Marco Borderi U. O. Malattie Infettive – Bologna Roma, 8 Maggio 2014 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 .

di sbagliare un calcio di rigore, non è mica da questi particolari 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.

HIV NRTI NRTI NNRTI INI PI/r

Linee Guida DHHS 2014

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/mL PI/r plus nRTIs Darunavir/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.

Linee Guida EACS 2013

Linee Guida Italiane 2013

Gravidanza: Linee Guida EACS 2013

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

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

Perché sempre 3?

HIV NRTI NRTI INI PI/r

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

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 15

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 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

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

Caratteristiche al basale Treatment group Characteristic   Total (N=1809) ATV/r (N=605) RAL (N=603) DRV/r (N=601) Sex Female 435 (24%) 144 (24%) 148 (25%) 143 (24%) Age (years) Mean 37 38 Race/Ethnicity White Non-His. 615 (34%) 212 (35%) 191 (32%) Black Non-His. 757 (42%) 252 (42%) 254 (42%) 251 (42%) Hispanic 390 (22%) 125 (21%) 117 (19%) HIV-1 RNA (log10 c/ml) Median (Q1-Q3) 4.6 (4.1-5.1) 4.6 (4.1-5.2) 4.7 (4.1-5.1) (copies/ml) <100,000 70% 68% 72% 100,000-500,000 23% 25% 24% 22% >500,000 7% 8% 6% CD4+ cells (/mm³) 308 (170-425) 309 (176-422) 304 (158-427) 310 (171-424) % <200 30% 29% 31% 18

Incidenza cumulativa di Fallimento Virologico Difference in 96 wk cumulative incidence (97.5% CI) -20 -10 10 20 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% 19

Incidenza cumulativa di Fallimento per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI) -20 -10 10 20 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% 20

Fallimento per Tollerabilità Cause di discontinuazione* ATV/r (N=605) RAL (N=603) DRV/r (N=601) Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity 25 2 14 Jaundice/Hyperbilirubinemia 47 Other hepatic toxicity 4 1 5 Skin toxicity 7 Metabolic toxicity 6 Renal toxicity (all nephrolithiasis) Abnormal chem/heme (excl. LFTs) Other toxicity 3 *Participants allowed to switch therapy for intolerable toxicity

% di discontinuazione di ATV/r per iperbilirubinemia/subittero negli studi CASTLE2-5++ n=440 A52026-7++ n=928** 1038,10++ n=355 0459++ 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) # Consequences of Discontinuation Off study Switch to LPV/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 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)

Incidenza cumulativa di Fallimento Virologico o per Tollerabilità Difference in 96 wk cumulative incidence (97.5% CI) -20 -10 10 20 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 RAL Favors DRV/r *Consistent results seen with TLOVR at a 200 copies/ml threshold

Insorgenza di resistenza 1809 Participants 1 Baseline Missing 56 VF Failed to Amplify 295 Virologic Failures ATV/r RAL 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 1 TDF+FTC 0 TDF+FTC 0 TDF+FTC 1 RAL 1 RAL 1 RAL 0 RAL+FTC 7 RAL+FTC 0 RAL+FTC 0 RAL+FTC+TDF 3 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

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 541 527 529 521 542 507 490 505 364 397 363 20 10 Diff from Baseline: Fasting TC (mg/dL) 24 48 96 144 Study week Number of subjects contributing data ATV/RTV RAL DRV/RTV (A) Fasting Total Cholesterol (TC) 40 602 600 595 ATV/RTV RAL DRV/RTV 542 527 528 522 507 490 505 364 397 363 20 -20 Diff from Baseline: Fasting Triglycerides (mg/dL) 24 48 96 144 Study week Number of subjects contributing data ATV/RTV RAL DRV/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 -5 Diff from Baseline: Fasting LDL-C (mg/dL) 24 48 96 144 Study week Number of subjects contributing data ATV/RTV RAL DRV/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) 24 48 96 144 Study week Number of subjects contributing data ATV/RTV RAL DRV/RTV (D) Fasting HDL-C 5.0

Sottostudio osseo Testo testo, testo

Sottostudio cardiovascolare

HIV NRTI NRTI

JFK & BMD

JFK & BMD → BMD & JFK

ACTG 5202 (wk 48) Median Change in Fasting Lipids (mg/dL) Cholesterol LDL HDL Triglycerides 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 EFV ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ABC/3TC TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC N= 326 290 300 303 270 310 281 322 288 324 299 325 289 324 300 Sax PE et al, J Infect Dis. 2011 Oct 15;204(8):1191-201 32

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

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 36

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

McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801 ACTG 5224s: BB and BMD A5224s Hip BMD percent change from week 0 -1 -2 -3 -4 -5 24 48 96 144 192 Visit Week from Randomization p=0.025* TDF/FTC ABC/3TC Lumbar spine BMD percent change from week 0 -1 -2 -3 -4 -5 24 48 96 144 192 Visit Week from Randomization p=0.004* 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 40

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

Bedimo R. Clin Infect Dis. 2011 Jul 1;53(1):84-91 GFR → CVA Estimated GFR, mL/min/1.73 m2 AMI CVA Rate per 1000 Pt-Yrs Unadjusted HR P Value < 60 11.33 3.85 < .0001 30.58 2.95 .002 60-89 3.89 1.33 .048 12.57 1.28 ≥ 90 2.92 Ref -- 9.74 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) Bedimo R. Clin Infect Dis. 2011 Jul 1;53(1):84-91 42

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

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

Perché ancora 3? HIV NRTI NRTI INI PI/r

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 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 Clinicaltrials.gov identifier: NCT01066962 21st CROI, Boston, March 3-6,2014, Abs 84LB 46

NEAT 001/ANRS 143 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) 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) 47

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 48

Tempo dalla randomizzazione all’obiettivo primario NEAT 001/ANRS 143 Primary endpoint Probability of reaching primary endpoint RAL + DRV/r TDF/FTC + DRV/r N 401 404 N with primary endpoint 76 (19%) 61 (15%) V1. Regimen change for insufficient response < 1 log10 c/ml HIV RNA reduction W18* 1 HIV RNA ≥ 400 c/ml W24* V2. HIV RNA ≥ 50 c/ml at W32* 27 28 V3. HIV RNA ≥ 50 c/ml after W32* 32 22 C1. Death 3 C2. AIDS event 5 C3. SNAIDS event 7 1.00 RAL + DRV/r TDF/FTC + DRV/r 0.75 0.50 log rank p=0.12 0.25 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 49

Mean (95% CI) Change From Baseline CD4+ Cell Count (cells/mm3) HIV-1 RNA < 50 cp/mL NEAT 001/ANRS 143 Percentage of participants with available data 93 % 100 91 % 89 % 80 89 % 60 RAL + DRV/r TDF/FTC + DRV/r 40 20 4 8 12 18 24 32 48 64 80 96 Weeks n 401 404 385 389 377 385 382 387 376 388 356 374 Mean (95% CI) Change From Baseline CD4+ Cell Count (cells/mm3) W48 W96 RAL + DRV/r + 197 (184, 210) + 267 (250, 285) TDF/FTC + DRV/r + 193 (180, 206) + 266 (249, 283) 50

Obiettivo primario per HIV-RNA e CD4+ al basale NEAT 001/ANRS 143 Obiettivo primario per HIV-RNA e CD4+ al basale Overall analysis: RAL + DRV/r non inferior to TDF/FTC + DRV/r RAL + DRV/r TDF/FTC + DRV/r Overall n = 805 10 -10 20 30 9 -1.1 8.6 17.4 % 13.7 % Baseline HIV-1 RNA < 100,000 c/ml n = 530 -3.9 3.5 7 % 7 % > 100,000 c/ml n = 275 -0.05 19.3 36 % 27 % p = 0.09* Baseline CD4+ 4.7 30.8 < 200/mm3 n = 123 39.0 % 21.3 % > 200/mm3 n = 682 13.6 % 12.2 % -3.4 6.3 p = 0.02* Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted * Test for homogeneity 51

Fallimenti virologici e insorgenza di resistenza NEAT 001/ANRS 143 Fallimenti virologici e insorgenza di resistenza RAL + DRV/r n=401 TDF/FTC + DRV/r n=404 Protocol-defined virological failure (PDVF), n 66 52 Number of PDVF who met criteria for genotype testing (HIV RNA > 500 copies/ml at or after W32) 33 9 Number of patients with single unconfirmed value of HIV RNA > 500 copies/ml at or after W32 (meeting criteria for genotype testing) 3 6 Genotype done, n 28/36 13/15 Major resistance mutations, n 5 NRTI 1 (K65R) PI INI 5 (N155H)* - * 1 additional patient with T97A 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 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 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. 52

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

NEAT 001/ANRS 143 Tollerabilità renale Creatinine clearance (eGFR, ml/min [Cockroft- Gault formula] Mean (95% CI) change from baseline 5 + 0.9 - 3.8 -5 p=0.02 -10 -15 4 8 12 18 24 32 32 48 64 80 96 Weeks RAL + DRV/r TDF/FTC + DRV/r No grade 2-4 creatinine elevation in either arm 54

RADAR: BMD

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/mm3) 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/mm3 56

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

Perché sempre e ancora 3?

di sbagliare un calcio di rigore, non è mica da questi particolari 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.

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