Financial disclosures for Dr Hicks

 Grant support, honoraria and/or advisory board from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Glaxo SmithKline, Merck, Pfizer, Tibotec, Monogram Biosciences, Gilead, Koronis

Pooled 24-week results of DUET-1 and -2: efficacy of TMC125 in treatment-experienced HIV-1-infected patients

(Abstract 1316) C Hicks,

P Cahn, J Leider, G Pialoux, M Peeters, J Vingerhoets and B Woodfall on behalf of the DUET-1 and DUET-2 study groups

Abstract 1316

DUET study design and major inclusion criteria

Screening 6 weeks 48-week treatment period with optional 48-week extension

24-week primary analysis

TMC125 + BR* Follow up 4 weeks 600 patients target per trial Placebo + BR*

*BR = darunavir/ritonavir with optimized NRTIs and optional enfuvirtide    DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified Major inclusion criteria: – Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks – – ≥1 NNRTI mutation,* at screening or in documented historical genotype ≥3 primary PI mutations at screening Patients recruited from Thailand, Australia, Europe and the Americas

*From extended list of NNRTI mutations (Tambuyzer et al. Abstract 67 EHDRW 2007); BR = background regimen

Abstract 1316

Baseline characteristics and background ARVs

Parameter, % or median (range)

Patient demographics Male, % Caucasian, % Disease characteristics Prior ARV use Detectable mutations Viral load (log 10 copies/mL), median (range) CD4 cells (cells/mL), median (range) CDC category C, %  10 ARVs, % Darunavir/r, %  2 NNRTI mutations,* %  2 IAS USA NNRTI mutations, %  4 primary PI mutations, % Background regimen Used enfuvirtide (total), % Used enfuvirtide

de novo,

% Active background agents § = 0, % Active background agents § = 1, %

TMC125 + BR (n=599)

90 70 4.8 (2.7

–6.8) 99 (1.0

–789) 58 80 4 66 43 62 46 26 17 36

Placebo + BR (n=604)

89 70 4.8 (2.2

–6.5) 109 (0.0

–912) 59 83 5 66 42 63 47 27 16 39

*From extended list of NNRTI mutations used in inclusion criteria;

§

assessed by phenotypic sensitivity score (PSS); BR = background regimen;

Abstract 1316

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 0 TMC125 + BR (n=599) Placebo + BR (n=604) p<0.0001

59% 41% Patients remaining on study (n) for: 4 TMC125 + BR: Placebo + BR: 8 12 Time (weeks) 558 577 16 553 568 20 541 562 24 545 559 BR = background regimen; CI = confidence interval; ITT = intent-to-treat population; TLOVR = time to loss of virologic response analysis

Abstract 1316

Mean viral load reduction from baseline (ITT NC=F)

0.0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

0 4 TMC125 + BR (n=599) Placebo + BR (n=604) 8 12 Time (weeks) 16 20 p<0.0001

–1.7

24 –2.4

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

Abstract 1316

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

100 75 50 25 0 0 +86 +67 p<0.0001

4 8 12 Time (weeks) TMC125 + BR (n=599) Placebo + BR (n=604) 16 20 24 BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failure analysis

Abstract 1316

CD4 cell count increase to 50 cells/mm

3

or above

TMC125 + BR (n=213) Placebo + BR (n=209) 100 80 60 74% 55% 40 20 0 Baseline CD4 cell count <50 cells/mm 3

  At baseline, 36% and 35% of patients in the TMC125 and placebo groups respectively had a CD4 cell count below 50 cells/mm 3 (n=422 in total) At Week 24 in the TMC125 group 74% of these patients had moved above the 50 cells/mm 3 threshold (n=157), compared with 55% in the placebo group (n=115)

BR = background regimen

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

TMC125 + BR Placebo + BR 80 67% 62% 60 56% 40 34% 20 0 251/446 149/444 Re-using or not using enfuvirtide p<0.0001

102/153 99/160 Using de-novo enfuvirtide p=0.427

The primary analysis divided patients according to ENF use

Abstract 1316

Response (<50 copies/mL) according to baseline darunavir fold change

TMC125 + BR Placebo + BR 100 75 71% 56% 57% 50 44% 30% 25 0 246/345 200/358 DRV FC<10 73/129 39/132 DRV FC 10 –40 31/71 DRV FC>40 2% 1/67 Analysis excludes patients who discontinued except for virologic failure; BR = background regimen; DRV = darunavir; FC = baseline fold change

Abstract 1316

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

TMC125 + BR Placebo + BR 0 40/88 7/91 8% a 45% 1 120/199 63/211 30% 60% ≥ 2 191/258 171/257 67% 74% 0 20 40 60 80 Patients with viral load <50 copies/mL at Week 24 (%) 100 Analysis excludes patients who discontinued except for virologic failure; PSS = phenotypic sensitivity score; darunavir and enfuvirtide are counted as fully active if FC<10 or used de novo, respectively

Abstract 1316

Response (<50 copies/mL) according to baseline viral load and CD4 cell count

80 76% TMC125 + BR 80 Placebo + BR 67% 73% 62% 61% 60 60 55% 39% 44% 39% 47% 40 40 26% 23% 20 20 0 126/ 165 108/ 174 126/ 206 84/ 213 101/ 228 56/ 217 83/ 213 49/ 209 139/ 208 97/ 208 130/ 177 102/ 186 <30,000 30,000 – 99,999 Baseline viral load ≥100,000 0 <50 50 –199 ≥200 Baseline CD4 cell count BR = background regimen; ITT = intent-to-treat population; TLOVR = time to loss of virologic response analysis

Mutations associated with a decreased response to TMC125

 Using the data from these trials, 13 baseline mutations were found to be associated with a decreased response to TMC125 (TMC125 RAMs) * : V90I L100I V106I Y181C/I/V A98G K101E/P V179D/F G190A/S  These TMC125 RAMs occurred mainly in the presence of other NNRTI mutations  K103N is not associated with resistance to TMC125

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

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

TMC125 + BR (n=406) Placebo + BR (n=414)

0 1 2

121/161 64/147 73/121 59/157 37/64 17/68

3

13/32 6/24

≥ 4

0 7/28 3/18 44% 60% 38% 58% 25% 41% 25% 25% 17% 20 40 60 Patients with viral load <50 copies/mL at Week 24 (%) 75% 80

  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

Analysis excludes patients who used de-novo enfuvirtide or discontinued except for virologic failure BR = background regimen; RAM = resistance-associated mutation;

Abstract 1316

Conclusions



In treatment-experienced patients, including those with NNRTI resistant virus, TMC125 was superior to placebo

–

59% of patients achieved confirmed undetectable viral load (<50 copies/mL) with TMC125 + BR at Week 24



Even in the absence of any other fully active background agents (PSS = 0), with TMC125, 45% of patients achieved undetectable (<50 copies/mL) viral load

–

response rates increased as more active agents were used in the BR



Better responses were achieved in patients with higher CD4 cell counts and lower viral loads for both treatment arms

–

higher responses were apparent with TMC125 compared with placebo, for all categories of baseline viral load or CD4 cell count



13 TMC125 RAMs were identified

–

an increasing number of TMC125 RAMs was associated a decreasing response in both treatment arms

– –

in the TMC125 group, the greatest added benefit was seen with <3 TMC125 RAMs 86% of patients had <3 TMC125 RAMs



TMC125 demonstrated significant activity and provides a new treatment option for patients with resistance to other NNRTIs BR = background regimen; RAM = resistance-associated mutation;

Abstract 1316

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, Tibotec personnel and following principal investigators:

DUET-1 Argentina:

H Ariza, J Benetucci, L Calanni, L Cassetti, J Corral, D David, A Krolewiecki, M Losso, P Patterson, R Teijeiro;

Brazil:

E Kallas, E Netto, J H Pilotto, M Schechter, J Suleiman, A Timerman;

Chile:

C A da Cunha, J Ballesteros, R Northland;

Costa Rica:

A Alvilés Montoya, G Herrera Martinez, A Solano Chinchilla;

France:

Dupon, C Katlama, J M Livrozet, P Morlat, C Piketty, I Poizot-Martin;

Mexico:

J Andrade Villanueva, G Reyes Terán, J Sierra-Madero; M

Panama: Rico:

A Canton, A Rodriguez, N Sosa;

Puerto

J O Morales Ramirez, J L Santana Bagur, R Soto-Malave;

Thailand:

P Mootsikapun, K Ruxrungtham; 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, 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.

T Anekthananon,

USA:

M Albrecht,

DUET-2 Australia: Belgium:

J Chuah, D Cooper, B Eu, J Hoy, C Workman; N Clumeck, R Colebunders, M Moutschen;

Canada

P Yeni; : J Gill, K Gough, P Junod, D Kilby, J Montaner, A Rachlis, C M Tsoukas, S L Walmsley;

Germany: Netherlands: France:

C Arvieux, L Cotte, J F Delfraissy, P M Girard, B Marchou, J M Molina, D Vittecoq, Y Yazdanpanah, 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; P H J Frissen, J M Prins, B J A Rijnders;

Poland:

A Horban;

Portugal:

F Antunes, M Miranda, J Vera;

UK: Spain:

P Domingo, G Garcia, J M Gatell, J González-Lahoz, J López-Aldeguer, D Podzamczer; P Easterbrook, M Fisher, C Orkin, E Wilkins; S Kerkar, N Markowitz, C Martorell, C McDonald, K Sathasivam, S Schneider, H Schrager, P Shalit, F P Siegal, L Sloan, K Smith, S Smith, P Tebas, L S Tkatch.

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, D McMahon, M Mogyoros, R A Myers Jr, G Richmond,