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

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

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

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  1. 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

  2. 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

  3. 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

  4. 1.5 Abacavir 1.29 kg (36%) ABC from week 24 d4T/AZT only 1 (mean change; kg) 0.55 kg (15%) 0.5 0.16 kg (4%) 0 0 12 24 36 48 60 72 MITOX Limb Fat Over 18 Months weeks N ABC 47 42 35 33 ABC Week 24 23 19 15 13 d4T/AZT 29 25 22 19 Martin AIDS 2004

  5. 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

  6. 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

  7. RAVEStatistical considerations • Primary endpoint: Change in total limb fat mass (by DEXA) over 48 weeks • 80% power to detect (5% significance level) a 0.5kg difference in primary endpoint  • Secondary endpoints: Changes in lipid measurements, VAT (from CT), CD4 count, HIV RNA, BMD and body fat over 48 weeks; incidence of clinical events • Analyses performed using intention-to-treat approach; missing values imputed using LOCF Moyle 12th CROI 2005: 44LB

  8. RAVEBaseline Characteristics Moyle 12th CROI 2005: 44LB

  9. RAVEBaseline Median Body Composition Moyle 12th CROI 2005: 44LB

  10. RAVEBaseline Median Metabolics Moyle 12th CROI 2005: 44LB

  11. 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 12th CROI 2005: 44LB

  12. 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

  13. RAVEMedian changes at week 48 in regional fat by DEXA p=0.66 p=0.69 Change in fat mass (g) by DEXA p=0.97 Within group change in Limb Fat from baseline TDF p=0.01, ABC p=0.001 Moyle 12th CROI 2005: 44LB

  14. 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

  15. RAVEMedian Changes in abdominal fat by CT p=0.86 p=0.71 p=0.36 Moyle 12th CROI 2005: 44LB

  16. RAVEMedian Change in Metabolic Outcomes to Week 48 Lactate Total Cholesterol HDL Cholesterol LDL Cholesterol Triglycerides P=0.16 P=0.043 P=0.031 P=0.016 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 P=0.27 Moyle 12th CROI 2005: 44LB *P values by Mann-Whitney U test

  17. RAVEMedian Fasting Cholesterol (mmol/l) Change from baseline +0.22 P=0.39 -0.49 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 91.5days Includes fasting and non-fasting samples. Observations are similar when only fasting samples are included Moyle 12th CROI 2005: 44LB

  18. RAVEMedian Change in Haemoglobin and Creatinine to Week 48 P=0.11 All d4T at baseline AZT at baseline *P values by Mann-Whitney U test Moyle 12th CROI 2005: 44LB

  19. RAVEChanges in Bone Mineral Density and proportion with osteopenia by T-score by DEXA to Week 48 Median T Score Mean T Score T score: BMD matched for sex *P values by Mann-Whitney U test all greater than 0.05 Moyle 12th CROI 2005: 44LB

  20. ABC RAVE% Patients <50 Copies/mL TDF % Patients with HIV RNA < 50 c/mL Number with 2 consecutive value >200copies/ml: TDF 0, ABC 1 Moyle 12th CROI 2005: 44LB

  21. RAVEMedian CD4 counts to week 48 Change from baseline (LOCF) +44 +10 P=0.51 Moyle 12th CROI 2005: 44LB

  22. RAVESummary • 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 arms • Lipid changes favoured the TDF arm. Fewer TDF patients initiated lipid lowering therapy • Rates of discontinuation were higher in the ABC group, in part due to HSR • No effects on BMD were observed Moyle 12th CROI 2005: 44LB

  23. 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 Acknowledgements

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