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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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ICAAC 2005


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    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 Mary’s Hosp London, 10 Western General Hosp Edinburgh, 11 Gilead Sciences UK ICAAC 2005

    2. 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

    3. 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

    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. 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

    9. 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

    10. 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

    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 d4T at Baseline AZT 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 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

    15. 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

    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