Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

1. TTCA0064-07282-1 Pooled 24-week Results of DUET-1 and -2: Efficacy of TMC125 in Treatment-experienced HIV-1-infected Patients 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 Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

2. TTCA0064-07282-2 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 • 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 48-week treatment period with optional 48-week extension 24-week primary analysis TMC125 + BR* Placebo + BR* *BR = darunavir/ritonavir with optimized NRTIs and optional enfuvirtide *From extended list of NNRTI mutations (Tambuyzer et al. Abstract 67 EHDRW 2007); BR = background regimen Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

3. TTCA0064-07282-3 Baseline Characteristics and Background ARVs *From extended list of NNRTI mutations used in inclusion criteria; §assessed by phenotypic sensitivity score (PSS); BR = background regimen; Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

4. TTCA0064-07282-4 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 TMC125 + BR (n=599) Placebo + BR (n=604) p<0.0001 59% Responders (%) ± 95% CIs 41% 0 4 8 12 16 20 24 Time (weeks) TMC125 + BR: 558 553 545 541 Patients remaining on study (n) for: 577 568 559 Placebo + BR: 562 BR = background regimen; CI = confidence interval; ITT = intent-to-treat population; TLOVR = time to loss of virologic response analysis Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

5. TTCA0064-07282-5 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 TMC125 + BR (n=599) Placebo + BR (n=604) 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 failure analysis; changes below detection limit (<50 copies/mL) were imputed as 49 copies/mL Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

6. TTCA0064-07282-6 Mean 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 TMC125 + BR (n=599) Placebo + BR (n=604) 0 4 8 12 16 20 24 Time (weeks) BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failureanalysis Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

7. TTCA0064-07282-7 Placebo + BR (n=209) CD4 Cell Count Increase to 50 Cells/mm3 or Above TMC125 + BR (n=213) • At baseline, 36% and 35% of patients in the TMC125 and placebo groups respectively had a CD4 cell count below 50 cells/mm3 (n=422 in total) • At Week 24 in the TMC125 group 74% of these patients had moved above the 50 cells/mm3 threshold (n=157), compared with 55% in the placebo group (n=115) 74% 55% Patients with CD4 cell count increased to above 50 cells/mm3 at Week 24 Baseline CD4 cell count <50 cells/mm3 BR = background regimen Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

8. TTCA0064-07282-8 Placebo + BR Response (<50 copies/mL) According to Enfuvirtide Use TMC125 + BR 67% 62% 56% Patients with viral load <50 copies/mL at Week 24 (%) 34% 102/153 251/446 99/160 149/444 Re-using or not using enfuvirtide Using de-novo enfuvirtide p<0.0001 p=0.427 The primary analysis divided patients according to ENF use Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

9. TTCA0064-07282-9 Placebo + BR Response (<50 copies/mL) According to Baseline Darunavir Fold Change TMC125 + BR 100 75 50 25 0 71% 57% 56% Patients with viral load <50 copies/mL at Week 24 (%) 44% 30% 2% 39/132 200/358 73/129 1/67 246/345 31/71 DRV FC>40 DRV FC<10 DRV FC 10–40 Analysis excludes patients who discontinued except for virologic failure; BR = background regimen; DRV = darunavir; FC = baseline fold change Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

10. TTCA0064-07282-10 Placebo + BR Response (<50 copies/mL) According to Number of Active Background ARVs TMC125 + BR 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 virologic failure; PSS = phenotypic sensitivity score; darunavir and enfuvirtide are counted as fully active if FC<10 or used de novo, respectively Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

11. TTCA0064-07282-11 Placebo + BR Response (<50 copies/mL) according to baseline viral load and CD4 cell count TMC125 + BR 76% 73% 67% 62% 61% 55% 47% 44% 39% 39% Patients with viral load <50 copies/mL at Week 24 (%) 26% 23% 126/ 165 56/ 217 130/ 177 102/ 186 108/ 174 84/ 213 83/ 213 49/ 209 139/ 208 97/ 208 126/ 206 101/ 228 <50 50–199 <30,000 ≥100,000 ≥200 30,000–99,999 Baseline CD4 cell count Baseline viral load BR = background regimen; ITT = intent-to-treat population; TLOVR = time to loss of virologic response analysis Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

12. TTCA0064-07282-12 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 A98G L100I K101E/P V106I V179D/F Y181C/I/V 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 Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

13. TTCA0064-07282-13 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 TMC125 + BR (n=406) Placebo + BR (n=414) 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 virologic failure BR = background regimen; RAM = resistance-associated mutation; Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207

14. TTCA0064-07282-14 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 Hicks C, et al. Oral presentation presented at IDSA 2007. Abst 1207