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,
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*
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
ATV 300 mg QD + RTV 100mg QD
RAL 400 mg BID +
DRV 800 mg QD + RTV 100 mg QD
+ FTC/TDF 200/300 mg QD
FTC/TDF 200/300 mg 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
*With the exception of RTV, all ART drugs were provided by the study
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
Considerazioni per l’analisi
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.
-20
Equivalence
Equivalence
Superiority
-10%
0
10%
20%
Difference in 96-week cumulative incidence
* 97.5% CI controls type I error at 5% for 3 pairwise equivalence comparisons.
Caratteristiche al basale
Characteristic
Total
(N=1809)
Treatment group
ATV/r
RAL
DRV/r
(N=605)
(N=603)
(N=601)
435 (24%)
144 (24%)
148 (25%)
143 (24%)
37
38
37
38
Sex
Female
Age (years)
Mean
Race/Ethnicity
White Non-His.
Black Non-His.
Hispanic
615 (34%)
757 (42%)
390 (22%)
212 (35%)
252 (42%)
125 (21%)
212 (35%)
254 (42%)
117 (19%)
191 (32%)
251 (42%)
148 (25%)
HIV-1 RNA
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)
<100,000
100,000-500,000
>500,000
70%
23%
7%
68%
25%
7%
68%
24%
8%
72%
22%
6%
(log10 c/ml)
(copies/ml)
CD4+ cells
(/mm³)
%
Median (Q1-Q3)
<200
308 (170-425) 309 (176-422) 304 (158-427) 310 (171-424)
30%
29%
31%
29%
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
-20
-10
96 week cumulative incidence of VF:
•ATV/r: 13%
•RAL: 10%
•DRV/r: 15%
0
10
20
-2.2% (-6.7%, 2.3%)
Incidenza cumulativa di
Fallimento per Tollerabilità
Difference in 96 wk cumulative incidence (97.5% CI)
Favors RAL
ATV/r vs RAL
13% (9.4%, 16%)
DRV/r vs RAL
3.6% (1.4%, 5.8%)
Favors DRV/r
-20
-10
0
96 week cumulative incidence of TF:
•ATV/r: 14%
•RAL: 1%
•DRV/r: 5%
10
20
ATV/r vs DRV/r
9.2% (5.5%, 13%)
Fallimento per Tollerabilità
Cause di discontinuazione*
Any toxicity discontinuation
Gastrointestinal toxicity
Jaundice/Hyperbilirubinemia
Other hepatic toxicity
Skin toxicity
Metabolic toxicity
Renal toxicity (all nephrolithiasis)
Abnormal chem/heme (excl. LFTs)
Other toxicity
ATV/r
(N=605)
RAL
DRV/r
(N=603) (N=601)
95 (16%)
25
47
4
7
6
4
0
2
8 (1%)
2
0
1
2
0
0
0
3
*Participants allowed to switch therapy for intolerable toxicity
32 (5%)
14
0
5
5
2
0
2
4
% di discontinuazione di ATV/r per
iperbilirubinemia/subittero negli studi
A52571++
n=605*
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)
2.6%
(16)
#
#
#
#
•
D/C due to clinical jaundice % (n)
5.0%
(30)
#
#
1.7%
(6)
#
Switch to
LPV/r or FPV/r
Off study
#
Off study
Consequences of Discontinuation
Off study
+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)
Favors RAL
ATV/r vs RAL
15% (10%, 20%)
Favors RAL
DRV/r vs RAL
7.5% (3.2%, 12%)
Favors DRV/r
-20
-10
0
10
20
*Consistent results seen with TLOVR at a 200 copies/ml threshold
ATV/r vs DRV/r
7.5% (2.3%, 13%)
Insorgenza di resistenza
1809 Participants
295 Virologic Failures
1 Baseline Missing
56 VF Failed to Amplify
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
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
Diff from Baseline:
Fasting TC (mg/dL)
30
ATV/RTV
RAL
(B) Fasting Triglycerides (TG)
DRV/RTV
20
10
0
Diff from Baseline:
Fasting
Triglycerides (mg/dL)
(A) Fasting Total Cholesterol (TC)
40
ATV/RTV
602
600
595
541
527
529
521
542
507
490
505
490
0
24
48
96
Study week
364
397
363
0
-20
ATV/RTV
RAL
DRV/RTV
144
ATV/RTV
15
RAL
DRV/RTV
10
5
0
-5
ATV/RTV
RAL
DRV/RTV
Number of subjects contributing data
490
364
505
397
490
363
602
600
595
542
527
528
522
542
507
0
24
48
96
Study week
144
(D) Fasting HDL-C
Number of subjects contributing data
596
593
581
529
518
508
512
531
486
480
493
468
0
24
48
96
Study week
360
385
346
144
Diff from Baseline:
Fasting HDL-C (mg/dL)
Diff from Baseline:
Fasting LDL-C (mg/dL)
(C) Fasting LDL-C
DRV/RTV
20
Number of subjects contributing data
ATV/RTV
RAL
DRV/RTV
RAL
ATV/RTV
10.0
RAL
DRV/RTV
7.5
5.0
2.5
0.0
ATV/RTV
RAL
DRV/RTV
Number of subjects contributing data
602
600
595
541
527
529
522
542
506
490
505
488
0
24
48
96
Study week
364
397
363
144
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)
LDL
Cholesterol
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
EFV
ATV/r
ATV/r
N=
ATV/r
EFV
EFV
ATV/r
ATV/r
EFV
EFV
ATV/r
ATV/r
EFV
EFV
ATV/r
ABC/3TC TDF/FTC
ABC/3TC TDF/FTC
ABC/3TC TDF/FTC
ABC/3TC TDF/FTC
326 290 326 300
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
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:
FE(p):
cGFR:
proximal renal tubulopathy
fractional excretion of phosphate >20% ->10% if hypophosphatemic
calculated Glomerular Filtration Rate (Cockroft-Gault)
Fux C. et al., CROI 2009; p743
Cumulative survival probability after
any type of fracture (Center JR et al. Lancet 1999)
ACTG 5224s: BB and BMD
A5224s
ABC/3TC
0
0
TDF/FTC
0 24 48
96
144
-1
-2
-3
-4
192
0 24 48
Visit Week from Randomization
No. of subjects
TDF/FTC
128 111 106
ABC/3TC
130 122 106
97
101
87
80
53
53
p=0.025*
-5
Hip BMD percent change
from week 0
-1
-2
-3
-4
-5
Lumbar spine BMD percent
change from week 0
p=0.004*
96
144
192
Visit Week from Randomization
No. of subjects
TDF/FTC
ABC/3TC
126 109 105
128 119 104
96
99
85
79
53
54
*linear regression
McComsey G, et al. Journal of Infectious Diseases 2011;203:1791–801
Association between current
ABC use and MI risk
Overall
Pre-March
2008
Post-March
2008
GFR → CVA
Estimated GFR,
mL/min/1.73 m2
AMI
CVA
Rate per
1000 Pt-Yrs
Unadjusted
HR
P Value
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
< .0001
• ≥ 90
2.92
Ref
--
9.74
Ref
--
• 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
J Acquir Immune Defic Syndr. 2011 oct 1;58(2):163-172
BMD → CVD
Osteoporosi
Osteopenia
Tankó LB. et al. JBMR. 2005;20:1912-1920
Perché ancora 3?
HIV
NRTI
NRTI
INI
PI/r
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
NEAT 001/ANRS 143
Disegno dello studio
• Phase III, randomised, open-label, multicenter, parallel-group, noninferiority, 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
Randomisation 1:1
stratified by country and participation in virology/immunology substudy
•
Composite virological and clinical primary endpoint (6 components)
Minimum
Week 96
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
NEAT 001/ANRS 143
Tempo dalla randomizzazione all’obiettivo
primario
Probability of reaching primary endpoint
Primary endpoint
N
N with primary endpoint
RAL
+ DRV/r
TDF/FTC
+ DRV/r
401
404
76 (19%)
1.00
RAL + DRV/r
TDF/FTC + DRV/r
0.75
61 (15%)
0.50
V1. Regimen change for
insufficient response
log rank p=0.12
< 1 log10 c/ml HIV RNA
reduction W18*
1
0
HIV RNA ≥ 400 c/ml W24*
1
0
V2. HIV RNA ≥ 50 c/ml at
W32*
27
28
V3. HIV RNA ≥ 50 c/ml after
W32*
32
0.25
0
0 8 18
22
C1. Death
3
1
C2. AIDS event
5
3
C3. SNAIDS event
7
7
* confirmed by a subsequent measurement
N at risk
32 48
64 80 96 112 128 144
Time (weeks)
400 384 375 347 329 317 308 211
402 395 393 361 350 340 331 215
90
90
11
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%)
NEAT 001/ANRS 143
HIV-1 RNA < 50 cp/mL
Percentage of participants with available data
100
93 %
91 %
80
89 %
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
RAL + DRV/r
TDF/FTC +
DRV/r
385
389
377 382
385 387
376
388
356
374
Mean (95% CI) Change From Baseline CD4+ Cell Count (cells/mm3)
W48
W96
+ 197 (184, 210)
+ 267 (250, 285)
+ 193 (180, 206)
+ 266 (249, 283)
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
Overall
n = 805
-1.1
Baseline HIV-1 RNA
< 100,000 c/ml n = 530
> 100,000 c/ml
8.6
-3.9
3.5
-0.05
n = 275
19.3
RAL +
DRV/r
TDF/FTC +
DRV/r
17.4 %
13.7 %
7%
7%
36 %
27 %
p = 0.09*
Baseline CD4+
< 200/mm3
n = 123
> 200/mm3
n = 682
4.7
-3.4
30.8
6.3
39.0 %
21.3 %
13.6 %
12.2 %
p = 0.02*
9
-10
0
10
20
30
Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted
* Test for homogeneity
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
28/36
13/15
5
0
1 (K65R)
0
PI
0
0
INI
5 (N155H)*
-
Genotype done, n
Major resistance mutations, n
NRTI
* 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.
NEAT 001/ANRS 143
Risultati di laboratorio
Mean changes in fasting lipids
at W96 from baseline (mmol/l)
Proportion with graded toxicity
RAL (n = 401)
TDF/FTC (n = 404)
%
10
8
Grade 3-4
Grade 3-4
CK elevation ALT elevation
2
6.2
6
Total
cholesterol
LDL-c
p < 0.001
p = 0.02
HDL-c
Triglycerides
p < 0.001 p = 0.49
Total chol:
HDL-c ratio
p = 0.7
1.5
5.0
0.9
4
1
3.0
0.5
2
0
1.0
0.5
0.5
0.4
0.2
0
0.3
0.1
0.2
0.0
0.0
NEAT 001/ANRS 143
Tollerabilità renale
Creatinine clearance (eGFR, ml/min [CockroftGault formula]
Mean (95% CI) change from baseline
5
0
+ 0.9
-5
- 3.8
p=0.02
-10
-15
0 4 8 12 18 24
32
48
64
80
Weeks
RAL + DRV/r
No grade 2-4 creatinine elevation in either arm
TDF/FTC + DRV/r
96
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
Cosa guida la scelta del regime?
Iter diagnostico
Anamnesi
Esame obiettivo
Algoritmi interpretativi
Studio laboratoristico
Studio morfometrico, QUS, DXA
Perché sempre e ancora 3?
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
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