Presentation on theme: "Marco Borderi U. O. Malattie Infettive – Bologna Roma, 8 Maggio 2014"— Presentation transcript:
1 Marco Borderi U. O. Malattie Infettive – Bologna Roma, 8 Maggio 2014 CROI 2014-ACTG 5257 e NEAT001/ANRS 143 quali nuove opportunità per i pazientiMarco BorderiU. O. Malattie Infettive – BolognaRoma, 8 Maggio 2014Seminario Nadir Iniziativa resa possibile grazie al supporto di MSD Italia.
2 di sbagliare un calcio di rigore, non è mica da questi particolari Ma Nino non aver pauradi sbagliare un calcio di rigore,non è mica da questi particolariche si giudica un giocatore,un giocatore lo vedi dal coraggio,dall'altruismo e dalla fantasia.
6 Linee Guida IAS 2012 Component Recommended Regimens NNRTI plus nRTIs Efavirenz/tenofovir/emtricitabine (AIa)Efavirenz plus abacavir/lamivudine (AIa) in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/mLPI/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/mLInSTI plus nRTIsRaltegravir plus tenofovir/emtricitabine (AIa)Thompson et al, JAMA, 2012.
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 QDDRV 800 mg QD + RTV 100 mg QD+ FTC/TDF 200/300 mg QDATV 300 mg QD + RTV 100mg QD+ FTC/TDF 200/300 mg QDStudy Conclusion 96 weeks after final participant enrolledFollow-up continued for 96 weeks after randomization of last subject (range 2-4 years) regardless of status on randomized ARTHIV-infected patients, ≥18 yr, with no previous ART,VL ≥ 1000 c/mL at US SitesRandomized 1:1:1 to Open Label TherapyStratified 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 study15
16 Disegno dello studio Hypothesis Primary Endpoints* FTC/TDF with ATV/r, RAL, or DRV/r will be equivalent in terms of virologic efficacy and tolerability over 96 weeksPrimary 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 EndpointThe earlier occurrence of either VF or TF in a given participant* Time measured from date of study entry/randomization
17 Considerazioni per l’analisi -20-10%20%10%Difference in 96-week cumulative incidenceEquivalence regionEquivalence 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.EquivalenceEquivalenceSuperiority* 97.5% CI controls type I error at 5% for 3 pairwise equivalence comparisons.
19 Incidenza cumulativa di Fallimento Virologico Difference in 96 wk cumulative incidence (97.5% CI)-20-1010203.4% (-0.7%, 7.4%)5.6% (1.3%, 9.9%)-2.2% (-6.7%, 2.3%)ATV/r vs RALDRV/r vs RALATV/r vs DRV/r96 week cumulative incidence of VF:ATV/r: 13%RAL: 10%DRV/r: 15%19
20 Incidenza cumulativa di Fallimento per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI)-20-10102013% (9.4%, 16%)3.6% (1.4%, 5.8%)9.2% (5.5%, 13%)ATV/r vs RALDRV/r vs RALATV/r vs DRV/rFavors RALFavors DRV/r96 week cumulative incidence of TF:ATV/r: 14%RAL: 1%DRV/r: 5%20
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 toxicity25214Jaundice/Hyperbilirubinemia47Other hepatic toxicity415Skin toxicity7Metabolic toxicity6Renal toxicity (all nephrolithiasis)Abnormal chem/heme (excl. LFTs)Other toxicity3*Participants allowed to switch therapy for intolerable toxicity
22 % di discontinuazione di ATV/r per iperbilirubinemia/subittero negli studi CASTLE2-5++n=440An=928**1038,10++n=3550459++n=119D/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)a0.7%(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)#Consequences of DiscontinuationOff studySwitch toLPV/r or FPV/r+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 hyperpigmentation1. Landovitz RJ, et al. CROI 2014; oral presentation 85; Available from: (accessed March 2014). 2. Molina JM, et al. Lancet. 2008;372: Molina JM, et al. JAIDS. 2010;53: Uy et al. HIV10, 2010, poster P CASTLE CSR (Table 5.3.1). 6. Daar et al. Ann Int Med (7) Ribaudo H, et al. J Infect Dis. Feb (3): DeJesus et al. Lancet. 2012;379(9835): Johnson et al AIDS 2006, 20:711– 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)-20-10102015% (10%, 20%)7.5% (3.2%, 12%)7.5% (2.3%, 13%)ATV/r vs RALDRV/r vs RALATV/r vs DRV/rFavors RALFavors RALFavors DRV/r*Consistent results seen with TLOVR at a 200 copies/ml threshold
24 Insorgenza di resistenza 1809 Participants1 Baseline Missing56 VF Failed to Amplify295 Virologic FailuresATV/rRALDRV/r75/94 VFAvailable65/85 VFAvailable99/115 VFAvailable9 Any Resistance(1.5%)18 Any Resistance(3%)4 Any Resistance(<1%)2 TDF0 TDF0 TDF5 FTC7 FTC3 FTC1 TDF+FTC0 TDF+FTC0 TDF+FTC1 RAL1 RAL1 RAL0 RAL+FTC7 RAL+FTC0 RAL+FTC0 RAL+FTC+TDF3 RAL+FTC+TDF0 RAL+FTC+TDF24
25 ConclusioniATV/r, RAL, and DRV/r were equivalent for virologic efficacyATV/r was less well tolerated than DRV/r or RALLargely due to cosmetic hyperbilirubinemiaRAL was superior to both PI/r regimens for combined tolerability and virologic efficacyDRV/r was superior to ATV/rVF with resistance was rareMore frequently observed with RALAnalyses are ongoing to evaluate:Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior, adherence, and key subgroup differences
26 Sottostudio lipidicoFigure 1. Mean of Changes from Baseline in Fasting Lipid Profile (mg/dL) Over Time with 95% CI30602600595ATV/RTV RAL DRV/RTV5415275295215425074905053643973632010Diff from Baseline: Fasting TC (mg/dL)244896144Study weekNumber of subjects contributing dataATV/RTVRALDRV/RTV(A) Fasting Total Cholesterol (TC)40602600595ATV/RTV RAL DRV/RTV54252752852250749050536439736320-20Diff from Baseline: Fasting Triglycerides (mg/dL)244896144Study weekNumber of subjects contributing dataATV/RTVRALDRV/RTV(B) Fasting Triglycerides (TG)15596593581ATV/RTV RAL DRV/RTV52951850851253148648049346836038534610-5Diff from Baseline: Fasting LDL-C (mg/dL)244896144Study weekNumber of subjects contributing dataATV/RTVRALDRV/RTV(C) Fasting LDL-C510.0602600595ATV/RTV RAL DRV/RTV5415275295225425064905054883643973618.104.22.168Diff from Baseline: Fasting HDL-C (mg/dL)244896144Study weekNumber of subjects contributing dataATV/RTVRALDRV/RTV(D) Fasting HDL-C5.0
32 ACTG 5202 (wk 48) Median Change in Fasting Lipids (mg/dL) CholesterolLDLHDLTriglyceridesp<0.001p-values: ATV/r vs. EFVp=0.07p<0.001p<0.001p=0.26p<0.001p=0.002p<0.001EFVATV/rATV/rATV/rATV/rATV/rATV/rATV/rATV/rABC/3TCTDF/FTCABC/3TCTDF/FTCABC/3TCTDF/FTCABC/3TCTDF/FTCN=326290300303270310281322288324299325289324300Sax PE et al, J Infect Dis Oct 15;204(8):32
36 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 tubulopathyFE(p): fractional excretion of phosphate >20% ->10% if hypophosphatemiccGFR: calculated Glomerular Filtration Rate (Cockroft-Gault)Fux C. et al., CROI 2009; p74336
39 Cumulative survival probability after any type of fracture (Center JR et al. Lancet 1999)
40 McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801 ACTG 5224s: BB and BMDA5224sHip BMD percent change from week 0-1-2-3-4-5244896144192Visit Week from Randomizationp=0.025*TDF/FTCABC/3TCLumbar spine BMD percent change from week 0-1-2-3-4-5244896144192Visit Week from Randomizationp=0.004*No. of subjectsTDF/FTCABC/3TCNo. of subjectsTDF/FTCABC/3TC*linear regressionMcComsey G, et al. Journal of Infectious Diseases 2011;203:1791–80140
41 Association between current ABC use and MI risk OverallPre-March2008Post-March
42 Bedimo R. Clin Infect Dis. 2011 Jul 1;53(1):84-91 GFR → CVAEstimated GFR, mL/min/1.73 m2AMICVARate per 1000 Pt-YrsUnadjusted HRP Value< 6011.333.85< .000130.582.95.00260-893.891.33.04812.571.28≥ 902.92Ref--9.74CKD is associated with higher risk of AMI and CVAHR for AMI: 2.41 (95% CI: )HR for CVA: 1.80 (95% CI: )Bedimo R. Clin Infect Dis Jul 1;53(1):84-9142
43 J Acquir Immune Defic Syndr. 2011 oct 1;58(2):163-172 43
44 BMD → CVD Tankó LB. et al. JBMR. 2005;20:1912-1920 Osteoporosi OsteopeniaTankó LB. et al. JBMR. 2005;20:
46 and the NEAT001/ANRS143 Study Group First-Line Raltegravir (RAL) + Darunavir/Ritonavir (DRV/r) is Non-inferior to Tenofovir/Emtricitabine (TDF/FTC) + DRV/r: The NEAT 001/ANRS 143 Randomised TrialFrançois 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 GroupClinicaltrials.gov identifier: NCT21st CROI, Boston, March 3-6,2014, Abs 84LB46
47 NEAT 001/ANRS 143Disegno dello studioPhase III, randomised, open-label, multicenter, parallel-group, non-inferiority, strategic trial78 sites, 15 countries (Austria, Belgium, Denmark, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Spain, Sweden)HIV-1 ART-naïve≥ 18 yearsHIV-1 RNA > 1000 c/mlCD4 ≤ 500/mm3HBs Ag negativeNo major IAS-USA resistance mutationsDRV+r mg QD + RAL 400 mg BIDDRV+r mg QD + TDF/FTC FDC QDMinimumWeek 96Randomisation 1:1stratified by country and participation in virology/immunology substudyComposite virological and clinical primary endpoint (6 components)47
48 ObiettiviNEAT 001/ANRS 143Primary endpoint : Time to failure, as the first occurrence of any of the following components:VirologicalV1. change of treatment before W32 because of insufficient virologic responseHIV-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*ClinicalC1 death due to any causeC2. 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-UNon-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 analysisMajor secondary endpoints: safety, changes in CD4 and HIV RNA, genotypic resistance* confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee48
49 Tempo dalla randomizzazione all’obiettivo primario NEAT 001/ANRS 143Primary endpointProbability of reaching primary endpointRAL+ DRV/rTDF/FTC + DRV/rN401404N with primary endpoint76(19%)61(15%)V1. Regimen change for insufficient response< 1 log10 c/ml HIV RNA reduction W18*1HIV RNA ≥ 400 c/ml W24*V2. HIV RNA ≥ 50 c/ml at W32*2728V3. HIV RNA ≥ 50 c/ml after W32*3222C1. Death3C2. AIDS event5C3. SNAIDS event71.00RAL + DRV/rTDF/FTC + DRV/r0.750.50log rank p=0.120.258183248648096112128144Time (weeks)N at risk40038437534732931730821190114023953933613503403312159012Estimated proportion reaching primary endpoint at W96RAL: 17.4% vs TDF/FTC: 13.7%Adjusted difference: 3.7% (95% CI: -1.1, 8.6%)* confirmed by a subsequent measurement49
50 Mean (95% CI) Change From Baseline CD4+ Cell Count (cells/mm3) HIV-1 RNA < 50 cp/mLNEAT 001/ANRS 143Percentage of participants with available data93 %10091 %89 %8089 %60RAL + DRV/rTDF/FTC + DRV/r4020481218243248648096Weeksn401404385389377385382387376388356374Mean (95% CI) Change From Baseline CD4+ Cell Count (cells/mm3)W48W96RAL + DRV/r+ 197(184, 210)+ 267(250, 285)TDF/FTC + DRV/r+ 193(180, 206)+ 266(249, 283)50
51 Obiettivo primario per HIV-RNA e CD4+ al basale NEAT 001/ANRS 143Obiettivo primario per HIV-RNA e CD4+ al basaleOverall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/rRAL + DRV/rTDF/FTC + DRV/rOveralln = 80510-1020309-1.18.617.4 %13.7 %Baseline HIV-1 RNA< 100,000 c/mln = 530-3.93.57 %7 %> 100,000 c/mln = 275-0.0519.336 %27 %p = 0.09*Baseline CD4+4.730.8< 200/mm3n = 12339.0 %21.3 %> 200/mm3n = 68213.6 %12.2 %-3.46.3p = 0.02*Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted* Test for homogeneity51
52 Fallimenti virologici e insorgenza di resistenza NEAT 001/ANRS 143Fallimenti virologici e insorgenza di resistenzaRAL + DRV/r n=401TDF/FTC + DRV/r n=404Protocol-defined virological failure (PDVF), n6652Number of PDVF who met criteria for genotype testing (HIV RNA > 500 copies/ml at or after W32)339Number of patients with single unconfirmed value of HIV RNA > 500 copies/ml at or after W32 (meeting criteria for genotype testing)36Genotype done, n28/3613/15Major resistance mutations, n5NRTI1 (K65R)PIINI5 (N155H)*-* 1 additional patient with T97AProtocol-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 log10 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 W32According to the protocol, genotypic testing was carried out by local laboratories when patients had a single VL > 500 copies/ml at or after W32.52
53 Risultati di laboratorio NEAT 001/ANRS 143Risultati di laboratorioProportion with graded toxicityMean changes in fasting lipidsat W96 from baseline (mmol/l)RAL (n = 401)TDF/FTC (n = 404)%108642Grade 3-4CK elevationGrade 3-4ALT elevationTotalcholesterolTotal chol:HDL-c ratioLDL-cHDL-cTriglycerides26.2p < 0.001p = 0.02p < 0.001p = 0.49p = 0.71.55.00.913.00.50.50.40.50.31.00.20.20.10.00.0
54 NEAT 001/ANRS 143Tollerabilità renaleCreatinine clearance (eGFR, ml/min [Cockroft- Gault formula] Mean (95% CI) change from baseline5+ 0.9- 3.8-5p=0.02-10-1548121824323248648096WeeksRAL + DRV/rTDF/FTC + DRV/rNo grade 2-4 creatinine elevation in either arm54
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 therapyPrimary endpoint incidence over 96 weeks was 17.4 % (RAL) vs % (TDF/FTC); adjusted absolute difference was 3.7%The upper 95% CI of 8.6% was below the pre-specified non-inferiority marginIn a planned subgroup analysis of the outcome for patients with low CD4 (<200/mm3) RAL + DRV/r was inferior to TDF/FTC + DRV/rComparable safety between the 2 strategiesSimilar rate of SAE, Grade 3-4 AE, AE leading to treatment modificationTreatment-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/mm356
57 Cosa guida la scelta del regime? Iter diagnostico AnamnesiEsame obiettivoAlgoritmi interpretativiStudio laboratoristicoStudio morfometrico, QUS, DXA57
59 di sbagliare un calcio di rigore, non è mica da questi particolari Ma Nino non aver pauradi sbagliare un calcio di rigore,non è mica da questi particolariche 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 Iniziativa resa possibile grazie al supporto di MSD Italia.