1. Simplification from Protease Inhibitors to Once or Twice Daily Raltegravir: the ODIS trial Eugenia Vispo, Pablo Barreiro, Francisco Blanco, Sonia Rodríguez-Novoa*, Judit Morello*, Inmaculada Jimenez-Nacher*, Juan Gonzalez-Lahoz and Vincent Soriano Department of Infectious Diseases and *Pharmacology Unit. Hospital Carlos III, Madrid, Spain

2. Background Raltegravir has demonstrated good antiviral activity and safety profile being dosed twice- daily (BID). However, its long intracellular half-life might allow once-daily (QD) administration.

3. Continuous infusion at 4 ng/mL and Q24h, Q12h and Q8h fractionated exposures gave the equivalent inhibition of virus replication Similar virus replication inhibition at different dosages of Raltegravir Weng Q et al, 10th International Workshop on Clinical Pharmacology of HIV, 2009

4. Raltegravir exhibits a long residence time on complexes assembled in vitro RAL exhibited a long residence time on the integrase-DNA complexes (t1/2 =7.3 h) that is comparable to or exceeds the half-life of the preintegration complex in the cell Grobler JA et al, 10th International Workshop on Clinical Pharmacology of HIV, 2009

5. Background The potent antiviral activity and good tolerance of RAL has prompted to assess its use as simplification strategy. The demonstration of equivalent efficacy of QD vs BID dosing might make this strategy even more attractive.

6. Simplification with RAL: previous studies EASIER (ANRS 138): Week 24 Analysis 0 10 80 90 100 0 4824 16 ENF RAL Week ENF 85 85 85 85 84 RAL 84 84 84 84 84 88% 85% 89% 88% No. of Pts Proportion of patients with HIV RNA <50 copies/mL De Castro et al, CID 2009

7. ODIS trial: Study Design All HIV-infected individuals under protease inhibitor (PI)-based regimens with plasma HIV- RNA <50 copies/mL for longer than 24 weeks were identified at Hospital Carlos III (2600 pt on follow-up) and invited to replace PIs by RAL. Patients were randomly assigned (2:1) to RAL 800mg QD or 400mg BID. Patients on BID with undetectable viral load at 3 months were then randomized (1:1) to continue BID or switch to QD. (www.clinicaltrials.gov-NCT00941083)

8. End-Points Primary: Comparison between the proportion of patients remaining with plasma HIV-RNA <50 copies/mL at week 24 of switching in the QD versus BID arms* Secondary: Evolution of CD4+ T-cell counts, incidence of side effects, evolution of lipids (total, LDL and HDL cholesterol and triglycerides) and serum glucose levels * If no significant differences appeared at week 12, patients switching from BID to QD were merged with the initial group of QD patients

9. Entered Study (n=311) Completed 24 weeks follow-up (n=224) Study Population (n=222) RAL 400 mg BID (n=73) Continue BID (n=35) Switch QD (n=38) RAL 800 mg QD (n=149) BASELINE 12 WEEKS24 WEEKS ANALYSIS Study Population 1 lost follow-up 1 stop due to adverse events

10. Baseline Characteristics AllRAL BID RAL BID  QD RAL QDp* No. of patients (%)22235 (16)38 (17)149 (67)-- Mean age, years 46±844±646±747±9 0.14 Male gender (%)149 (67)31 (89)24 (63)94 (63)0.01 Mean time under ART (months) 101.7±34.0100.1±41.7101.5±40.2102.2±30.3 0.96 Prior suboptimal ART (%)93 (42)11 (31)12 (32)70 (47)0.09 Prior virological failure (%)150 (68)23 (66)26 (68)101 (68)0.96 Prior NRTI resistance (%)74 (33)12 (34.3)12 (31.6)50 (33.6)0.95 Chronic hepatitis C (%)98 (46)13 (37)20 (61)65 (44)0.23 Mean CD4 count, cells/µL 574±308535±357417±238623±296 0.01 Mean ALT, IU/L 60±4745±3844±4567±51 0.58 Mean total cholesterol, mg/dL 187±41191±38176±43189±41 0.20 Mean LDL cholesterol, mg/dL 115±36121±30110±36115±37 0.42 Mean HDL cholesterol, mg/dL 40±1338±1139±1341±13 0.35 Mean total : HDL-cholesterol ratio 5.2±3.05.4±1.84.9±1.85.2±3.5 0.81 Mean triglycerides, mg/dL 166±129177±145132±96173±131 0.20 Mean glucose, g/dL 105±28103±13106±29105±30 0.84 NRTI backbone (%) ABC+3TC TDF+FTC 68 (31) 154 (69) 10 (29) 25 (71) 11 (29) 27 (71) 47 (31) 102 (69) 0.80

11. 20% 10% Virological failures All BID QD n 13 1 12 Prior suboptimal ART Prior virological failure Prior NRTI resistance 4 0 4 12 1 11 5.9% 2.9% 6.4% 4.3% 0% 4.9% 8% 4.3% 8.7% 16.2% 8.3% 17.7% Proportion of patients experiencing virological failure after switching PIs to RAL p=0.18 p=0.45p=0.48 p=0.14 The rate of virological failure was 16.2% in patients with prior NRTI resistance compared to 0.7% in the rest (p<0.001)

12. Evolution of lipids after switching from PIs to RAL

13. RAL QD vs BID ABC vs TDF in the NRTI backbone Prior suboptimal ART Prior virological failure Prior NRTI resistance RAL QD vs BID Prior suboptimal ART Prior virological failure Prior NRTI resistance 0.1 1 10 20 30 40 50 290 Adjusted RR (95% CI) Predictors of virological failure following a switch from PIs to RAL Univariate analysis Multivariate analysis* * Including variables with p<0.5 in the univariate analysis

14. Conclusion A switch from PIs to RAL in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression as long as prior NRTI resistance had not been selected in the past In this setting, the efficacy of RAL may not differ providing the drug BID or QD

15. LaboratoryClinical AreaPharmacology Unit Carolina GarridoPablo BarreiroElena Alvarez Angélica del CorralIvana MaidaJudit Morello Eva PovedaLuz Martín-CarboneroSonia Rodríguez-Novoa Natalia ZahoneroFrancisco BlancoInmaculada Jiménez-Nacher Mariana La PazPablo Labarga Carmen de MendozaJose Medrano Dolores Herrero José Vicente FernándezVicente Soriano Pablo RivasJuan González-Lahoz Acknowledgments

16. Sub-analysis of patients carrying prior NRTI resistance n=74 FAILURE p YESNO RAL dosing (%) BID QD 1 (8) 11 (92) 11 (18) 51 (82) 0.41 RAL plasma levels Median (IQR), ng/mL below Cmin (68 ng/mL), % 154.21 (35.78-459.37) 4 (36) 316.61 (106.07-726.20) 6 (14) 0.19 0.08 Nº concomitant active drugs in regimen <1 1-2 ≥2 7 (58) 5 (42) 0 (0) 26 (42) 28 (45) 8 (13) 0.33

17. FAILURE RAL BID to QD10 % (4/38) RAL BID3 % (1/35) RAL QD5% (8/149) Failure according to RAL dosage