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

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/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.

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. HIV
NRTI
NRTI
INI
PI/r

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 15

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 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
-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.

18. 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 ( )
4.6 ( )
4.7 ( )
(copies/ml)
<100,000
70%
68%
72%
100, ,000
23%
25%
24%
22%
>500,000 7% 8% 6%
CD4+ cells
(/mm³)
308 ( )
309 ( )
304 ( )
310 ( ) %
<200
30%
29%
31% 18

19. 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

20. 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

21. 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

22. % di discontinuazione di ATV/r per iperbilirubinemia/subittero negli studi
CASTLE2-5++
n=440 A
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: (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
-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

24. 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

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
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

27. Sottostudio osseo
Testo testo, testo

28. Sottostudio cardiovascolare

29. HIV
NRTI
NRTI

30. JFK & BMD

31. JFK & BMD
→ BMD & JFK

32. 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 Oct 15;204(8): 32

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

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 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

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 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
ABC/3TC
No. of subjects
TDF/FTC
ABC/3TC
*linear regression
McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801 40

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

42. 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: )
HR for CVA: 1.80 (95% CI: )
Bedimo R. Clin Infect Dis Jul 1;53(1):84-91 42

43. J Acquir Immune Defic Syndr. 2011 oct 1;58(2):163-17243

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

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

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 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: NCT
21st CROI, Boston, March 3-6,2014, Abs 84LB 46

47. 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 mg QD + RAL 400 mg BID
DRV+r 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

48. 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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

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 % (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

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

58. Perché sempre e ancora 3?

59. 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.

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