A Randomised, Open-Label Comparative Trial of …archives.who.int/eml/expcom/expcom15/applications/newmed/tenofovir...Baseline by NRTI Assignment. RAVE ... ABC Week 24 23 19 15 13

A Randomised, Open-Label Comparative Trial of Abacavir or Tenofovir DF as Replacement for a

Thymidine Analogue in Persons with Lipoatrophy and Suppressed HIV RNA on HAART

The RAVE Study

G Moyle1 , C Sabin2, J Cartledge3, M Johnson2, E Wilkins4, D Churchill5 , P Hay6, A Fakoya7, M Murphy8, G Scullard9, C Leen10, G Reilly11

for the RAVE study group UK

1 Chelsea and Westminster Hosp, London, 2 Royal Free & UC Medical School, London, 3 UCL London, 4 North Manchester Hosp, 5 Lawson Unit Royal Sussex County Hosp,

6 St Georges Hosp London, 7 Newham General London, 8 St Barts & The London, 9 St Mary’s Hosp London, 10 Western General Hosp Edinburgh, 11 Gilead Sciences UK

12th Conference on Retroviruses and Opportunistic Infections, Boston USA 23rd February 2005

RAVERationaleThymidine analogue therapy is associated with peripheral fat loss and lipoatrophy

Treatment modification of thymidine analogue to abacavir is associated with gradual recovery of peripheral fat

Neither Abacavir nor Tenofovir DF have been convincingly associated with peripheral fat loss in prospective studies in treatment naïve persons

-30-30

-40-40

-50-50

-20-20

-10-10

00

1010

2020

1616 3232 4848 6464 8080

**** **

††

††

††††

††

††

AZT + 3TCAZT + 3TCddI + d4TddI + d4T

00

Med

ian

% C

hang

eM

edia

n %

Cha

nge

WeeksWeeks

* p<0.05 between groups* p<0.05 between groups† p<0.05 within groups† p<0.05 within groups

Dubé MP, et al. 4th IWADRLH;2002; San Diego, Calif. Abstract 27.Dubé MP, et al. 4th IWADRLH;2002; San Diego, Calif. Abstract 27.

ACTG 384 Median Percent Change in Limb Fat From Baseline by NRTI Assignment

RAVERationaleThymidine analogue therapy is associated with peripheral fat loss and lipoatrophy



MITOX Limb Fat Over 18 Months

weeksN ABC 47 42 35 33

ABC Week 24 23 19 15 13d4T/AZT 29 25 22 19

Martin AIDS 2004

(mea

n ch

ange

; kg)

1.29 kg (36%)

0.55 kg (15%)

0.16 kg (4%)0

0.5

1

1.5

0 12 24 36 48 60 72

Abacavir

ABC from week 24

d4T/AZT only

RAVERationale

Thymidine analogue therapy is associated with peripheral fat loss and lipoatrophy



FIRSTRates of Change of Skinfold Fat Area

Mid-arm (cm^2)

ddI+d4TABC+3TC

Change P-valueSE(cm^2/month)

-0.220.03

<0.010.040.04

Months0 4 8 12 16 20 24 28 32

Mid-thigh (cm^2)

ddI+d4TABC+3TC

Change P-valueSE(cm^2/month)

-0.35-0.02

<0.010.080.08

Months0 4 8 12 16 20 24 28 32

Shlay JAIDS 2005

Study 903Mean (95% CI) Total Limb Fat at Weeks 96 and 144

TDF + 3TC + EFV 128 115d4T + 3TC + EFV 134 117

Weeks

*p < 0.001

TDF + 3TC + EFVd4T + 3TC + EFV

Kilo

gram

s

8.6*

4.5

0123456789

10

48 96 144

5.0

7.9*

Gallant JE. XV Int AIDS Conf, July 2004, Bangkok, #4538

RAVEDesign

Thymidine analogue recipients

(n = 105)

randomised 1:1

48 wks

48 wks

Moderate-Severe LipoatrophyAny CD4 cell countHIV RNA <50 c/mL

Stable ARV Therapy for >24 weeks

TDF QD+ NRTI + PI, PI/r or NNRTI

No history of TDF or ABC use or resistance

Adequate Renal and Hepatic Function at baseline

ABC BD+ NRTI + PI, PI/r or NNRTI

RAVEStatistical considerations

Primary endpoint: Change in total limb fat mass (by DEXA) over 48 weeks80% power to detect (5% significance level) a 0.5kg difference in primary endpointSecondary endpoints: Changes in lipid measurements, VAT (from CT), CD4 count, HIV RNA, BMD and body fat over 48 weeks; incidence of clinical eventsAnalyses performed using intention-to-treat approach; missing values imputed using LOCF

Moyle 12th CROI 2005: 44LB

RAVEBaseline Characteristics

59%77%d4T41%23%AZT

Current thymidine analogue:

4.9 (0.8, 8.1)74%

5.7 (0.8, 11.5)63%

Years on ART (median, IQR):Current PI-sparing regimen

478 (340, 653)522 (314, 724)Current CD4 (median, IQR):154 (2, 783)114 (0, 818)Nadir CD4 (median, IQR):

4342Median age (years):83%85%White race:87%94%Male sex:

ABC (n=53)

TDF (n=52)


RAVEBaseline Median Body Composition

7274Weight (kg)

81241

87237

SAT (cm3)TAT (cm3)

148150VAT (cm3)

6.87.1Trunk Fat (kg)2.93.0Total Limb Fat (kg)

10.611.1Total Body Fat (kg)

ABC (n=53)

TDF (n=52)


RAVEBaseline Median Metabolics

1.31.5Lactate (mmol/l)

7.25.2

8.85.1

Insulin (IU/l)Fasting Glucose (mmol/l)

1.72.0Triglycerides (mmol/l)

3.03.3LDL-C (mmol/l)1.31.3HDL-C (mmol/l)5.35.6Total Cholesterol (mmol/l)

ABC (n=53)

TDF (n=52)


RAVEPatient Disposition through Week 48

19 (1.6, 40)36 (4, 39)Median time to discontinuation (weeks, range)

-1 (2%)- Other3 (6%)*1 (2%)- Adverse event2 (4%)-- Protocol violation2 (4%)1 (2%)- Patient withdrew consent1 (2%)-- Lost to follow-up

8 (15%)3 (6%)N (%) discontinued study

ABC (n=53)

TDF (n=52)

* All discontinuations due to adverse events in ABC group were due to hypersensitivity reaction, TDF related discontinuation was secondary to diarrhoea


RAVEMedian Change in Limb FatDEXA arm fat + total leg fat in grams (ITT m=f analysis)

393

199

316

198

0

50

100

150

200

250

300

350

400

450

Baseline Week 24 Week 48Time (weeks)

Lim

b fa

t (gr

ams)

TDF (n=52) ABC (n=52)

Median Baseline Limb Fat TDF 3.0kg, ABC 2.9kg


p=0.97

RAVEMedian changes at week 48 in regional fat by DEXA

393

522

1061

316

791

1046

0

200

400

600

800

1000

1200

Limb Trunk Total Fat

TDF

ABC

p=0.97

p=0.69

p=0.66

Cha

nge

in fa

t mas

s (g

) by

DEX

A

Within group change in Limb Fat from baseline TDF p=0.01, ABC p=0.001Moyle 12th CROI 2005: 44LB

RAVEMedian changes at week 48 in Limb Fat by DEXA by baseline characteristics

393

66

529

374

432

316

210

357 363

247

0

100

200

300

400

500

600

All Subjects AZT at Baseline d4T at Baseline On PI No PI

TDF ABC

p=0.97

Cha

nge

in fa

t mas

s (g

) by

DEX

A


n: 49 44 12 16 37 28 31 32 18 12

Median Baseline Limb Fat

3.0kg 2.9kg 2.91kg 2.74kg5.12kg 2.97kg

RAVEMedian Changes in abdominal fat by CT

78

25

-1

11

25

-5

0

5

10

15

20

25

30

VAT SAT TAT

Fat m

ass

cubi

c cm

DEX

A

TDF

ABC

p=0.36

p=0.71

p=0.86


RAVEMedian Change in Metabolic Outcomes to Week 48

*P values by Mann-Whitney U test

-0.3

-0.2

-0.01

-0.1

-0.17

-0.1

0 0 0 0

-0.35

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

Cha

nge

in m

mol

/l

TDF ABC

P=0.27

P=0.016

P=0.16

P=0.043P=0.043

P=0.031

Lactate Total Cholesterol

HDL Cholesterol

LDL Cholesterol

Triglycerides

All data LOCF

All individuals included. Lipid lowering therapy commenced during study for TDF n=1, at 273 days , ABC n=8, at median 91.5days

Includes fasting and non-fasting samples. Observations are similar when only fasting samples are included


RAVEMedian Fasting Cholesterol (mmol/l)

5.4

5.5

5.7

5.3

5

5.2

5.4

5.6

5.8

. Baseline Week 4 Week 12 Week 24 Week 36 Week 48

TDF ABC

P=0.39

Fast

ing

Cho

lest

erol

(m

mol

/l)

Change from baseline

+0.22

-0.49


All data LOCF

All individuals included. Lipid lowering therapy commenced during study for TDF n=1, at 273 days , ABC n=8, at median 91.5days

Includes fasting and non-fasting samples. Observations are similar when only fasting samples are included

RAVEMedian Change in Haemoglobin and Absolute Creatinine to Week 48

0.25

0.05

0.85

0

-0.1

0.45

-0.2

0

0.2

0.4

0.6

0.8

1

Hb

mg/

dl

TDF ABC

*P values by Mann-Whitney U test

P=0.11P=0.11

All d4T at baseline

AZT at baseline


8385

8083

60

70

80

90

100

110

120

Baseline Week 48

Crea

tinin

e m

icro

mol

/l TDF ABC

RAVEChanges in Bone Mineral Density and proportion with osteopenia by T-score by DEXA to Week 48

-0.10

-0.06

-0.02

0.00

-0.12

-0.1

-0.08

-0.06

-0.04

-0.02

0

Chan

ge in

scor

e valu

el

TDF

ABC

*P values by Mann-Whitney U test all greater than 0.05

Median T Score Mean T Score

T score: BMD matched for sex


19%

27%

19%16%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Baseline Week 48

TDFABC

10094

9193

0102030405060708090

100

Baseline Week 4 Week 12 Week 24 Week 36 Week 48

RAVE% Patients <50 Copies/mL

% P

atie

nts

with

HIV

RN

A <

50

c/m

L

TDF

Number with 2 consecutive value >200copies/ml: TDF 0, ABC 1


ABC

590

521

465529

0

100

200

300

400

500

600

Baseline Week 4 Week 12 Week 24 Week 36 Week 48

CD

4 C

ell c

ount

(cel

ls/m

m3 )

TDF (n=52) ABC (n=53)

RAVEMedian CD4 counts to week 48

+10

+44

Change from baseline (LOCF)

P=0.51


TDF and ABC similarly allow restoration of limb and SAT over 48 weeks when switching from thymidine analogues in persons with lipoatrophy CD4 and control of HIV RNA were similar across armsLipid changes favoured the TDF arm. Fewer TDF patients initiated lipid lowering therapyRates of discontinuation were higher in the ABC group, in part due to HSRNo effects on BMD were observed

RAVESummary


Acknowledgements

♦ Graeme Moyle♦ Caroline Sabin♦ Jonathan Cartledge ♦ Margaret Johnson ♦ Edmund Wilkins ♦ Duncan Churchill ♦ Phillip Hay♦ Ade Fakoya ♦ Maurice Murphy ♦ George Scullard ♦ Clifford Leen ♦ Geraldine Reilly♦ RAVE study group UK

♦ Medinova♦ Exp-e-data♦ Inveresk♦ UCL Medical Imaging Group♦ Gilead Sciences UK & USA

Documents

A Randomised, Open-Label Comparative Trial of …archives.who.int/eml/expcom/expcom15/applications/newmed/tenofovir...Baseline by NRTI Assignment. RAVE ... ABC Week 24 23 19 15 13