can dose-optimization trials be conducted ethically in low-income countries? dr andrew hill world...
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Can dose-optimization trials be conductedethically in low-income countries?
Dr Andrew HillWorld 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________________________________________________
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________________________________________________________________
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 002 ARV 065 ETOX Barcelona Madrid
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: 395-402Haubrich et al AIDS 2007, 21: F11-F18
1 2 3 40
10
20
30
40
50
60
70
80
90
100
1 2 3 40
10
20
30
40
50
60
70
80
90
100DRV FC <4 (sensitive) DRV FC >4 (resistant)
400/100 800/100 400/100 600/100OD OD BID BID
400/100 800/100 400/100 600/100OD OD BID BID
DRV/r dose group 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
1 2 3 40
20
40
60
80
100
84.687.5
83.6
66.1
Quartile of DRV Cmin
HIV RNA<50 c/mL(%)Week48
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
0 2 4 6 8 10 12 14 16
Efavirenz 200 mg + ZDV/3TC
Efavirenz 400 mg + ZDV/3TC
Efavirenz 600 mg + ZDV/3TC
0
20
40
60
80
100
Per
cen
t H
IV R
NA
<40
0
Weeks in study
EFV 200 mg N = 32 34 34 30 29 32 31EFV 400 mg N = 31 31 33 28 30 28 28EFV 600 mg N = 32 29 32 28 30 27 28
Haas et al. 5th CROI 1998. 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 consentN=9
RandomizedN=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 screenedN=768
Total ineligible N=123
SingaporeMalaysia
Australia
Israel
United Kingdom
Germany
Nigeria
South Africa
Mexico
Chile
Argentina
Thailand
Hong Kong
Baseline characteristics Characteristic EFV 400mg EFV 600mg Total
N=321 N=309 N=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 (%)
African 118 (36.8) 116 (37.4) 234 (37.1)
Asian 106 (33.0) 103 (33.2) 209 (33.1)
Caucasian 97 (30.2) 90 (29.0) 187 (29.6)
Aboriginal Australian 0 (0.0) 1 (0.3) 1 (0.2)
CDC category A, n (%) 264 (82.2) 265 (85.8) 529 (84.0)
Median pVL in log10 copies/mL (IQR) 4.76 (0.84) 4.73 (0.90) 4.75 (0.88)
pVL copies/mL, n (%)
<100,000 214 (66.7) 202 (64.4) 416 (66.0)
≥100,000 107 (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 trialHIV RNA <200 copies/mL at Week 48
90.0% 94.0%86.0%
92.0%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
EFV400 EFV600 EFV400 EFV600
% HIV RNA<50, c/mLWeek 48
Non-completer equals failure (FDA method)
n=321 n=309 n=321 n=309
Main ITT analysisOutcome 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*
0 4 8 12 16 20 24 28 32 36 40 44 48-50
0
50
100
150
200
250
300
EFV 400 mg EFV 600 mg
CD
4+
T c
ell
s/µ
L
Adverse events - related to study drug
EFV400N=321
EFV600N=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*
CNS Psychiatric Rash Gastrointestinal Respiratory Hepatotoxicity0
10
20
30
40
50
60
Pro
po
rtio
n o
f p
art
icip
an
ts (
%)
231
272
13 12
68
105
62
21 221 0
EFV400
EFV600
78
*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?________________________________________________
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
________________________________________________________________
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 ODTDF 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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