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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 Moyle 1 , C Sabin 2 , J Cartledge 3 , M Johnson 2 , E Wilkins 4 , D Churchill 5 ,

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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 Mary’s Hosp London, 10 Western General Hosp Edinburgh, 11 Gilead Sciences UK

ICAAC 2005

rave rationale
RAVERationale
  • 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

rave design
RAVEDesign

48 wks

TDF

QD

+ NRTI

+ PI, PI/r or NNRTI

Thymidine analogue recipients

(n = 105)

randomised 1:1

Moderate-Severe Lipoatrophy

Any CD4 cell count

HIV RNA <50 c/mL

Stable ARV Therapy for >24 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

rave statistical methods
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

rave baseline characteristics
RAVEBaseline Characteristics

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

rave baseline median metabolics
RAVEBaseline Median Metabolics

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

rave patient disposition through week 48
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

slide8

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

Median Baseline Limb Fat TDF 3.0kg, ABC 2.9kg

p=0.97

Moyle 12th CROI 2005: 44LB

rave median changes at week 48 in limb fat by dexa by baseline characteristics
RAVEMedian changes at week 48 in Limb Fat by DEXA by baseline characteristics

Median Baseline Limb Fat

3.0kg 2.9kg

5.12kg 2.97kg

2.91kg 2.74kg

p=0.97

Change in fat mass (g) by DEXA

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

Moyle 12th CROI 2005: 44LB

rave mean change in metabolic outcomes to week 48
RAVEMean Change in Metabolic Outcomes to Week 48

Lactate

Total Cholesterol

HDL Cholesterol

LDL Cholesterol

Triglycerides

P=0.003

P=0.04

P=0.34

P=0.12

P=0.71

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

*P values by paired t- test

rave changes in mean fasting cholesterol mmol l by baseline thymidine analog
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

rave changes in mean fasting ldl c mmol l by baseline thymidine analogue
RAVEChanges in Mean Fasting LDL-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

rave changes in mean fasting hdl c mmol l by baseline thymidine analogue
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

rave changes in mean fasting triglycerides mmol l by baseline thymidine analogue
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 n=1, at 273 days , ABC n=8, 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

rave patients with dyslipidemia at baseline and week 48 by randomized group
RAVE: % patients with dyslipidemia* at baseline and week 48 by randomized group

HDL Cholesterol <0.9mmol/l or 35mg/dl

Total Cholesterol >6.2mmol/l or 240mg/dl

LDL Cholesterol >4.1mmol/l or 160mg/dl

Triglycerides <2.3mmol/l or 200mg/dl

P=0.24

P=1.00

P=1.00

P=1.00

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

rave summary
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

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