1. Clinical development programme for Second-Line treatment Anton Pozniak World AIDS Conference, July 2014

2. 2 Current second-line treatment WHO standard: 2 new NRTIs plus LPV/r or ATV/r Efficacy of LPV/r + 2NRTIs in EARNEST and SECOND-LINE studies ? Use PI/r with Integrase Issues: –overlapping NRTI resistance –pill count, –twice daily (LPV/r), –NRTI safety –Cost versus first-line treatment

3. What do the patients look like? Baseline characteristics- Earnest (at randomisation / switch to second-line) PI/NRTIPI/RALPImono+Total Randomised4264334181277 Female264 (62%)263 (61%)215 (51%)742 (58%) Age (years) 37 (31-43)37 (30-43)38 (32-44)37 (31-44) Years since started ART 4.0 (2.8-5.4) 4.0 (2.9-5.5) 3.9 (2.7-5.4) 4.0 (2.8-5.4) CD4 (cells/mm 3 )72 (29-143)70 (27-142)70 (33-149)71 (30-146) Pre-ART CD462 (23-144)63 (23-135)63 (22-152)62 (23-145) VL (c/ml)67515 (23065-175800) 74500 (25004-205000) 70874 (21584-210000) 69782 (23183-194690) VL ≥100,000 c/ml168 (40%)181 (41%)181 (43%)530 (42%) 3 Note: n(%) or median (IQR)

4. VL suppression at 96 weeks 4 PI/RAL vs PI/NRTIP=0.36P=0.87P=0.97P=0.88

5. First-line to second Line TDF/3TC/EFV400 or NRTI /NNRTIs First-line DRV/r +DTG Second-line VF Option 1 TDF/3TC/DTG First-line PI/r+NNRTI Second-line VF Option 2

6. OPTION 1 Pill A to Pill B – two single tablet regimens? Pill A TDF/3TC/EFV400 $100 Pill B DRV400/r/DTG $250 Two pills, used in sequence Simple treatment rule – task shifting No overlapping drug resistance Mass generic production for Universal Access Low cost: $100 and $250 per person-year

7. Data for low dose DRV/r Phase 2 trials: %HIV RNA >1 log reduction at Week 24, by dose and baseline DRV resistance Katlama C et al AIDS 2007, 21: 395-402 Haubrich et al AIDS 2007, 21: F11-F18 DRV FC <4 (sensitive)DRV FC >4 (resistant) 400/100 800/100 400/100 600/100 OD OD BID BID 400/100 800/100 400/100 600/100 OD OD BID BID DRV/r dose group

8. No PK/PD relationship ODIN trial: HIV RNA <50 copies/mL at Week 48, treatment experienced, DRV sensitive patients DRV/r 800/100 mg OD +2NRTIs, by DRV Cmin Quartile of DRV Cmin HIV RNA <50 c/mL (%) Week 48 Kakuda et al, HIV11, Glasgow 2012 [abstr P072] p=0.004, inverse correlation

9. 9 DRV/r 600/100 OD + 2NRTIs: 12 naïve patients ___________________________________________________________________________ PatientRNA BLRNA FUTimeDRV Cmin ___________________________________________________________________________ Naïve85,501<5020 months2866 Naïve115,853<5019 months3140 Naïve334,500<5010 months3627 Naïve154,000<5024 months2553 Naïve87,350<5018 months3824 Naïve88,110<5019 months1700 Naïve34,793<5012 months1268 Naïve4,526<5018 months3732 Naïve235,520<5020 months2019 Naïve7,251 <5015 months2818 Naïve63,244<5016 months4562 Naïve397,932<505 monthsno data ____________________________________________________________________ ___________________________________________________________________ Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

10. 10 DRV/r 600/100 OD+2NRTIs: 7 pre-treated patients ___________________________________________________________________________ Prior ARV’sRNA BLRNA FUTimeDRV Cmin ___________________________________________________________________________ TDF/FTC/FPV/r33,250<5055 months2143 ZDV/3TC/TDF15,226<5055 months4518 TDF/FTC/FPV/r586<5043 months844 TDF/FTC/ATV/r8,450<5038 monthsno data TDF/FTC/LPV/r11,426<5038 monthsno data TDF/FTC/FPV119<5022 monthsno data TDF/FTC/FPV/r112<5020 monthsno data ____________________________________________________________________ ___________________________________________________________________ Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

11.  Study endpoints –The proportion of patients with HIV-1 RNA <50 c/mL at w48 (ITT). Non inferiority if lower limit of the 95% CI for  < -15%, 80% power –Changes in CD4+ T cell count –Changes in DRV C trough in plasma –The proportion of patients with AEs during follow-up –The economic cost derived from ARV drugs DRV/r 800/100 mg QD + 2 NRTIs DRV/r 600/100 mg QD + 2 NRTIs Randomisation 1 : 1 Open-label 100 HIV+ adults On 2 NRTIs + DRV 800mg qd > 4 weeks HIV-1 RNA 3 months No history of prior virologic failure to PI-based ART N = 50 W48 DRV600. Study Design

12. Results w48 94% 90% 96% 94% Non inferiority of DRV/r 600/100 mg QD 0 -15% ITT Observed data 50 4948 95% CI for the difference ITT -4.0 (-12.9; 4.9) Observed data -2,2 (-9.6; 5.2)

13. 13 Clinical experience with DRV/r + DTG There is no effect of DTG on DRV/r PK FDA label DRV/r 600/100 BID lowers DTG Cmin by 38%. This is not considered clinically significant, given the 50mg OD dose of DTG used FDA label. DRV/r + integrase proof of principle: NEAT (DRV/r + RAL vs DRV/r + TDF/FTC) CROI 2014 DRV/r + DTG was the most common combination used in the SAILING trial. Lancet 2013, 382, 700-708 In the SAILING trial, 72 patients treated with DRV/r + DTG + NRTIs with no primary PI mutations: HIV RNA <50 copies/mL at Week 48 in 69%, versus 70% for DRV/r + RAL + NRTIs.

14. Pill A, Pill B: Phase 2B-Dose ranging study Treatment naive SL2: Second-line, 2 drugs Randomised, 48 weeks 24 week interim justifies progression of programme TDF/FTC + DRV/r 800/100 OD DTG + DRV/r 800/100 OD DTG + DRV/r 400/100 OD

15. Pill A, Pill B: Phase 3 -pivotal study NNRTI experienced n=1050 (350 per arm) Randomised, 96 weeks Africa, Asia 2NRTI + PI/r (Control) DTG + DRV/r 800/100 OD DTG + DRV/r 400/100 OD

16. 16 Phase 3 study – design Inclusion: HIV RNA >1000 on two visits while taking NNRTI based treatment Primary endpoint: HIV RNA >1000 on two visits, 96 week follow up Recruitment: Africa, SE Asia, E Europe Statistics: powered to demonstrate non-inferiority for DRV/r + DTG versus control arm.

17. Clinical development programme for Second-Line treatment Need for FDC second line pill Low dose Darunavir and DTG attractive option as no overlapping resistance Co formulated as STR so easy to take Components well tolerated Cost savings Can Task shift Phase 2b into phase 3 for patient safety