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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.

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Presentation on theme: "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."— Presentation transcript:

1 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.

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 NRTI NNRTI PI/r INI HIV

4 Linee Guida DHHS 2014

5

6 Linee Guida IAS 2012 ComponentRecommended Regimens NNRTI plus nRTIsEfavirenz/tenofovir/emtricitabine (AIa) Efavirenz plus abacavir/lamivudine (AIa) in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/mL PI/r plus nRTIsDarunavir/r plus tenofovir/emtricitabine (AIa) Atazanavir/r plus tenofovir/emtricitabine (AIa) Atazanavir/r plus abacavir/lamivudine (AIa) in patients with plasma HIV-1 RNA <100,000 copies/mL InSTI plus nRTIs Raltegravir plus tenofovir/emtricitabine (AIa) Thompson et al, JAMA, 2012.

7 Linee Guida EACS 2013

8 Linee Guida Italiane 2013

9 Gravidanza: Linee Guida EACS 2013

10 PEP: Linee Guida Italiane 2013 Interazioni farmacologiche: Linee Guida Italiane 2013

11 Perché sempre 3? Immagini + Colonna sonora Dialoghi + Colonna sonora Immagini + Dialoghi

12 Perché sempre 3?

13 NRTI PI/r INI HIV

14 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

15 Disegno dello studio* RAL 400 mg BID + FTC/TDF 200/300 mg QD DRV 800 mg QD + RTV 100 mg QD + FTC/TDF 200/300 mg QD ATV 300 mg QD + RTV 100mg QD + 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 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

16 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

17 Considerazioni per l’analisi 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. -20 0 -10%20%10% Difference in 96-week cumulative incidence Equivalence region * 97.5% CI controls type I error at 5% for 3 pairwise equivalence comparisons. Equivalence Superiority

18 Caratteristiche al basale Treatment group Characteristic Total (N=1809) ATV/r (N=605) RAL (N=603) DRV/r (N=601) SexFemale435 (24%)144 (24%)148 (25%)143 (24%) Age (years)Mean37383738 Race/EthnicityWhite Non-His.615 (34%)212 (35%) 191 (32%) Black Non-His.757 (42%)252 (42%)254 (42%)251 (42%) Hispanic390 (22%)125 (21%)117 (19%)148 (25%) HIV-1 RNA (log 10 c/ml) Median (Q1-Q3)4.6 (4.1-5.1)4.6 (4.1-5.2)4.7 (4.1-5.1)4.6 (4.1-5.1) (copies/ml) <100,00070%68% 72% 100,000-500,00023%25%24%22% >500,000 7% 8% 6% CD4+ cells (/mm³) Median (Q1-Q3)308 (170-425)309 (176-422)304 (158-427)310 (171-424) % <20030%29%31%29%

19 Incidenza cumulativa di Fallimento Virologico Difference in 96 wk cumulative incidence (97.5% CI) -200-10 1020 3.4% (-0.7%, 7.4%) 5.6% (1.3%, 9.9%) -2.2% (-6.7%, 2.3%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r 96 week cumulative incidence of VF: ATV/r: 13% RAL: 10% DRV/r: 15%

20 Incidenza cumulativa di Fallimento per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI) -200-10 1020 13% (9.4%, 16%) 3.6% (1.4%, 5.8%) 9.2% (5.5%, 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors DRV/r 96 week cumulative incidence of TF: ATV/r: 14% RAL: 1% DRV/r: 5%

21 Fallimento per Tollerabilità Cause di discontinuazione* ATV/r (N=605) RAL (N=603) DRV/r (N=601) Any toxicity discontinuation95 (16%)8 (1%)32 (5%) Gastrointestinal toxicity25214 Jaundice/Hyperbilirubinemia4700 Other hepatic toxicity415 Skin toxicity725 Metabolic toxicity602 Renal toxicity (all nephrolithiasis)400 Abnormal chem/heme (excl. LFTs)002 Other toxicity234 *Participants allowed to switch therapy for intolerable toxicity

22 % di discontinuazione di ATV/r per iperbilirubinemia/subittero negli studi A5257 1++ n=605 * CASTLE 2-5++ n=440 A5202 6-7++ n=928 ** 103 8,10++ n=355 045 9++ n=119 D/C due to toxicity % (n) 15.7% (95) 7.1% (33) 3.0% (13 $ ) 7% (24) 8% (10) D/C due to HBR/jaundice % (n) 7.8% (47 ^ ) 2.9% (19) a 0.7% (3) 1.7% (6) 5.9% (7) D/C due to lab HBR % (n) D/C due to clinical jaundice % (n) 2.6% (16) 5.0% (30) #### #### # 1.7% (6) #### Consequences of DiscontinuationOff study Switch to LPV/r or FPV/r Off study # + Week 48 analysis + + Week 96 analysis *600 in analysis **646 in analysis. # Data not available. $ N=438 a Discontinuations 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)

23 Incidenza cumulativa di Fallimento Virologico o per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI) -200-10 1020 15% (10%, 20%) 7.5% (3.2%, 12%) 7.5% (2.3%, 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors DRV/r *Consistent results seen with TLOVR at a 200 copies/ml threshold

24 0 TDF+FTC 1 RAL 0 RAL+FTC 0 RAL+FTC+TDF 1 TDF+FTC 1 RAL 0 RAL+FTC 0 RAL+FTC+TDF Insorgenza di resistenza 75/94 VF Available RAL 99/115 VF Available 9 Any Resistance (1.5%) 18 Any Resistance (3%) 4 Any Resistance (<1%) 2 TDF 0 TDF 5 FTC 7 FTC3 FTC 0 TDF+FTC ATV/rDRV/r 295 Virologic Failures 1 Baseline Missing 56 VF Failed to Amplify 1809 Participants 1 RAL 7 RAL+FTC 3 RAL+FTC+TDF 65/85 VF Available

25 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

26 Sottostudio lipidico Figure 1. Mean of Changes from Baseline in Fasting Lipid Profile (mg/dL) Over Time with 95% CI 30 602 600 595 ATV/RTV RAL DRV/RTV 541 527 529 521 542 507 490 505 490 364 397 363 20 10 0 Diff from Baseline: Fasting TC (mg/dL) 0244896144 Study week Number of subjects contributing data ATV/RTVRALDRV/RTV (A) Fasting Total Cholesterol (TC) 40 602 600 595 ATV/RTV RAL DRV/RTV 542 527 528 522 542 507 490 505 490 364 397 363 20 0 -20 Diff from Baseline: Fasting Triglycerides (mg/dL) 0244896144 Study week Number of subjects contributing data ATV/RTVRALDRV/RTV (B) Fasting Triglycerides (TG) 15 596 593 581 ATV/RTV RAL DRV/RTV 529 518 508 512 531 486 480 493 468 360 385 346 10 0 -5 Diff from Baseline: Fasting LDL-C (mg/dL) 0244896144 Study week Number of subjects contributing data ATV/RTVRALDRV/RTV (C) Fasting LDL-C 5 10.0 602 600 595 ATV/RTV RAL DRV/RTV 541 527 529 522 542 506 490 505 488 364 397 363 7.5 2.5 0.0 Diff from Baseline: Fasting HDL-C (mg/dL) 0244896144 Study week Number of subjects contributing data ATV/RTVRALDRV/RTV (D) Fasting HDL-C 5.0

27 Testo testo, testo Sottostudio osseo

28 Sottostudio cardiovascolare

29 NRTI HIV

30 JFK & BMD

31 → BMD & JFK

32 ACTG 5202 (wk 48) Median Change in Fasting Lipids (mg/dL) ATV/r EFV ABC/3TC TDF/FTC N= 326 290 326300 303 270 310281 322 288 324299 325 289 324300 p<0.001 p=0.07 Cholesterol LDLHDL Triglycerides p<0.001 p=0.002 p<0.001 p=0.26 p-values: ATV/r vs. EFV Sax PE et al, J Infect Dis. 2011 Oct 15;204(8):1191-201

33

34 p=0.003 January 2012 | Volume 7 | Issue 1 | e29977

35

36 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 Tenofovir and Protease Inhibitor Use Are Associated with an Increased Prevalence of Proximal Renal Tubular Dysfunction in the Swiss HIV Cohort Study (SHCS)

37

38

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

40 0 Lumbar spine BMD percent change from week 0 -2 -3 -4 -5 0244896144192 Visit Week from Randomization p=0.004* 0 Hip BMD percent change from week 0 -2 -3 -4 -5 0244896144192 Visit Week from Randomization p=0.025* TDF/FTC ABC/3TC 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 ACTG 5224s: BB and BMD McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801 A5224s

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

42 GFR → CVA CKD is associated 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) Estimated GFR, mL/min/1.73 m 2 AMICVA Rate per 1000 Pt-Yrs Unadjusted HR P ValueRate per 1000 Pt-Yrs Unadjusted HR P Value < 6011.333.85<.000130.582.95.002 60-893.891.33.04812.571.28<.0001 ≥ 902.92Ref--9.74Ref-- Bedimo R. Clin Infect Dis. 2011 Jul 1;53(1):84-91

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

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

45 NRTI PI/r INI HIV Perché ancora 3?

46 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 Raffi 1, Abdel G Babiker 2, Laura Richert 3, Jean-Michel Molina 4, Elizabeth C George 2, Andrea Antinori 5, Jose Arribas 6, Stefano Vella 7, Geneviève Chêne 3, Anton L Pozniak 8, and the NEAT001/ANRS143 Study Group 21st CROI, Boston, March 3-6,2014, Abs 84LB Clinicaltrials.gov identifier: NCT01066962

47 Disegno dello studio 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) DRV+r 800+100 mg QD + TDF/FTC FDC QD DRV+r 800+100 mg QD + RAL 400 mg BID Minimum Week 96 Randomisation 1:1 stratified by country and participation in virology/immunology substudy HIV-1 ART-naïve ≥ 18 years HIV-1 RNA > 1000 c/ml CD4 ≤ 500/mm 3 HBs Ag negative No major IAS-USA resistance mutations Composite virological and clinical primary endpoint (6 components) NEAT 001/ANRS 143

48 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 log 10 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 Obiettivi * confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee NEAT 001/ANRS 143

49 Tempo dalla randomizzazione all’obiettivo primario Primary endpoint * confirmed by a subsequent measurement 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%) log rank p=0.12 0 0.25 0.50 0.75 1.00 Probability of reaching primary endpoint 4023953933613503403312159012 4003843753473293173082119011 08183248648096112128144 Time (weeks) RAL + DRV/r TDF/FTC + DRV/r N at risk NEAT 001/ANRS 143 RAL + DRV/r TDF/FTC + DRV/r N401404 N with primary endpoint76(19%)61(15%) V1. Regimen change for insufficient response < 1 log 10 c/ml HIV RNA reduction W18* 10 HIV RNA ≥ 400 c/ml W24* 10 V2. HIV RNA ≥ 50 c/ml at W32* 2728 V3. HIV RNA ≥ 50 c/ml after W32* 3222 C1. Death31 C2. AIDS event53 C3. SNAIDS event77

50 0 0481218243248648096 401 404 385 389 377 385 382 387 376 388 356 374 RAL + DRV/r TDF/FTC + DRV/r 20 40 60 80 100 Weeks Percentage of participants with available data 89 % 91 % 93 % 89 % HIV-1 RNA < 50 cp/mL n Mean (95% CI) Change From Baseline CD4 + Cell Count (cells/mm 3 ) W48W96 RAL + DRV/r+ 197(184, 210)+ 267(250, 285) TDF/FTC + DRV/r + 193(180, 206)+ 266(249, 283) NEAT 001/ANRS 143

51 Overall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/r Obiettivo primario per HIV-RNA e CD4+ al basale n = 805 n = 530 n = 275 n = 123 n = 682 Overall < 100,000 c/ml > 100,000 c/ml < 200/mm 3 > 200/mm 3 Baseline HIV-1 RNA Baseline CD4+ 17.4 % 7 % 36 % 39.0 % 13.6 % 13.7 % 7 % 27 % 21.3 % 12.2 % RAL + DRV/r TDF/FTC + DRV/r 100-102030 9 Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted * Test for homogeneity p = 0.09* p = 0.02* -1.18.6 -3.93.5 -0.0519.3 4.730.8 -3.46.3 NEAT 001/ANRS 143

52 Fallimenti virologici e insorgenza di resistenza Protocol-defined virological failure change of any component of the initial randomised regimen before W32 because of confirmed insufficient virological response, defined as HIV-1 RNA reduction < 1 log 10 copies/ml by W18 or HIV-1 RNA ≥ 400 copies/ml at W24 ; failure to achieve virological response by W32 (confirmed HIV-1 RNA ≥ 50 copies/ml at W32) ; confirmed HIV-1 RNA ≥ 50 copies/ml at any time after W32 According to the protocol, genotypic testing was carried out by local laboratories when patients had a single VL > 500 copies/ml at or after W32. * 1 additional patient with T97A NEAT 001/ANRS 143 RAL + DRV/r n=401 TDF/FTC + DRV/r n=404 Protocol-defined virological failure (PDVF), n 6652 Number of PDVF who met criteria for genotype testing (HIV RNA > 500 copies/ml at or after W32) 339 Number of patients with single unconfirmed value of HIV RNA > 500 copies/ml at or after W32 (meeting criteria for genotype testing) 36 Genotype done, n28/3613/15 Major resistance mutations, n50 NRTI1 (K65R)0 PI00 INI5 (N155H)*-

53 6.2 0 10 8 6 4 2 5.0 0.9 0.5 0.0 0.4 0.5 % Grade 3-4 CK elevation LDL-c Total chol: HDL-c ratio Total cholesterol RAL (n = 401) TDF/FTC (n = 404) 2 1.5 1 0.5 Grade 3-4 ALT elevation Mean changes in fasting lipids at W96 from baseline (mmol/l) Proportion with graded toxicity p < 0.001 HDL-c p = 0.02 0.1 0.2 p < 0.001p = 0.7 3.0 1.0 Triglycerides p = 0.49 0.3 0.2 0 NEAT 001/ANRS 143 Risultati di laboratorio

54 Creatinine clearance (eGFR, ml/min [Cockroft- Gault formula] Mean (95% CI) change from baseline No grade 2-4 creatinine elevation in either arm -15 -10 -5 0 5 04812182432 48648096 Weeks RAL + DRV/rTDF/FTC + DRV/r - 3.8 + 0.9 p=0.02 NEAT 001/ANRS 143 Tollerabilità renale

55 RADAR: BMD

56 Conclusioni In this well powered, open-label randomised study Overall twice daily RAL was well tolerated and had comparable efficacy to once daily TDF/FTC, when co-administered with once daily DRV/r, over 96 weeks in first-line ARV therapy –Primary endpoint incidence over 96 weeks was 17.4 % (RAL) vs. 13.7 % (TDF/FTC); adjusted absolute difference was 3.7% –The upper 95% CI of 8.6% was below the pre-specified non-inferiority margin –In a planned subgroup analysis of the outcome for patients with low CD4 (<200/mm 3 ) RAL + DRV/r was inferior to TDF/FTC + DRV/r Comparable safety between the 2 strategies –Similar rate of SAE, Grade 3-4 AE, AE leading to treatment modification Treatment-emergent resistance was seen in 5/28 (RAL) vs. 0/13 (TDF/FTC) patients with available genotype at failure  RAL + DRV/r represents an alternative option to TDF/FTC + DRV/r for first line therapy, particularly in patients with CD4 > 200/mm 3

57 Cosa guida la scelta del regime? Iter diagnostico Anamnesi Esame obiettivo Algoritmi interpretativi Studio laboratoristico Studio morfometrico, QUS, DXA

58 Perché sempre e ancora 3?

59 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.

60 Marco Borderi U. O. Malattie Infettive – Bologna Roma, 8 Maggio 2014 Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di MSD Italia.


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