Can dose-optimization trials be conducted ethically in low-income countries?

1. Can dose-optimization trials be conductedethically in low-income countries? Dr Andrew Hill World AIDS Conference, Melbourne, Australia July 2014 [TUWS1104]

2. Background • Most people on antiretroviral treatment are probably overdosed with one or more antiretrovirals • These high doses can increase the risk of drug-related adverse events, with no improvements in efficacy • Pharmaceutical companies do not normally support research to change approved doses.

3. Safety issues from current ARV doses ________________________________________________ ARV Dose Main adverse event Optimised dose ________________________________________________________________ EFV 600mg OD CNS 400 mg OD ATV/r 300/100 OD Renal stones, bilirubin 200/100 OD TDF (+PI) 300 OD Renal 250 OD (+PI) DRV/r 800/100 OD Lipids / GI / renal 400/100 OD D4T (Africa) 30 BID Neuropathy/lipoatrophy 20 BID ________________________________________________________________

4. Stavudine Original dose: 40mg BID Current dose: 30mg BID Target dose: 20mg BID

5. 100% 40mg BID 90% 30mg BID 80% 70% 60% 50% 40% 30% 20% 10% 0% • HIV NAT 002 • ARV 065 • Barcelona • Madrid • ETOX Low dose stavudine: efficacy • HIV RNA<50 cp/ml at 24 weeks (ITT) for • standard (40mg) versus low dose (30mg bid) d4T in randomised trials • WHO then recommended a switch to d4T 30mg BID. • This dose is now included in WHO treatment guidelines.

6. WRHI-001 study design: fully recruited • Treatment naïve patients • n=1068 TDF + 3TC/EFV n=534 • d4T 20 mg BID • + 3TC/EFV • n=534 • Double-blinded trial, recruiting in South Africa, Uganda and India. • Primary endpoint: HIV RNA suppression at Week 96 • Includes lipoatrophy sub-study

7. Atazanavir/r Current dose: 300/100 mg OD Target dose: 200/100mg OD

8. LASA trial: fully recruited • HIV RNA <50 on ART • n=560 ATV/r 300/100 mg OD +2NRTIs n=280 • ATV/r 200/100 mg OD • + 2NRTIs • n=280 • Patients enrolled in Thailand. Maintenance trial, with primary analysis at Week 48 (HIV RNA suppression endpoint)

9. Darunavir/r Current dose: 800/100 mg OD (PI naïve) Target dose: 400/100mg OD (PI naïve)

10. DRV/r Phase 2 trials: %HIV RNA >1 log reduction at Week 24, by dose and baseline DRV resistance 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 DRV/r dose group Katlama C et al AIDS 2007, 21: 395-402 Haubrich et al AIDS 2007, 21: F11-F18

11. 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 p=0.004, inverse correlation HIV RNA <50 c/mL (%) Week 48 Quartile of DRV Cmin Kakuda et al, HIV11, Glasgow 2012 [abstr P072]

12. Efavirenz Current dose: 600 mg OD Target dose: 400mg OD, potentially 200mg OD in the future

13. 100 80 60 Percent HIV RNA <400 Efavirenz 200 mg + ZDV/3TC 40 Efavirenz 400 mg + ZDV/3TC Efavirenz 600 mg + ZDV/3TC 20 0 0 2 4 6 8 1 0 1 2 1 4 1 6 DMP-005 trial – efavirenz dose-ranging ZDV/3TC + EFV 200, 400, 600 mg OD HIV RNA < 400 copies/ml after 16 weeks EFV 200 mg N = 32 34 34 30 29 32 31 EFV 400 mg N = 31 31 33 28 30 28 28 EFV 600 mg N = 32 29 32 28 30 27 28 Weeks in study Haas et al. 5th CROI 1998. Abstract 698

14. A daily dose of 400 mg efavirenz (EFV) is non-inferior to the standard 600 mg dose: week 48 data from the ENCORE1 study, a randomised, double-blind, placebo controlled, non-inferiority trialRebekah Puls for the ENCORE1 Study Group

15. ENCORE-1 Participant disposition Total screened N=768 Total ineligible N=123 Withdrew consent N=9 United Kingdom Germany Israel Hong Kong Randomized N=636 Mexico Thailand Nigeria Malaysia Singapore South Africa Australia Chile Argentina EFV 400mg, N=324 Withdrew prior to commencing randomized therapy N=3 ITT and NC=F, N=321 PP, N=293 EFV 600mg, N=312 Withdrew prior to commencing randomized therapy N=3 ITT and NC=F, N=309 PP, N=271

16. Baseline characteristics

17. ENCORE-1 trialHIV RNA <200 copies/mL at Week 48 Non-completer equals failure (FDA method) Main ITT analysis Outcome at Week 48 % HIV RNA <50, c/mL Week 48 n=321 n=309 n=321 n=309

18. Mean change from baseline to week 48 CD4+ T cells mean difference (SD) 25 cells (6, 44) p=0.009* Time (weeks)

19. Adverse events - related to study drug

20. Efavirenz adverse events* EFV400 EFV600 272 231 105 68 62 78 13 12 1 0 21 22 *categorised according to the EFV Product Information

21. Conclusions400 mg EFV was non-inferior to 600 mg EFV when combined with Truvada in a treatment-naive, HIV-infected adult population over 48 weeksEvidence of reduced EFV-related side effects with lower dose400 mg EFV should be considered for initial ARV treatment.

22. When could we get results on lower doses? ________________________________________________ ARV Dose Optimised dose Results ________________________________________________________________ EFV 600mg OD 400 mg OD ready ATV/r 300/100 OD 200/100 OD 4Q2014 D4T 30 BID 20 BID 2Q2015 TDF (+PI) 300 OD 200-250 OD (+PI) tbd DRV/r 800/100 OD 400/100 OD 4Q2015 ________________________________________________________________

23. Conclusions • There is a programme of clinical trials in progress, to validate the use of lower doses of antiretrovirals • More clinical trials are needed: • EFV 200mg OD? • DRV/r 400/100mg OD • TDF 200-250mg with PIs • ATV/r 200/100 OD in naives • Switches to lower doses could significantly improve drug safety for the millions of people taking these drugs worldwide.