Transcript Protecting cognitive function in hematological cancers

Pooled 48-Week Analysis of DUET-1
and DUET-2: Durable Efficacy and
Safety Results of Etravirine (ETR;
TMC125) in Treatment-Experienced
HIV-infected Patients
Arnaud Cheret,1 Christine Katlama,2 Benoit Trottier,3
Margaret Johnson,4 Jose-Valdez Madruga,5 Robin Keen,6
Diego Miralles,7 Marie-Pierre de Bethune,7 Monika Peeters,7 Goedele De Smedt7
1Tibotec,
Janssen-Cilag, France; 2Hôpital Pitié-Salpêtrière, Paris, France; 3Clinique Médicale l'Actuel,
Montréal, Canada; 4Royal Free Hospital, London, England; 5Centro de Referência e Treinamento
DST/AIDS, São Paulo, Brazil; 6Tibotec Inc, Yardley, PA, USA; 7Tibotec bvba, Mechelen, Belgium
DUET study design
and major inclusion criteria
Screening
6 weeks
48-week treatment period
with optional 48-week extension
24-week primary analysis
Follow-up
4 weeks
48-week analysis
ETR 200mg bid + BR*
600 patients
target per trial
Placebo + BR*
*BR = DRV/r with optimised NRTIs and optional ENF

Plasma viral load >5000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks

≥1 NNRTI RAM, at screening or in documented historic genotype

≥3 primary protease inhibitor (PI) mutations at screening

DUET-1 and DUET-2 differ only in geographic location
–
in DUET-1, patients were recruited from Thailand, Europe and the Americas
–
in DUET-2, patients were recruited from Europe, Australia, Canada, and the USA

Pooled analysis was prespecified
BR = background regimen; DRV/r = darunavir/ritonavir; ENF = enfuvirtide;
RAM = resistance-associated mutation
Baseline characteristics
and background ARVs
Parameter
Patient demographics
Male, %
Caucasian, %
Disease characteristics Viral load, log10 copies/mL (range)
CD4 cells, cells/mL (range)
CDC category C, %
Prior ARV use
10–15 ARVs, %
NNRTIs in screening, %
DRV/r, %
Detectable mutations ≥2 NNRTI RAMs,* %
≤3 primary PI RAMs, %
BR
Used ENF (total), %
Used ENF de novo, %
Active background agents = 0,‡ %
Active background agents = 1,‡ %
ETR + BR
(n=599)
Placebo + BR
(n=604)
90
70
4.8 (2.7–6.8)
99 (1–789)
58
66
12
4
69
31
45
26
17
89
70
4.8 (2.2–6.5)
109 (0–912)
59
65
12
5
69
31
47
26
16
37
39
ARVs = antiretrovirals; *From extended NNRTI RAM list (Tambuyzer L, et al. EHDRW 2007. Abstract 67)
‡Assessed by phenotypic sensitivity score (PSS)
Patients with viral load <50 copies/mL
at Week 48 (ITT-TLOVR)
ETR + BR (n=599)
Placebo + BR (n=604)
100
Responders (%) ± 95% CIs
90
80
70
61%
60
p<0.0001*
50
40%
40
30
20
10
0
02 4
8
12 16 20 24
32
40
48
Time (weeks)
ITT = intent-to-treat; TLOVR = time to loss of virologic response;
CI = confidence interval; *Logistic regression model
Sustained virological response
at Week 48 (ITT-TLOVR)
Virological
response
at Week 24
(copies/mL)
<50
50–400
400

Virological
response
at Week 48
(copies/mL)
ETR + BR
(n=599), %
Placebo + BR
(n=604), %
<50
92
89
50–400
5
6
400
3
6
<50
35
31
50–400
53
45
400
12
24
<50
0
<1
50–400
3
1
400
97
99
92% of patients receiving ETR + BR achieving <50 copies/mL at Week
24 maintained virological suppression at Week 48
Viral load reduction from baseline
at Week 48 (ITT; NC=F)
ETR + BR (n=599)
Mean change in viral load from
baseline (log10 copies/mL) ± SE
0.5
Placebo + BR (n=604)
0
–0.5
–1.0
–1.49
–1.5
–2.25
–2.0
p<0.0001*
–2.5
–3.0
–3.5
02 4
8
12 16 20 24
32
40
48
Time (weeks)
NC=F = non-completer=failure imputation algorithm: changes below the detection limit (<50 copies/mL)
were imputed as 49 copies/mL; SE = standard error; *ANCOVA (analysis of covariance) model
Change in CD4 cell count from
baseline at Week 48 (ITT; NC=F)
ETR + BR (n=599)
Mean change in CD4 cell count
from baseline (cell/mm3) ± SE
150
Placebo + BR (n=604)
125
+98
100
p=0.0006*
75
+73
50
25
0
–25
02 4
8
12 16 20 24
32
40
48
Time (weeks)
*ANCOVA model
Virological benefit of ETR versus
placebo at Week 48 irrespective of ENF use
ETR + BR
100

Virological response was
higher in the ENF de novo
group compared with the
group who were reusing or
not using ENF

ETR provided an added
benefit to the regimen, which
was also observed when ENF
was used de novo
Placebo + BR
Responders* (%)
80
60
40
71%
58%
57%
33%
20
0
254/446 147/445
109/153 93/159
Reusing or
not using ENF
ENF
de novo
p<0.0001‡
p=0.0116‡
*Responders (<50 copies/mL) at Week 48 according to ENF use (ITT-TLOVR)
‡Logistic regression
Response (<50 copies/mL) at Week 48 according
to baseline viral load and CD4 cell count
INTELENCE + BR
80
Placebo + BR
76%
Patients with viral load
<50 copies/mL at week 48 (%)
80
74%
61%
60
65%
56%
60
49%
52%
45%
38%
40
72%
51%
48%
40
28%
22%
20
20
125/ 97/
165 174
0
126/ 82/
206 213
112/ 61/
228 217
30,000– ≥100,000
99,999
Baseline viral load
<30,000
96/ 45/
213 209
136/ 99/
208 208
88/ 65/
119 125
42/ 31/
58 61
<50
50-200
200-350
≥ 350
0
Baseline CD4 cell count
Response (<50 copies/mL) by PSS
at Week 48 (TLOVR)*
ETR + BR (n=539)
ETR + BR (n=355)
Placebo + BR (n=536)
Number of active background
ARVs (PSS)
All patients‡
0
5/83
6%
64/201
0 4/51 8% p<0.0001
63%
32%
47/127
78%
169/252
0
67%
37%
p<0.0001
82%
2 139/169
p=0.0022
60
40
80
20
Patients with viral load <50 copies/mL
at Week 48 (%)
71%
93/131
1
p<0.0001
197/252
2
56%
31/55
p<0.0001
125/200
1
ETR FC ≤3‡
46%
40/87
Placebo + BR (n=357)
100
122/179
0
68%
p=0.0004
60
100
40
80
20
Patients with viral load <50 copies/mL
at Week 48 (%)
*Darunavir (DRV) considered sensitive if fold-change (FC) ≤10; ‡Analysis excludes patients who discontinued
except for virological failure; ENF is counted as sensitive if used de novo
Overview of AEs
(regardless of causality) at Week 48
ETR + BR
(n=599)
Placebo + BR
(n=604)
Any AE (any cause)
Grade 3 or 4 AE
Discontinuation due to AE
Serious AE
Death (any cause)*
96
33
7
20
2
96
35
6
23
3
Most common AEs
Rash (any type)
Diarrhoea
Nausea
19
18
15
11
24
13
Headache
Nasopharyngitis
11
11
13
10
AEs of interest
Nervous system disorders
Psychiatric disorders
Hepatic AEs
17
17
7
20
20
6
Parameter, %

The incidence and severity of laboratory abnormalities, including hepatic and lipid parameters, was
generally similar between the ETR and placebo groups
AE = adverse effect; *All deaths in the ETR group were considered not or doubtfully related to trial
medication. One death in the pooled placebo group was considered possibly related to the BR
Summary of rash in ETR
group at Week 48
ETR + BR (n=599)
Placebo + BR (n=604)

Early onset

most frequent in second week of
therapy
–
median onset Day 14

Duration
–
median duration 15 days

Infrequently led to discontinuation
–
2% of patients permanently
discontinued
–
most rashes resolved with
continued treatment
–
there was a higher incidence of
rash in women than men in the
ETR group (30% vs 18%),
although there were no clear
differences in severity or
treatment discontinuations
according to gender
12
Patients with new onset (%)
10
8
6
4
2
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Time (weeks)
Conclusions

At 48 weeks, ETR + BR demonstrated superior
virological responses over placebo in treatmentexperienced patients, irrespective of ENF use
– overall 61% of patients in the ETR group achieved
confirmed undetectable (<50 copies/mL) viral load
compared with 40% in the placebo group

Virological and immunological responses with ETR were
sustained
– 92% of patients receiving ETR + BR achieving <50
copies/mL at Week 24 maintained virological
suppression at Week 48
The safety and tolerability profile of ETR was generally
comparable to placebo, with the exception of rash which
occurred early in treatment

Acknowledgments

We express our gratitude to the patients that participated in the studies, as well as the study centre staff, the data
safety and monitoring board, clinical event adjudication panels, Virco, Tibotec personnel and the following principal
investigators
DUET-1
Argentina: HA Ariza, J Benetucci, P Cahn, LM Calanni,
LI Cassetti, J Corral, DO David, A Krolewiecki, MH Losso,
P Patterson, RA Teijeiro; Brazil: CA da Cunha, B Grinsztejn,
EG Kallas, EM Netto, JH Pilotto, M Schechter, J Suleiman,
A Timerman; Chile: J Ballesteros, R Northland; Costa Rica:
AA Alvilés Montoya, G Herrera Martinez, A Solano Chinchilla;
France: M Dupon, JM Livrozet, P Morlat,
G Pialoux, C Piketty, I Poizot-Martin; Mexico: J AndradeVillanueva, G Reyes-Terán, J Sierra-Madero; Panama:
A Canton, A Rodriguez, N Sosa; Puerto Rico: JO Morales
Ramirez, JL Santana Bagur, R Soto-Malave; Thailand:
T Anekthananon, P Mootsikapun, K Ruxrungtham; USA: M
Albrecht, N Bellos, R Bolan, P Brachman, C Brinson,
F Cruickshank, R Elion, WJ Fessel, R Haubrich,T Hawkins,
S Hodder, P Hutcherson, T Jefferson, H Katner, C Kinder,
M Kozal, J Lalezari, J Leider, D McDonough, A Mills,
K Mounzer, J Nadler, D Norris, W O’Brien, G Pierone,
K Raben, B Rashbaum, M Rawlings, B Rodwick, P Ruane,
J Sampson, S Schrader, A Scribner, M Sension, D Sweet,
B Wade, D Wheeler, A Wilkin, T Wills, M Wohlfeiler,
K Workowski
DUET-2
Australia: J Chuah, D Cooper, B Eu, J Hoy, C Workman;
Belgium: N Clumeck, R Colebunders, M Moutschen;
Canada: J Gill, K Gough, P Junod, D Kilby, J Montaner,
A Rachlis, CM Tsoukas; France: C Arvieux, L Cotte,
JF Delfraissy, PM Girard, B Marchou, JM Molina, D Vittecoq,
Y Yazdanpanah, P Yeni; Germany: K Arasteh, S Esser,
G Fätkenheuer, H Gellermann, K Göbels, FD Goebel,
H Jäger, A Moll, JK Rockstroh, D Schuster, S Staszewski,
A Stoehr; Italy: A Antinori, G Carosi, G Di Perri,R Esposito, A
Lazzarin, F Mazzotta, G Pagano, E Raise, S Rusconi,
L Sighinolfi, F Suter; The Netherlands: PHJ Frissen,
JM Prins, BJA Rijnders; Poland: A Horban; Portugal:
F Antunes, M Miranda, J Vera; Spain: P Domingo, B Clotet,
G Garcia, JM Gatell, J González-Lahoz, J López-Aldeguer,
D Podzamczer; UK: P Easterbrook, M Fisher, C Orkin,
E Wilkins; USA: B Barnett, J Baxter, G Beatty,
D Berger, C Borkert, T Campbell, C Cohen, M Conant,
J Ernst, C Farthing, T File, M Frank, JE Gallant,
AE Greenberg, C Hicks, DT Jayaweera, S Kerkar,
N Markowitz, C Martorell, C McDonald, D McMahon,
M Mogyoros, RA Myers Jr, G Richmond, K Sathasivam,
S Schneider, H Schrager, P Shalit, FP Siegal, L Sloan,
K Smith, S Smith, P Tebas, LS Tkatch, W Towner