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

Background 1.Most people on antiretroviral treatment are probably overdosed with one or more antiretrovirals 2.These high doses can increase the risk of drug-related adverse events, with no improvements in efficacy 3.Pharmaceutical companies do not normally support research to change approved doses.

Safety issues from current ARV doses ________________________________________________ ARVDose Main adverse eventOptimised dose ________________________________________________________________ EFV600mg ODCNS400 mg OD ATV/r300/100 ODRenal stones, bilirubin200/100 OD TDF (+PI)300 ODRenal250 OD (+PI) DRV/r800/100 ODLipids / GI / renal400/100 OD D4T (Africa)30 BIDNeuropathy/lipoatrophy20 BID ________________________________________________________________

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

Manufacture, formulation and dose 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% HIV NAT 002ARV 065 ETOX BarcelonaMadrid 40mg BID 30mg BID 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. Low dose stavudine: efficacy

Manufacture, formulation and dose WRHI-001 study design: fully recruited d4T 20 mg BID + 3TC/EFV n=534 TDF + 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 Treatment naïve patients n=1068

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

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

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

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: Haubrich et al AIDS 2007, 21: F11-F18 DRV FC <4 (sensitive)DRV FC >4 (resistant) 400/ / / /100 OD OD BID BID 400/ / / /100 OD OD BID BID DRV/r dose group

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

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

13 DMP-005 trial – efavirenz dose-ranging Efavirenz 200 mg + ZDV/3TC Efavirenz 400 mg + ZDV/3TC Efavirenz 600 mg + ZDV/3TC Percent HIV RNA <400 Weeks in study EFV 200 mg N = EFV 400 mg N = EFV 600 mg N = Haas et al. 5th CROI Abstract 698 ZDV/3TC + EFV 200, 400, 600 mg OD HIV RNA < 400 copies/ml after 16 weeks

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 trial Rebekah Puls for the ENCORE1 Study Group

ENCORE-1 Participant disposition Withdrew consent N=9 Randomized N=636 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 Total screened N=768 Total ineligible N=123 Singapore Malaysia Australia Israel United Kingdom Germany Nigeria South Africa Mexico Chile Argentina Thailand Hong Kong

Baseline characteristics CharacteristicEFV 400mgEFV 600mgTotal N=321N=309N=630 Male, n (%)221 (68.8)206 (66.5)427 (67.7) Mean age in years (SD)36.1 (10.0)35.8 (10.0)36.0 (10.0) Ethnicity, n (%) African118 (36.8)116 (37.4)234 (37.1) Asian106 (33.0)103 (33.2)209 (33.1) Caucasian97 (30.2)90 (29.0)187 (29.6) Aboriginal Australian0 (0.0)1 (0.3)1 (0.2) CDC category A, n (%)264 (82.2) 265 (85.8)529 (84.0) Median pVL in log 10 copies/mL (IQR) 4.76 (0.84)4.73 (0.90)4.75 (0.88) pVL copies/mL, n (%) <100, (66.7)202 (64.4)416 (66.0) ≥100, (33.3)107 (34.6)214 (34.0) Mean CD4+ T cells/µL (SD)273 (97)272 (101)273 (99) 100 < CD4+ T cells/µL ≤ 350, n (%)244 (76)224 (72)468 (74)

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

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

Adverse events - related to study drug EFV400 N=321 EFV600 N=309 Difference (95%CI) p Number (%) patients reporting AE 286 (89.1)273 (88.4) Number (%) patients with study drug related AE 118 (36.8)146 (47.2)-10.5% (-18.2, -2.8)0.008* Number (%) patients stopping drug due to related AE 6 (1.9)18 (5.8)-3.96 (-6.96, -0.95)0.010*

Efavirenz adverse events* EFV400 EFV *categorised according to the EFV Product Information

Conclusions 400 mg EFV was non-inferior to 600 mg EFV when combined with Truvada in a treatment-naive, HIV- infected adult population over 48 weeks Evidence of reduced EFV-related side effects with lower dose 400 mg EFV should be considered for initial ARV treatment.

When could we get results on lower doses? ________________________________________________ ARVDose Optimised doseResults ________________________________________________________________ EFV600mg OD400 mg ODready ATV/r300/100 OD200/100 OD4Q2014 D4T 30 BID20 BID2Q2015 TDF (+PI)300 OD OD (+PI)tbd DRV/r800/100 OD400/100 OD4Q2015 ________________________________________________________________

Conclusions 1.There is a programme of clinical trials in progress, to validate the use of lower doses of antiretrovirals 2.More clinical trials are needed: EFV 200mg OD? DRV/r 400/100mg OD TDF mg 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.