duet-1 and duet-2: tmc125 versus placebo in treatment-experienced hiv-1-infected patients duet-1:...

DUET-1 and DUET-2: TMC125 versus placebo in treatment-experienced

HIV-1-infected patients

DUET-1: Anthony Mills, Pedro Cahn, Beatriz Grinsztejn, Richard Haubrich, Jacob Lalezari, José Valdez Madruga, Gilles Pialoux, Timothy Wilkin,

Monika Peeters, Johan Vingerhoets, Goedele De Smedt, Lorant Leopold, Roberta Trefiglio and Brian Woodfall

DUET-2: Christine Katlama, Thomas Campbell, Bonaventura Clotet, Margaret Johnson, Adriano Lazzarin, Keikawus Arastéh, William Towner, Benoit Trottier, Monika Peeters, Johan Vingerhoets, Goedele De Smedt,

Benny Baeten, Greet Beets, Rekha Sinha and Brian Woodfall

DUET-1: Thailand, France, North and South America. Madruga JV, et al. Lancet 2007:370;29–38DUET-2: Australia, Europe, North America. Lazzarin A, et al. Lancet 2007:370;39–48

DUET-11 and DUET-22 trials:design and inclusion criteria

1. Madruga, et al. Lancet 2007;370:29–382. Lazzarin, et al. Lancet 2007;370:39–48

24-week primary analysis

Viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks ≥1 NNRTI RAM, at screening or in documented historical genotype ≥3 primary PI mutations at screening Primary endpoint was the proportion of patients achieving viral load

<50 HIV-1 RNA copies/mL when all patients had reached Week 24 or discontinued

Screening6 weeks

600 patients target per trial

48-week treatment period with optional 48-week extension

*BR = DRV/r with optimised NRTIs and optional enfuvirtide

TMC125 + BR* (including DRV/r)

Placebo + BR* (including DRV/r)

Follow up4 weeks

c/mL = HIV-1 RNA copies/mL; PSS = phenotypic sensitivity score

Parameter

DUET-1 DUET-2

TMC125 + BR(n=304)

Placebo + BR(n=308)

TMC125 + BR(n=295)

Placebo + BR(n=296)

Patient demographics

Male 87 86 94 92

Caucasian 65 65 77 76

Disease characteristics

Viral load (log10 c/mL)* 4.8 (2.7–6.2) 4.9 (2.4–6.5) 4.8 (3.0–6.8) 4.8 (2.2–6.3)

CD4 cells (cells/µL)* 99 (1–789) 109 (1–694) 100 (1–708) 108 (0–912)

CDC category C 61 63 55 55

Prior ARV use 10–15 ARVs (%) 67 65 62 67

Darunavir/r (%) 5 5 3 5

Detectable mutations

≥2 NNRTI RAMs (%) 66 67 65 65

≥4 primary PI RAMs (%) 60 59 65 66

Background regimen

Used ENF (total) (%) 40 41 52 53

Used ENF de novo (%) 24 26 27 27

PSS = 0 (%) 15 15 16 16

PSS = 1 (%) 35 31 35 42

DUET-1 and DUET 2:baseline characteristics and background ARVs

DUET-1 and DUET-2 primary endpoint: patients with viral load <50 copies/mL at Week 24 TLOVR

CI = confidence interval; intent-to-treat (ITT) population;TLOVR = time to loss of virological response imputation algorithm

DUET-1

20

100

80

60

40

0 0 4 8 12 16 20 24

p=0.0050 56%

39%

Res

po

nd

ers

(%)

+ 9

5% C

I

Time (weeks)

TMC125 + BR (n=304)Placebo + BR (n=308)

62%

20

100

80

60

40

0

Time (weeks) 0 4 8 12 16 20 24

DUET-2

p=0.0003

Res

po

nd

ers

(%)

+ 9

5% C

I


44%

DUET-1 and -2: patients with HIV-RNA <400 copies/mL to week 24

20

100

80

60

40

0

Time (weeks)

74%

51%p=0.0001

0 4 8 12 16 20 24

Res

po

nd

ers

(%)

+ 9

5% C

I

CI = confidence interval; intent-to-treat (ITT) population; time to loss of virological response (TLOVR) imputation algorithm


DUET-1

54%p=0.0001

75%

20

100

80

60

40

0

Time (weeks) 0 4 8 12 16 20 24

Res

po

nd

ers

(%)

+ 9

5% C

I


DUET-2

DUET-1 and DUET-2: viral load reduction from baseline to week 24

Mea

n c

han

ge

in v

iral

load

fro

m

bas

elin

e (l

og

10 c

op

ies/

mL

) +

SE

16 20 24

0.0

–1.0

–2.0

–3.00 4 8 12

–1.7

–2.4

p<0.0001

Time (weeks)

CI = confidence interval; intent-to-treat (ITT) population; time to loss of virological response (TLOVR) imputation algorithm


DUET-1

0.0

–1.0

–2.0

–3.00 4 8 12 16 20 24

–1.7

–2.3

p<0.0001

Time (weeks)

Mea

n c

han

ge

in v

iral

load

fro

m

bas

elin

e (l

og

10 c

op

ies/

mL

) +

SE


DUET-2

DUET-1 and DUET-2: change in CD4 cell count from baseline

20

100

80

60

40

0

Mea

n c

han

ge

in C

D4

cell

cou

nt

fro

m b

asel

ine

(cel

ls/μ

L)

+ S

E

Time (weeks)

+89

+64

p=0.0002

SE = standard error; intent-to-treat (ITT) population; non-completer = failure (NC=F) imputation

0 4 8 12 16 20 24


DUET-1

+66

+78p=0.3692

20

100

80

60

40

0

Time (weeks) 0 4 8 12 16 20 24


DUET-2

Mea

n c

han

ge

in C

D4

cell

cou

nt

fro

m b

asel

ine

(cel

ls/μ

L)

+ S

E

DUET-1 and DUET-2: response (VL <50 copies/mL) according to number of active background ARVs

Darunavir and enfuvirtide are counted as active if FC<10 or used de novo, respectively; PSS = phenotypic sensitivity score

Nu

mb

er o

f ac

tive

b

ackg

rou

nd

AR

Vs

(PS

S)

Patients with viral load <50 copies/mL at Week 24 (%)

65%

61%

9%

24%

66%

68%

59%

47%

0 20 40 60 80 100

0

1

2

3


DUET-1

0

0 20 40 60 80 100

7%

35%

70%

73%

44%

82%

62%

80%

1

2

3

Patients with viral load <50 copies/mL at Week 24 (%)

Nu

mb

er o

f ac

tive

b

ackg

rou

nd

AR

Vs

(PS

S)


DUET-2

0

20

40

60

80

DUET-1 and DUET-2: response according to enfuvirtide use (primary analysis)

55%

Pat

ien

ts w

ith

vir

al lo

ad

<50

co

pie

s/m

L a

t W

eek

24 (

%)

Using enfuvirtide

de novo

Re-using or not using

enfuvirtide

56%60%

33%

p=0.7935p<0.0001

DUET-1


0

20

40

60

80

Using enfuvirtide

de novo

Re-using or not using

enfuvirtide

68%73%

34%

58%

p<0.0001 p=0.3838

DUET-2


Pat

ien

ts w

ith

vir

al lo

ad

<50

co

pie

s/m

L a

t W

eek

24 (

%)

DUET-1 and DUET-2: virological response (<50 copies/mL) according to baseline mutations

13 baseline Resistance-Associated Mutations were associated with a decreased response to TMC125 (TMC125 RAMs):

V90I A98GL100I K101E/P V106I V179D/FY181C/I/V G190A/S

†analysis performed in n=406 (100%); *overall placebo response = 36%

940 30 16 8 5Pts† (%) =

% p

atie

nts

with

con

firm

ed

<50

HIV

-1 R

NA

cop

ies/

mL

Number of TMC125 RAMs

0 1 2 3 4 50

20

40

60

80

When 3 of these TMC125 RAMs were present the response rate was comparable to the overall placebo response*

Only 14% of patients had 3 or more TMC125 RAMs

What is the effect of Y181C on TMC125 response rates?

What is the effect of Y181C on TMC125 response rates?

Y181C is a common mutation conferring resistance to currently available NNRTIs

The TMC125 response rate is not compromised when Y181C is present, with either 0 or 1 other TMC125 RAM

When Y181C is present with two or more TMC125 RAMs (13% of all patients), response rates were substantially reduced

N =

% p

atie

nts

with

con

firm

ed

<50

HIV

-1 R

NA

cop

ies/

mL

0

20

40

60

80

406 23 36 26 17 8

Overall

TMC125

TMC125 RAMs

Y181C+ 0

Y181C+ 2

Y181C+ 3

Y181C+ 1

Y181C+ 4

DUET-1 and DUET-2: overview of adverse events (AEs)

No deaths in the TMC125 group were considered at least possibly related to trial medication;*In >10% patients in TMC125 group in either trial

DUET-1 DUET-2

Parameter, %TMC125 + BR

(n=304)Placebo + BR

(n=308)TMC125 + BR

(n=295)Placebo + BR

(n=296)

Any AE (any cause) 93 93 92 92

Grade 3/4 AE 21 28 28 27

Discontinuation due to AE 5 5 6 4

Serious AE 12 20 15 17

Death (any cause), n (%) 4 (1.3%) 7 (2.3%) 4 (1.4%) 7 (2.4%)

DUET-1 DUET-2

Parameter, %TMC125 + BR

(n=304)Placebo + BR

(n=308)TMC125 + BR

(n=295)Placebo + BR

(n=296)

Any AE (any cause) 93 93 92 92

Grade 3/4 AE 21 28 28 27

Discontinuation due to AE 5 5 6 4

Serious AE 12 20 15 17

Death (any cause), n (%) 4 (1.3%) 7 (2.3%) 4 (1.4%) 7 (2.4%)

Most common AEs*

Rash (any type) 20 10

Nausea 14 12

Diarrhoea 12 20

Headache 10 13

Injection site reaction 7 7

AEs of interest

Nervous system disorders 15 20

Psychiatric disorders 10 14

Hepatic AEs 5 7

DUET-1 DUET-2

Parameter

TMC125 + BR

(n=304)

Placebo + BR

(n=308)

TMC125 + BR

(n=295)

Placebo + BR

(n=296)

Any AE (any cause) 93 93 92 92Grade 3/4 AE 21 28 28 27Discontinuation due to AE, % 5 5 6 4Serious AE, % 12 20 15 17Death (any cause), n (%) 4 (1.3%) 8 (2.6%) 4 (1.4%) 7 (2.4%)

Most common AEs*

Rash (any type), % 20 10 14 9Nausea, % 14 12 14 10Diarrhoea, % 12 20 18 20Headache 10 13 9 11Injection site reaction 7 7 13 15

AEs of interest

Nervous system disorders 15 20 15 17Psychiatric disorders 10 14 16 17Hepatic AEs 5 7 5 4

DUET-1 and DUET-2: summary of rash

Overall incidence– 17% in TMC125 group vs 9% in placebo group

Onset: most frequent in 2nd week of therapy Severity

– usually mild to moderate; 1% grade 3 and 0% grade 4– no rashes with mucosal involvement

Infrequently lead to discontinuation (2%)– most self-limiting with continued treatment

Higher incidence in women, but no gender difference in severity or treatment discontinuations

No association between rash and baseline CD4 cell count In patients with a history of NNRTI-related rash, there was no

apparent increased risk

DUET-1 and DUET-2: incidence of treatment-emergent lipid and liver abnormalities

DUET-1 DUET-2

Grade 3/4abnormalities

TMC125 + BR

(n=304)

Placebo+ BR

(n=308)

TMC125 + BR

(n=295)

Placebo + BR

(n=296)

Triglycerides increased, % 7 5 7 4

Total cholesterol increased, % 6 5 5 4

LDL increased, % 3 4 7 7

ALT, % 3 2 2 1

AST, % 2 2 3 1

The profile of abnormalities was generally similar between the TMC125 and placebo groups with no consistent or clinically-relevant trends in laboratory, vital signs or ECG data

Conclusions In treatment-experienced patients, including those with NNRTI resistant virus,

TMC125 consistently demonstrated superiority over placebo– 56% (DUET-1) and 62% (DUET-2) of patients achieved confirmed

undetectable VL (<50 copies/mL) with TMC125 plus BR at Week 24 Even in the absence of any other fully active background agents, with

TMC125, over 40% of patients achieved undetectable (<50 copies/mL)viral load

– response rates increased as more active agents were used in the background regimen

Thirteen TMC125 resistance-associated mutations (TMC125 RAMs) were identified– in the presence of 0, 1 and 2 TMC125 RAMs, virological responses were

greater than the overall placebo response– only 14% of all patients had ≥3 TMC125 RAMs

Except for rash, incidence and severity of AEs with TMC125 were similar to placebo

TMC125 has the ability to extend and enhance the NNRTI class and provide a new treatment option for patients with resistance to and/or unable to tolerate other NNRTI’s

DUET-1 and DUET-2: acknowledgements

Argentina: H Ariza, J Benetucci, L Calanni, L Cassetti, J Corral, D David, A Krolewiecki, M Losso, P Patterson, R Teijeiro; Brazil: C A da Cunha, E Kallas, E Netto, J H Pilotto, M Schechter, J Suleiman, A Timerman; Chile: J Ballesteros, R Northland; Costa Rica: A Alvilés Montoya, G Herrera Martinez, A Solano Chinchilla; France: M Dupon, C Katlama, J M Livrozet, P Morlat, C Piketty, I Poizot-Martin; Mexico: J Andrade-Villanueva, G Reyes-Terán, J Sierra-Madero; Panama: A Canton, A Rodriguez, N Sosa; Puerto Rico: J O Morales Ramirez, J L 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, W J Fessel, T Hawkins, S Hodder, T Jefferson, H Katner, C Kinder, M Kozal, J Leider, D McDonough, K Mounzer, 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.

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, C M Tsoukas, S L Walmsley; France: C Arvieux, L Cotte, J F Delfraissy, P M Girard, B Marchou, J M Molina, D Vittecoq, Y Yazdanpanah, P Yeni; Germany: S Esser, G Fätkenheuer, H Gellermann, K Göbels, F D Goebel, H Jäger, A Moll, J K Rockstroh, D Schuster, S Staszewski, A Stoehr; Italy: A Antinori, G Carosi, G Di Perri, R Esposito, F Mazzotta, G Pagano, E Raise, S Rusconi, L Sighinolfi, F Suter; Netherlands: P H J Frissen, J M Prins, B J A Rijnders; Poland: A Horban; Portugal: F Antunes, M Miranda, J Vera; Spain: P Domingo, G Garcia, J M 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, C Cohen, M Conant, J Ernst, C Farthing, T File, M Frank, J E Gallant, A E Greenberg, C Hicks, D T Jayaweera, S Kerkar, N Markowitz, C Martorell, C McDonald, D McMahon, M Mogyoros, R A Myers Jr, G Richmond, K Sathasivam, S Schneider, H Schrager, P Shalit, F P Siegal, L Sloan, K Smith, S Smith, P Tebas, L S Tkatch.

We express our gratitude to the patients that participated in the study, as well as the study centre staff, DSMB, Tibotec personnel and following principal investigators:

DUET-1 DUET-2

duet-1 and duet-2: tmc125 versus placebo in treatment-experienced hiv-1-infected patients duet-1:...

Documents