, No. 9712 pp 396-407.

21. 02-15 INFC-1022464-0001 SWITCHMRK-1 and -2 combined data1 a Subgroup analysis: Efficacy at 24 Weeks 128 130219 222 111 123228 221 Difference (95% CI) b −2.5 (−10.6, 5.4)−8.3 (−14.8, − 2.1)−15.3 (−24.9, −6.2)−1.0 (−6.9, 4.9) LPV/r as first regimenHistory of virologic failure LPV/r first regimenLPV/R not first regimen Prior virologic failure No prior virologic failure c c CI = confidence interval; LPV/r = lopinavir/ritonavir; RAL = raltegravir. a All patients who did not complete the study were regarded as failures. b Calculated by the method of Miettinen and Nurminen. c Plus existing baseline regimen. 2. Eron JJ et al. Lancet. 2010; Vol. 375, No. 9712 pp 396-407.

22. 02-15 INFC-1022464-0001 SPIRAL compared with SWITCHMRK 1 & 2 The SPIRAL efficacy results are in contrast with the efficacy results reported in SWITCHMRK 1 & 2 studies In a posthoc analysis of the combined SWITCHMRK studies, the investigators assumed that the inability to show noninferiority of raltegravir to lopinavir/r was driven by patients who had prior virological failure Despite design similarities between the SPIRAL and SWITCHMRK studies, some factors may account for differences in efficacy: –SWITCHMRK - double blinded & double dummy –SWITCHMRK - shorter minimum duration of virological suppression before entry –Median duration of virological suppression before entry to SPIRAL > 6 years Response rate was very high in both arms in both studies 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707. 2. Eron JJ et al. Lancet. 2010; Vol. 375, No. 9712 pp 396-407.

23. 02-15 INFC-1022464-0001 Conclusions of SPIRAL study In patients with sustained virological suppression on PI/r- based cART, switching from PI/r to raltegravir demonstrated non-inferior efficacy and resulted in a better lipid profile at 48 weeks than continuing PI/r. ISENTRESS® (raltegravir) should be used in combination with other active anti-retroviral therapies 3 1. Martinez E, et al. JAIDS 2010; 24 (11): 1697–1707. 3. ISENTRESS® Summary of Product Characteristics. Merck Sharp & Dohme Limited.

24. 02-15 INFC-1022464-0001 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

25. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

26. 3. CROI 2012. Martinez E et al. Paper #834

27. 02-15 INFC-1022464-0001 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

28. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

29. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

30. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

31. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

32. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

33. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

34. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

35. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

36. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

37. 3. CROI 2012. Martinez E et al. Paper #834 02-15 INFC-1022464-0001

38. Date of Preparation: February 2012