Pooled 24-week results of DUET-1 and DUET-2:
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Pooled 24-week results of DUET-1 and DUET-2: TMC125 (etravirine; ETR) versus placebo in treatment-experienced HIV-1-infected patients.

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Duet study design and major inclusion criteria
Pooled 24-week results of DUET-1 and DUET-2: TMC125 (etravirine; ETR) versus placebo in treatment-experienced HIV-1-infected patients

P Cahn, R Haubrich, J Leider, G Pialoux, M Schechter, S Walmsley, J Vingerhoets, M Peeters, G De Smedt, MP de Béthune and B Woodfallon behalf of the DUET-1 and DUET-2 study groups


Duet study design and major inclusion criteria

Screening

6 weeks

Follow up

4 weeks

600 patients target per trial

DUET study design and major inclusion criteria

  • DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified

  • Plasma 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

  • Patients recruited from Thailand, Australia, Europe and the Americas

48-week treatment period with optional 48-week extension

24-week primary analysis

TMC125 + BR*

Placebo + BR*

*BR = darunavir/ritonavir with optimised NRTIs and optional enfuvirtide

BR = background regimen; RAM = resistance-associated mutation


Baseline characteristics and background arvs
Baseline characteristics and background ARVs

*from extended NNRTI RAM list (Tambuyzer et al. Abstract 67 EHDRW 2007); §assessed by phenotypic sensitivity score (PSS); BR = background regimen; RAM = resistance-associated mutation


Patients with viral load 50 copies ml at week 24 primary endpoint itt tlovr

TMC125 + BR (n=599)

Placebo + BR (n=604)

Patients with viral load <50 copies/mL at Week 24 (primary endpoint; ITT TLOVR)

100

90

80

70

60

50

40

30

20

10

0

p<0.0001

59%

Responders (%) ± 95% CI

41%

0 4 8 12 16 20 24

Time (weeks)

BR = background regimen; CI = confidence interval; ITT = intent-to-treat population; TLOVR = time to loss of virologic response imputation algorithm


Viral load reduction from baseline itt nc f

TMC125 + BR (n=599)

Placebo + BR (n=604)

Viral load reduction from baseline (ITT NC=F)

0.0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

p<0.0001

Mean change in viral load from baseline (log10 copies/mL) ± SE

–1.7

–2.4

0 4 8 12 16 20 24

Time (weeks)

BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failureimputation algorithm; changes below the detection limit (<50 copies/mL) were imputed as 49 copies/mL


Change in cd4 cell count from baseline itt nc f

TMC125 + BR (n=599)

Placebo + BR (n=604)

Change in CD4 cell count from baseline (ITT NC=F)

100

75

50

25

0

+86

+67

p<0.0001

Mean change in CD4 cell count from baseline (cells/mm3) ± SE

0 4 8 12 16 20 24

Time (weeks)

BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failureimputation algorithm


Response 50 copies ml according to enfuvirtide use primary analysis

TMC125 + BR (n=599)

Placebo + BR (n=604)

p=0.427

p<0.05

80

73%

62%

60

56%

34%

40

Adjusted for differences in baseline DRV FC between groups

20

Unadjusted

response rates

0

Using de novo ENF

DRV = darunavir FC = baseline fold change

Response (<50 copies/mL) according to enfuvirtide use (primary analysis)

p<0.0001

67%

62%

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

Re-using or not using ENF

Using de novo ENF


Response 50 copies ml according to number of active background arvs

TMC125 + BR (n=545)

Placebo + BR (n=559)

Response (<50 copies/mL) according to number of active background ARVs

45%

40/88

8%a

7/91

60%

120/199

Number of fully active background ARVs (PSS)

30%

63/211

74%

191/258

67%

171/257

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

Analysis excludes patients who discontinued except for virological failure; PSS = phenotypic sensitivity score; darunavir and enfuvirtide are counted as fully active if FC<10 or used de novo, respectively


Mutations associated with a decreased response to tmc125
Mutations associated with a decreased response to TMC125

  • 13 baseline NNRTI RAMs were associated with a decreased response to TMC125 (TMC125 RAMs):

    V90I A98G

    L100I K101E/P

    V106I V179D/F

    Y181C/I/V G190A/S

  • These RAMs seldom occurred in the absence of other NNRTI RAMs

  • K103N is not associated with resistance to TMC125

A decreased response was defined as ≤75% of the response for patients with zero NNRTI RAMs at baseline from the extended NNRTI RAM list; RAM = resistance-associated mutation


Response 50 copies ml according to number of tmc125 rams

TMC125 + BR (n=406)

Placebo + BR (n=414)

Response (<50 copies/mL) according to number of TMC125 RAMS

  • The greatest added benefit in the TMC125 versus placebo group was seen in patients with <3 TMC125 RAMs

  • 86% of patients had <3 TMC125 RAMs

75%

121/161

64/147

44%

60%

73/121

38%

59/157

Number of TMC125 RAMs present at baseline

58%

37/64

25%

17/68

41%

13/32

25%

6/24

25%

7/28

3/18

17%

0 20 40 60 80

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

Analysis excludes patients who used de-novo enfuvirtide or discontinued except for virological failure

BR = background regimen; RAM = resistance-associated mutation;


Proportion of patients with any new aids defining illness or death

Placebo + BR (n=604)

Proportion of patients with any new AIDS-defining illness or death

TMC125 + BR (n=599)

10

8

6.8%

Patients with any new AIDS-defining illness or death (%)

6

3.7%

4

2

22/599

41/604

0

Overall population

p=0.4419

BR = background regimen


Proportion of patients with any new aids defining illness or death1

Placebo + BR (n=604)

10

8

6

4

2

0

Proportion of patients with any new AIDS-defining illness or death

TMC125 + BR (n=599)

8.3%

6.8%

Patients with any new AIDS-defining illness or death (%)

3.7%

3.8%

22/599

41/604

17/446

37/444

Overall population

Re-using or not using ENF

p=0.4419

p=0.0051

ENF = enfuvirtide; BR = background regimen


Overview of adverse events aes regardless of causality
Overview of adverse events (AEs; regardless of causality)

  • There were no consistent or clinically relevant trends in laboratory, vital signs or ECG data

  • The profile of laboratory abnormalities, including hepatic and lipid parameters, was generally similar between the TMC125 and placebo groups

*no deaths in the TMC125 group were considered at least possibly related to trial medication; ‡ in >10% patients in either group, excluding injection site reactions; §p=0.0001 vs placebo


Summary of rash in the tmc125 group
Summary of rash in the TMC125 group

  • Overall incidence: 17% in TMC125 group versus 9% in placebo group (p=0.0001)

  • Early onset: most frequent in 2nd week of therapy; median onset Day 12

  • Short duration: median duration 11 days

  • Usually mild to moderate severity: 1.3% grade 3 and no grade 4 events

    • no rashes with mucosal involvement

  • Infrequently lead to discontinuation

    • 2.2% of patients permanently discontinued

    • most self-limiting with continued treatment

  • Higher incidence in women, but no clear difference in severity or treatment discontinuations according to gender

  • No association with baseline CD4 cell count

  • No increased risk in patients with a history of NNRTI-related rash


Conclusions
Conclusions

  • In treatment-experienced patients, including those with NNRTI resistant virus, TMC125 consistently demonstrated superiority over placebo

    • 59% 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, 45% of patients achieved undetectable (<50 copies/mL)viral load

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

  • 13 TMC125 resistance-associated mutations (TMC125 RAMs) were identified

    • the greatest added benefit in the TMC125 versus placebo group was seen in patients with <3 TMC125 RAMs

    • 86% 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 other NNRTIs


Acknowledgements
Acknowledgements

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

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, B Grinsztejn, E Kallas, JV Madruga, E Netto, J H Pilotto, 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 Lalezari, D McDonough, A Mills, 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 Wilkin, T Wills, M Wohlfeiler, K Workowski.

DUET-2

DUET-1

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, B Trottier, C M Tsoukas; France: C Arvieux, L Cotte, J F Delfraissy, P M Girard, C Katlama, B Marchou, J M Molina, D Vittecoq, Y Yazdanpanah, P Yeni; Germany: K Arasteh,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, A Lazzarin, 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: B Clotet,P Domingo, G Garcia, J M Gatell, J González-Lahoz, J López-Aldeguer, D Podzamczer; UK: P Easterbrook, M Fisher, M Johnson, 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, 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, W Towner.