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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.

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DUET study design and major inclusion criteria

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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;

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

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