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Simplification from Protease Inhibitors to Once or Twice Daily Raltegravir: the ODIS trial

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

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Simplification from Protease Inhibitors to Once or Twice Daily Raltegravir: the ODIS trial

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  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. Similar virus replication inhibition at different dosages of Raltegravir • Continuous infusion at 4 ng/mL and Q24h, Q12h and Q8h fractionated exposures gave the equivalent inhibition of virus replication 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. Simplificationwith RAL: previousstudies EASIER (ANRS 138): Week 24 Analysis 100 88% 89% 90 88% 85% 80 Proportion of patients with HIV RNA <50 copies/mL ENFRAL 10 0 4 8 24 0 16 Week No. of Pts ENF 85 85 85 85 84RAL 84 84 84 84 84 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. StudyPopulation BASELINE 12 WEEKS 24 WEEKS ANALYSIS 1 lost follow-up 1 stop due to adverse events

  10. Baseline Characteristics

  11. Proportion of patients experiencing virological failure after switching PIs to RAL All BID QD p=0.14 20% 17.7% 16.2% p=0.45 p=0.48 p=0.18 10% 8% 8.3% 8.7% 6.4% 5.9% 4.9% 4.3% 4.3% 2.9% 0% Virological failures Prior suboptimal ART Prior virological failure Prior NRTI resistance n 13 1 12 4 0 4 12 1 11 12 1 11 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. Predictors of virological failure following a switch from PIs to RAL Univariate analysis Multivariate analysis* 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) * Including variables with p<0.5 in the univariate analysis

  14. Conclusion • A switchfrom 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. Acknowledgments Laboratory Clinical Area Pharmacology Unit Carolina Garrido Pablo Barreiro Elena Alvarez Angélica del Corral Ivana Maida Judit Morello Eva Poveda Luz Martín-Carbonero Sonia Rodríguez-Novoa Natalia Zahonero Francisco Blanco Inmaculada Jiménez-Nacher Mariana La Paz Pablo Labarga Carmen de Mendoza Jose Medrano Dolores Herrero José Vicente Fernández Vicente Soriano Pablo Rivas Juan González-Lahoz

  16. Sub-analysis of patients carrying prior NRTI resistance

  17. Failure according to RAL dosage

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