a randomised, open-label comparative trial of...
TRANSCRIPT
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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
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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
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-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
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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
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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
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RAVERationale
Thymidine 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
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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
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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
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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
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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
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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)
Moyle 12th CROI 2005: 44LB
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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)
Moyle 12th CROI 2005: 44LB
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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)
Moyle 12th CROI 2005: 44LB
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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
Moyle 12th CROI 2005: 44LB
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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
Moyle 12th CROI 2005: 44LB
p=0.97
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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
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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
Moyle 12th CROI 2005: 44LB
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
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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
Moyle 12th CROI 2005: 44LB
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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
Moyle 12th CROI 2005: 44LB
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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
Moyle 12th CROI 2005: 44LB
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
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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
Moyle 12th CROI 2005: 44LB
8385
8083
60
70
80
90
100
110
120
Baseline Week 48
Crea
tinin
e m
icro
mol
/l TDF ABC
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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
Moyle 12th CROI 2005: 44LB
19%
27%
19%16%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Baseline Week 48
TDFABC
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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
Moyle 12th CROI 2005: 44LB
ABC
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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
Moyle 12th CROI 2005: 44LB
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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
Moyle 12th CROI 2005: 44LB
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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