TIMs ICAAC 2004

1
Changes in Lipids in 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
Marys Hosp London, 10 Western General Hosp
Edinburgh, 11 Gilead Sciences UK
ICAAC 2005
2
RAVE Rationale

• Thymidine analogue therapy is associated with
  peripheral fat loss and dyslipidemia
• Duration of exposure to HAART has been associated
  with increased risk of CV disease. This may, in
  part, be mediated through ART-associated
  dyslipidemia
• In initial treatment regimens tenofovir is
  associated with smaller changes in total
  cholesterol and triglycerides than either d4T or
  AZT
• The lipid profile of abacavir relative to
  thymidine analogues has not been well
  characterised

Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
3
RAVEDesign
48 wks
TDF
QD
NRTI
PI, PI/r or NNRTI
Thymidine analogue recipients (n 105)
randomised 11

• Moderate-Severe Lipoatrophy
• Any CD4 cell count
• HIV RNA lt50 c/mL
• Stable ARV Therapy for gt24 weeks

48 wks
ABC
BD
NRTI
PI, PI/r or NNRTI
No history of TDF or ABC use or
resistance Adequate Renal and Hepatic Function at
baseline
Moyle 12th CROI 2005 44LB
4
RAVEStatistical Methods

• Trial endpoints change in total limb fat mass
  (by DEXA) and lipids from baseline to 48 weeks
• Changes in lipids were approximately normally
  distributed
• Changes in values over 48 weeks were tested for
  significance using paired t-tests the changes in
  the two treatment groups were compared using
  unpaired t-tests
• Analyses of changes in lipids were based on all
  values as measured, disregarding any information
  on the use of lipid-lowering therapy
• All analyses were performed on an
  intention-to-treat basis.  Missing values were
  imputed using a last-observation-carried-forward
  approach

Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
5
RAVEBaseline Characteristics
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
6
RAVEBaseline Median Metabolics
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
7
RAVEPatient Disposition through Week 48
All discontinuations due to adverse events in
ABC group were due to hypersensitivity reaction,
TDF related discontinuation was secondary to
diarrhoea
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
8
RAVEMedian Change in Limb FatDEXA arm fat
total leg fat in grams (ITT mf analysis)
Median Baseline Limb Fat TDF 3.0kg, ABC 2.9kg
p0.97
Moyle 12th CROI 2005 44LB
9
RAVEMedian changes at week 48 in Limb Fat by
DEXA by baseline characteristics
Median Baseline Limb Fat
3.0kg 2.9kg
2.91kg 2.74kg
5.12kg 2.97kg
p0.97
Change in fat mass (g) by DEXA
n 49 44 12 16
37 28 31 32 18 12
Moyle 12th CROI 2005 44LB
10
RAVEMean Change in Metabolic Outcomes to Week 48
Lactate
Total Cholesterol
HDL Cholesterol
LDL Cholesterol
Triglycerides
P0.003
P0.04
P0.34
P0.12
P0.71
All individuals included. Lipid lowering therapy
commenced during study for TDF n1, at 273 days
, ABC n8, at median 91.5days Includes fasting
and non-fasting samples. Observations are similar
when only fasting samples are included
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
P values by paired t- test
11
RAVEChanges in Mean Fasting Cholesterol (mmol/l)
by baseline Thymidine analog
d4T at Baseline
AZT at Baseline
Fasting Cholesterol (mmol/l)
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
12
RAVEChanges in Mean Fasting LDL-c (mmol/l) by
baseline thymidine analogue
AZT at Baseline
d4T at Baseline
Fasting Cholesterol (mmol/l)
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
13
RAVEChanges in Mean Fasting HDL-c (mmol/l) by
baseline Thymidine analogue
d4T at Baseline
AZT at Baseline
Fasting Cholesterol (mmol/l)
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
14
RAVEChanges in Mean Fasting Triglycerides
(mmol/l) by baseline Thymidine analogue
d4T at Baseline
AZT at Baseline
Fasting Cholesterol (mmol/l)
All data LOCF. All individuals included. Lipid
lowering therapy commenced during study for TDF
n1, at 273 days , ABC n8, at median
91.5daysIncludes fasting and non-fasting
samples. Observations are similar when only
fasting samples are included
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
15
RAVE patients with dyslipidemia at baseline
and week 48 by randomized group
Total Cholesterol gt6.2mmol/l or 240mg/dl
HDL Cholesterol lt0.9mmol/l or 35mg/dl
LDL Cholesterol gt4.1mmol/l or 160mg/dl
Triglycerides lt2.3mmol/l or 200mg/dl
P0.24
P1.00
P1.00
P1.00
Baseline
Baseline
Week 48
Week 48
Baseline
Baseline
Week 48
Week 48
NCEP ATPIII Category high
Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340
16
RAVESummary

• TDF and ABC similarly allow restoration of limb
  fat over 48 weeks when switching from thymidine
  analogues in persons with lipoatrophy
• Lipid changes favored the TDF arm. Fewer TDF
  patients initiated lipid lowering therapy
• Baseline lipids were generally higher in the d4T
  arm
• Falls in total cholesterol and TGs were
  predominately seen in individuals on d4T at
  baseline

Moyle et al. 45th ICAAC Sept 21-24, 2005
abstract H-340