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Ethical Conduct of Dose Optimization Trials in Low-Income Countries

Discusses the ethical implications of dose optimization trials for antiretroviral drugs in low-income countries based on research by Dr. Andrew Hill presented at the World AIDS Conference in Melbourne, Australia in July 2014. The study explores risks of drug-related adverse events and lack of support from pharmaceutical companies for dose adjustments. Safety issues and optimized doses for various ARVs are analyzed. Potential impact on treatment efficacy and patient outcomes are considered.

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Ethical Conduct of Dose Optimization Trials in Low-Income Countries

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  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.

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