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.