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CROI 2014-ACTG 5257 e NEAT001/ANRS 143 quali nuove opportunità per i pazienti

CROI 2014-ACTG 5257 e NEAT001/ANRS 143 quali nuove opportunità per i pazienti. Marco Borderi U. O. Malattie Infettive – Bologna Roma, 8 Maggio 2014. Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di MSD Italia. Ma Nino non aver paura di sbagliare un calcio di rigore,

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CROI 2014-ACTG 5257 e NEAT001/ANRS 143 quali nuove opportunità per i pazienti

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  1. CROI 2014-ACTG 5257 e NEAT001/ANRS 143quali nuove opportunità per i pazienti Marco Borderi U. O. Malattie Infettive – Bologna Roma, 8 Maggio 2014 Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di MSD Italia .

  2. Ma Nino non aver paura di sbagliare un calcio di rigore, non è mica da questi particolari che si giudica un giocatore, un giocatore lo vedi dal coraggio, dall'altruismo e dalla fantasia.

  3. HIV NRTI NRTI NNRTI INI PI/r

  4. Linee Guida DHHS 2014

  5. Linee Guida IAS 2012 Thompson et al, JAMA, 2012.

  6. Linee Guida EACS 2013

  7. Linee Guida Italiane 2013

  8. Gravidanza:Linee Guida EACS 2013

  9. PEP:Linee Guida Italiane 2013 Interazioni farmacologiche:Linee Guida Italiane 2013

  10. Perché sempre 3? Immagini + Colonna sonora Dialoghi + Colonna sonora Immagini + Dialoghi

  11. Perché sempre 3?

  12. HIV NRTI NRTI INI PI/r

  13. Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir with FTC/TDF: ACTG A5257 Landovitz RJ, Ribaudo HJ, Ofotokun I, Wang H, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS, and Lennox JL for the A5257 Study Team

  14. Disegno dello studio* HIV-infected patients, ≥18 yr, with no previous ART, VL ≥ 1000 c/mL at US Sites Randomized 1:1:1 to Open Label Therapy Stratified by screening HIV-1 RNA level (≥ vs < 100,000 c/mL), A5260s metabolic substudy participation, cardiovascular risk *With the exception of RTV, all ART drugs were provided by the study ATV 300mg QD + RTV 100mgQD + FTC/TDF 200/300 mg QD RAL 400 mg BID + FTC/TDF200/300mgQD DRV 800mgQD+RTV 100mgQD + FTC/TDF 200/300 mg QD Study Conclusion 96 weeks after final participant enrolled Follow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ART

  15. Disegno dello studio • Hypothesis • FTC/TDF with ATV/r, RAL, or DRV/r will be equivalent in terms of virologic efficacy and tolerability over 96 weeks • Primary Endpoints* • Time to HIV-1 RNA >1000 c/mL wk 16 to before wk 24, or >200 c/mL at or after wk 24 (VF) • Time to discontinuation of randomized component for toxicity (TF) • Pre-planned Composite Endpoint • The earlier occurrence of either VF or TF in a given participant * Time measured from date of study entry/randomization

  16. Considerazioni per l’analisi Equivalence region Equivalence Equivalence Superiority -20 -10% 10% 20% 0 Difference in 96-week cumulative incidence Equivalence shown if 97.5% CI on the pairwise difference in 96-week cumulative incidence falls entirely within -10% and +10%. If equivalence not demonstrated, superiority shown if 97.5% CI excludes zero. * 97.5% CI controls type I error at 5% for 3 pairwise equivalence comparisons.

  17. Caratteristiche al basale

  18. Incidenza cumulativa di Fallimento Virologico Difference in 96 wk cumulative incidence (97.5% CI) ATV/r vs RAL 3.4% (-0.7%, 7.4%) DRV/r vs RAL 5.6% (1.3%, 9.9%) ATV/r vs DRV/r -2.2% (-6.7%, 2.3%) -20 -10 0 10 20 • 96 week cumulative incidence of VF: • ATV/r: 13% • RAL: 10% • DRV/r: 15%

  19. Incidenza cumulativa di Fallimento per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI) ATV/r vs RAL Favors RAL 13% (9.4%, 16%) DRV/r vs RAL 3.6% (1.4%, 5.8%) Favors DRV/r ATV/r vs DRV/r 9.2% (5.5%, 13%) • 96 week cumulative incidence of TF: • ATV/r: 14% • RAL: 1% • DRV/r: 5% -20 -10 0 10 20

  20. Fallimento per TollerabilitàCause di discontinuazione* *Participants allowed to switch therapy for intolerable toxicity

  21. % di discontinuazione di ATV/r per iperbilirubinemia/subittero negli studi +Week 48 analysis + + Week 96 analysis *600 in analysis **646 in analysis. #Data not available. $ N=438 aDiscontinuations due to bilirubin-associated issues in sub-analysis; N=646. ^1 subject discontinued due to hyperpigmentation 1. Landovitz RJ, et al. CROI 2014; oral presentation 85; Available from: http://www.natap.org/2014/CROI/croi_30.htm (accessed March 2014). 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Molina JM, et al. JAIDS. 2010;53:323-332. 4. Uy et al. HIV10, 2010, poster P93. 5. CASTLE CSR (Table 5.3.1). 6. Daar et al. Ann Int Med 2011 154 (7) 445-456 7. Ribaudo H, et al. J Infect Dis. Feb (3):420-425 8. DeJesus et al. Lancet. 2012;379(9835):2429-2438 9. Johnson et al AIDS 2006, 20:711–718 10. Rockstroh et al JAIDS 2013;62:483–486)

  22. Incidenza cumulativa di Fallimento Virologico o per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI) ATV/r vs RAL Favors RAL 15% (10%, 20%) Favors RAL DRV/r vs RAL 7.5% (3.2%, 12%) Favors DRV/r ATV/r vs DRV/r 7.5% (2.3%, 13%) -20 -10 0 10 20 *Consistent results seen with TLOVR at a 200 copies/ml threshold

  23. Insorgenza di resistenza 1809 Participants 1 Baseline Missing 56 VF Failed to Amplify 295 Virologic Failures RAL ATV/r DRV/r 75/94 VF Available 65/85 VF Available 99/115 VF Available 9 Any Resistance (1.5%) 18 Any Resistance (3%) 4 Any Resistance (<1%) 2 TDF 0 TDF 0 TDF 5 FTC 7 FTC 3 FTC 0 TDF+FTC 0 TDF+FTC 1 TDF+FTC 1 RAL 1 RAL 1 RAL 0 RAL+FTC 7 RAL+FTC 0 RAL+FTC 3 RAL+FTC+TDF 0 RAL+FTC+TDF 0 RAL+FTC+TDF

  24. Conclusioni • ATV/r, RAL, and DRV/r were equivalent for virologic efficacy • ATV/r was less well tolerated than DRV/r or RAL • Largely due to cosmetic hyperbilirubinemia • RAL was superior to both PI/r regimens for combined tolerability and virologic efficacy • DRV/r was superior to ATV/r • VF with resistance was rare • More frequently observed with RAL • Analyses are ongoing to evaluate: • Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior, adherence, and key subgroup differences

  25. Sottostudio lipidico Figure 1. Mean of Changes from Baseline in Fasting Lipid Profile (mg/dL) Over Time with 95% CI (A) Fasting Total Cholesterol (TC) (B) Fasting Triglycerides (TG) 30 40 ATV/RTV ATV/RTV ATV/RTV ATV/RTV RAL RAL RAL RAL DRV/RTV DRV/RTV DRV/RTV DRV/RTV 20 20 Diff from Baseline: Fasting Triglycerides (mg/dL) Diff from Baseline: Fasting TC (mg/dL) 10 0 0 -20 Number of subjects contributing data Number of subjects contributing data ATV/RTVRALDRV/RTV 602 600 595 542 527 528 522 542 507 490 505 490 364 397 363 ATV/RTVRALDRV/RTV 602 600 595 541 527 529 521 542 507 490 505 490 364 397 363 0 24 48 96 144 0 24 48 96 144 Study week Study week (C) Fasting LDL-C (D) Fasting HDL-C 15 10.0 10 7.5 Diff from Baseline: Fasting LDL-C (mg/dL) Diff from Baseline: Fasting HDL-C (mg/dL) 5 5.0 0 2.5 -5 0.0 Number of subjects contributing data Number of subjects contributing data ATV/RTVRALDRV/RTV 596 593 581 529 518 508 512 531 486 480 493 468 360 385 346 ATV/RTVRALDRV/RTV 602 600 595 541 527 529 522 542 506 490 505 488 364 397 363 0 24 48 96 144 0 24 48 96 144 Study week Study week

  26. Testo testo, testo Sottostudio osseo

  27. Sottostudio cardiovascolare

  28. HIV NRTI NRTI

  29. JFK & BMD

  30. JFK & BMD → BMD & JFK

  31. LDL HDL Cholesterol Triglycerides EFV EFV EFV EFV EFV EFV EFV EFV 303 310 281 270 322 324 299 326 326 300 288 290 ACTG 5202 (wk 48) Median Change in Fasting Lipids (mg/dL) p<0.001 p-values: ATV/r vs. EFV p=0.07 p<0.001 p<0.001 p=0.26 p<0.001 p=0.002 p<0.001 ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC ABC/3TC N= 325 324 300 289 Sax PE et al, J Infect Dis. 2011 Oct 15;204(8):1191-201

  32. p=0.003 January 2012 | Volume 7 | Issue 1 | e29977

  33. Tenofovir and Protease Inhibitor Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction in the Swiss HIV Cohort Study (SHCS) PRT: proximal renal tubulopathy FE(p): fractional excretion of phosphate >20% ->10% if hypophosphatemic cGFR: calculated Glomerular Filtration Rate (Cockroft-Gault) Fux C. et al., CROI 2009; p743

  34. Cumulative survival probability after any type of fracture (Center JR et al. Lancet 1999)

  35. A5224s TDF/FTC ABC/3TC 0 0 p=0.004* -1 -1 Lumbar spine BMD percent change from week 0 Hip BMD percent change from week 0 -2 -2 p=0.025* -3 -3 -4 -4 -5 -5 0 24 48 96 144 192 0 24 48 96 144 192 Visit Week from Randomization Visit Week from Randomization ACTG 5224s: BB and BMD No. of subjects TDF/FTC 128 111 106 97 87 53 ABC/3TC 130 122 106 101 80 53 No. of subjects TDF/FTC 126 109 105 96 85 53 ABC/3TC 128 119 104 99 79 54 *linear regression McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801

  36. Association between current ABC use and MI risk Pre-March 2008 Overall Post-March 2008

  37. GFR → CVA Bedimo R. Clin Infect Dis. 2011 Jul 1;53(1):84-91 • CKD isassociated with higher risk of AMI and CVA • HR for AMI: 2.41 (95% CI: 1.73-3.36) • HR for CVA: 1.80 (95% CI: 1.44-2.24)

  38. J Acquir Immune Defic Syndr. 2011 oct 1;58(2):163-172

  39. BMD → CVD Osteoporosi Osteopenia Tankó LB. et al. JBMR. 2005;20:1912-1920

  40. Perché ancora 3? HIV NRTI NRTI INI PI/r

  41. First-Line Raltegravir (RAL) + Darunavir/Ritonavir (DRV/r) is Non-inferior to Tenofovir/Emtricitabine (TDF/FTC) + DRV/r: The NEAT 001/ANRS 143 Randomised Trial François Raffi1, Abdel G Babiker2, Laura Richert3, Jean-Michel Molina4, Elizabeth C George2, Andrea Antinori5, Jose Arribas6, Stefano Vella7, Geneviève Chêne3, Anton L Pozniak8, and the NEAT001/ANRS143 Study Group 21st CROI, Boston, March 3-6,2014, Abs 84LB Clinicaltrials.gov identifier: NCT01066962

  42. Disegno dello studio NEAT 001/ANRS 143 HIV-1 ART-naïve ≥ 18 years HIV-1 RNA > 1000 c/ml CD4 ≤ 500/mm3 HBs Ag negative No major IAS-USA resistance mutations DRV+r 800+100 mg QD + RAL 400 mg BID DRV+r 800+100 mg QD + TDF/FTC FDC QD Minimum Week 96 Randomisation 1:1 stratified by country and participation in virology/immunology substudy • Composite virological and clinical primary endpoint (6 components) Phase III, randomised, open-label, multicenter, parallel-group, non-inferiority, strategic trial 78 sites, 15 countries (Austria, Belgium, Denmark, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden)

  43. Obiettivi NEAT 001/ANRS 143 • Primary endpoint : Time to failure, as the first occurrence of any of the following components: Virological • V1. change of treatment before W32 because of insufficient virologic response • HIV-1 RNA reduction < 1 log10 c/ml by W18* • or HIV-1 RNA ≥ 400 c/ml at W24* • V2. HIV-1 RNA ≥ 50 c/ml at W32* • V3. HIV-1 RNA ≥ 50 c/ml at any time after W32* Clinical • C1 death due to any cause • C2. any new or recurrent AIDS defining event** • C3. any new serious non AIDS defining event** • All patients followed-up until last patient reached W96, events recorded until end of F-U • Non-inferiority margin: absolute difference of at most 9% for the failure rate of RAL vs. TDF/FTC by W96 (estimated by Kaplan-Meier methods) in the ITT analysis • Major secondary endpoints: safety, changes in CD4 and HIV RNA, genotypic resistance * confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee

  44. Tempo dalla randomizzazione all’obiettivo primario NEAT 001/ANRS 143 Primary endpoint Probability of reaching primary endpoint 1.00 TDF/FTC + DRV/r RAL + DRV/r 0.75 0.50 log rank p=0.12 0.25 0 0 8 18 32 48 64 80 96 112 128 144 Time (weeks) N at risk 400 384 375 347 329 317 308 211 90 11 402 395 393 361 350 340 331 215 90 12 Estimated proportion reaching primary endpoint at W96 RAL: 17.4% vs TDF/FTC: 13.7% Adjusted difference: 3.7% (95% CI: -1.1, 8.6%) * confirmed by a subsequent measurement

  45. NEAT 001/ANRS 143 HIV-1 RNA < 50 cp/mL Percentage of participants with available data 93 % 100 91 % 89 % 80 89 % RAL + DRV/r 60 TDF/FTC + DRV/r 40 20 0 0 4 8 12 18 24 32 48 64 80 96 Weeks n 401 404 385 389 377 385 382 387 376 388 356 374

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