1. Agenda  Update on Darunavir: Perry Mohammed  Update on Etravirine: Rekha Sinha  Update on TMC278: Peter Williams  Update on TMC207: Karel De Beule  HCV pipeline: Daniel de Schryver  Questions and hopefully answers….

2. Darunavir  Once daily dosing  Monotherapy  Co-infection  Formulation changes

3. Once daily dosing  DRV/r currently licensed in treatment experienced patients –600mg/100mg po bid  Positive CHMP approval Q408  New indication: HIV naïve adult population –800mg/100mg po od  Paediatric indication: Q309 –75mg and 150mg tablets

4. Once daily: treatment experienced patients?

5. Tibotec. Data on file. Target concentration for HIV with FC ≤ 40* Target concentration for HIV with FC ≤ 10** Plasma concentration of darunavir/r (ng/mL) Time (hours) 0 2000 4000 6000 8000 024681012141618202224 Darunavir/r 800/100 mg q.d.: trough levels remain above target concentrations *resistant virus **wild-type virus

6. The ODIN study  Worldwide Pre-treated patients on stable HAART; VL > 1,000 copies/mL no DRV RAMs N = 612 DRV/r QD + OBR n = 306 DRV/r BID + OBR n = 306 Available from www.clinicaltrials.gov accessed November 2008www.clinicaltrials.gov Primary endpoint: –non inferiority DRV/r QD vs DRV/r BID –Results available: Q1 10 Treatment phase (48 weeks)

7. Monotherapy

8.  European study (13 countries, 250 patients)  First results expected Q309 Follow-up (4 weeks) Screening phase (4 weeks) Treatment phase (96 weeks) Pre-treated patients on stable HAART DRV/r 800/100 mg q.d. DRV/r 800/100 mg q.d. plus 2 NRTIs Follow-up Tibotec, data on file. MONET study

9. HBV/HCV co-infection

10.  35 (10)  17 (5)  31 (9)  10 (3)   29 (8)  12 (4)   2 (9)  13 (4)  Alanine aminotransferase (ALT)  Grade 2–4  Grade 3–4  Aspartate aminotransferase (AST)  Grade 2–4  Grade 3–4  LPV/r qd or bid  (N=346)  PREZISTA/r qd  (N=343)  Laboratory abnormalities, n (%) ARTEMIS: Liver-related laboratory abnormalities in treatment-naive patients De Jesus E, et al. Oral Presentation at 47th ICAAC 2007.

11. Co-infection and treatment-emergent liver- related AEs in treatment-naïve patients in ARTEMIS † Occurring with an incidence  1% in either treatment group, regardless of severity & causality; laboratory abnormalities reported as AEs are included in the overall incidence of liver-related AEs, but not shown in the table PREZISTA/rLPV/r Preferred term, n (%) † Co-infected (N=43) Non-co- infected (N=300) Co-infected (N=48) Non-co- infected (N=298) Any liver-related AE7 (16)9 (3)18 (38)13 (4) Ascites1 (2)000 Hepatitis01 (<1)1 (2)0 Hepatitis C003 (6)2 (<1) Ortiz R, et al. HEP DART 2007. Abstract 94 13% (n=91) of patients in ARTEMIS were co-infected with HBV and/or HCV at baseline*

12. New formulations

13.  For treatment-experienced patients: administer from 2 x 300mg DRV tablets bid to 1 x 600mg DRV tablet bid 1.100mg RTV capsule 2.300mg DRV tablet (on the market) 1.100 mg RTV capsule 2.600mg DRV tablet 100mg RTV 300mg DRV600mg DRV 100mg RTV DRV/r dosing regimen for treatment-experienced patients

14. 1. 100mg RTV capsule 2. 400mg DRV tablet DRV/r dosing regimen for treatment-naïve patients under development 100mg RTV 400mg DRV

15. QD PK Study Design 24-hour PK analysis of etravirine 24-hour PK analysis of darunavir, ritonavir Fasting lipid assessment  Phase IIa, open label, single arm study (23 subjects enrolled)  Key eligibility criteria –ARV-naïve adults with HIV-1 –No evidence of resistance to study drugs a –HBV/HCV co-infection not allowed a Based on screening or historical resistance assays; presence of <3 ETR resistance-associated mutations (list of 13 RAMs) defined susceptibility to ETR 14 days 14 days 42 weeks ETR 400mg qd + TDF/FTC 300/200mg qd + DRV/r 800/100mg qd Treatment A Treatment B Treatment C Optional Extension Phase DRV/r 800/100mg qd + TDF/FTC 300/200mg qd ETR 400mg qd + TDF/FTC 300/200mg qd DRV/r 800/100mg qd + TDF/FTC 300/200mg qd

16. Demographics and Baseline Characteristics a Predicted fold change in EC 50 according to VircoTYPE; fold change values were not available for ETR at time of screening b 1 patient had ETR fold change of 2.5  23 patients enrolled; 20 completed through Day 42 ParameterN=23 Demographics Age, mean (SD), y35.7 (13.6) Male, n (%)20 (87) Race/ethnicity, n (%) Black Caucasian Hispanic 9 (39) 5 (22) Disease characteristics Viral load, mean (SD), log 10 copies/mL4.2 (0.75) CD4 count, median (range), cells/mm 3 403 (144-895) ETR fold change a ≤1.6, n (%)22 (95.7) b DRV fold change a ≤10, n (%)23 (100)

17. Plasma Concentration-time Profile of ETR 400 mg qd Time (hours) 04812162024 Mean ±SD plasma ETR concentration (ng/mL) 0 200 400 600 800 1000 1200 Treatment A: ETR 400mg qd + TDF/FTC 300/200mg qd (n=21) Protein binding- adjusted EC 50 for WT virus (4 ng/mL) Treatment B: ETR 400mg qd + TDF/FTC 300/200mg qd + DRV/r 800/100mg qd (n=20)

18. Adverse Events Parameter, n (%)N=23 Serious adverse events0 Grade 3/4 clinical adverse events0 Adverse events leading to discontinuation0 Adverse events at least possibly related to study drug, ≥5% a Related to ETR: Nausea Headache Flatulence Rash 4 (17.4) 3 (13.0) 2 (8.7) Related to DRV Nausea Rash 3 (13.0) 2 (8.7) a Any grade; Individual adverse events could be assigned dual causality by investigator No Grade 3/4 AST, ALT or lipid elevations One Grade 3 neutropenia during Treatment A

19. Changes in Metabolic Parameters from Baseline Treatment A: ETR + TDF/FTC (Day 14) Treatment B: ETR + DRV/r + TDF/FTC (Day 28) Treatment C: DRV/r + TDF/FTC (Day 42) Baseline, median (range) Triglycerides Total cholesterolDirect LDL cholesterol HDL cholesterol -2 0 2 1 -2 0 1 -0.5 0 1 0.5 Median (range [IQR]) concentration, change from baseline, mmol/L -2 0 2 1 2 0.01 0.27 0.37 -0.08 0.03 0.28 -0.21 -0.16 0.04 0 -0.05 -0.03 0.79 (0.40-2.81) 3.75 (2.84-5.74) 2.38 (1.53-3.59)1.06 (0.78-1.55)

20. Changes in Metabolic Parameters from Baseline InsulinGlucose -2 0 3 1 Median (range [IQR]) concentration, change from baseline, μU/mL -18 -9 0 36 9 18 27 2 Treatment A: ETR + TDF/FTC (Day 14) Treatment B: ETR + DRV/r + TDF/FTC (Day 28) Treatment C: DRV/r + TDF/FTC (Day 42) 5.05 (4.16-5.94) 5.00 (1.9-23.0) Baseline, median (range) Median (range [IQR]) concentration, change from baseline, mmol/L -0.11 -0.08 -0.80 0

21. Improving safety and convenience: efavirenz to etravirine switch study  Four UK- based hospitals (40 patients)  First results available Q409 ETR 400 mg q.d. + BR + placebo EFV 600 mg q.d. + BR + placebo ETR 400 mg q.d. + BR 12 weeks Patients on EFV HAART with CNS or neuropsychiatric toxicity