Switching from Kivexa [KVX] (ABC/3TC) + Efavirenz [EFV] to [ATR] (EFV/FTC/TDF) Reduces Cholesterol in Hypercholesterolaemic Subjects: Primary Endpoint Results of a 24- Week Randomised Study C Orkin, 1 G Moyle, 2 M Fisher, 3 H Wang, 4 J Ewan 4 and ROCKET I Study Group 1 Barts and The London NHS Trust, London, UK; 2 Chelsea and Westminster Hospital, London, UK; 3 Brighton and Sussex University Hospitals, UK; 4 Gilead Sciences Ltd, Cambridge, UK Second Joint Conference of the British HIV Association (BHIVA) with the British Association for Sexual Health and HIV (BASHH) April 2-23, 21 Manchester, UK Abstract No. 417 17 UK Sites Newcastle Central Middlesex Royal Free North Middlesex Homerton Edinburgh Belfast Bolton Heartlands North Manchester Leicester Whittle street C & W Barts St. Georges Gloucester Brighton
Background Dyslipidaemia contributes to CV risk 1 in HIV infection Higher Triglyceride levels are independently associated with an increased risk of MI in HIV-infected people 2 Comparative studies suggest tenofovir DF-based regimens have a favourable lipid profile relative to abacavir-based regimens 3 We sought to investigate if these changes are seen in hypercholesterolaemic subjects when switched from Kivexa + Efavirenz to a single tablet regimen (STR) of 1. Grover, SA, et al., Am J Cardiol 25; 95 (5): 586-591 2. Worm, S, et al., CROI 21, Paper # 127 3. Moyle, G et al., AIDS 26; 2 (16): 243-25 RAVE Study Lipid Effects of Switching Thymidine Analogues to ABC or TDF Switch to TDF associated with improved lipid parameters Mean Change From BL at Week 48 (mg/dl (mmol/l)) 15 1 5-5 -1-15 -2-25 * P =.3* 8.1 (.21) P =.4 * P =.34 * 3.5 (.9) P =.12.4 (.1) 6.2 (.7) -4.2 (-.11) -9.7 (-.25) -29.2 (-.33) -17.5 (-.45) TC LDL HDL TG 3 2 1-1 -2-3 -4-5 * P values for between arm differences Moyle GJ, et al. AIDS. 26;2:243-25. Switch to TDF Switch to ABC
SWEET study Lipid Effects of Switching AZT to TDF Switch to TDF associated with improved lipid parameters Median Change From BL at Week 24 (mmol/l).1 - -..1 -.2 -.3 -.4 -.5 5 97 89 84 84 95 89 97 89 N c Total Cholesterol p* =.8 b LDL-c p* =.45 HDL-c p* =.82 FTC/TDF AZT/3TC c Triglyceridese p* <.1 * TVD vs CBV comparison p-value from Wilcoxon Rank Sum test s a. Treated Analysis Set, Fasted b. p <.2 c. p <.1. from Wilcoxon sign rank test orf significant change from baseline Fisher et al., JAIDS 29; 51 (5): 562-568 Objectives Primary objective: Determine whether switching from Kivexa + EFV to QD leads to a reduction in total fasting cholesterol at 12 weeks The secondary objectives: Evaluation of fasting metabolic parameters (e.g., LDL *, HDL, triglycerides, non-hdl cholesterol and cholesterol ratios) Evaluation of efficacy and safety Evaluation of changes in the 1-year risk for coronary heart disease outcomes as measured by Framingham risk score * LDL measured directly
ROCKET: Randomised Open Label Switch for Cholesterol on Kivexa Evaluation Trial* Stable Kivexa (ABC/3TC) + EFV 6 months (N=159) randomised 1:1 (TDF/FTC/EFV) KVX (ABC/3TC) + EFV Week 12 primary endpoint (TDF/FTC/EVF) (TDF/FTC/EVF) Week 24 Confirmation of Week 12 Undetectable viral load ( 5 copies/ml) 12 weeks Total cholesterol 5.2 mmol/l Adequate Baseline renal (CrCl 6mL/min and Hepatic (AST / ALT 5 x ULN) function 157 / 159 subjects enrolled received at least one dose of study drug * Presentation of data up to Week 12 Baseline Characteristics a Kivexa + Efavirenz Number of subjects 79 78 Median age in yrs (IQR) 42 (36, 48) 44 (4, 5) Race White Black Asian Other 45 (57.%) 29 (36.7%) 2 (2.5%) 3 (3.8%) 48 (61.5%) 27 (34.6%) 3 (3.9%) Gender Male 61 (77.2%) 64 (82.1%) HIV RNA b < 5 copies/ml < 4 copies/ml 76/79 (96.2%) 79/79 (1%) 71/77 (92.2%) 77/77 (1%) Median BMI (kg/m 2 ) (IQR) 25.7 (23.5, 29.3) 25.8 (23.7, 28.) Median Fasting Total Cholesterol ( IQR) 6.62 (5.97, 7.26) 6.19 (5.8, 6.78) Number of Subjects on Prior Lipid Modifying Agents a. Treated Analysis Set b. One subject in Kivexa arm did not have a baseline viral load sample 9 (11.4%) 13 (16.7%)
Subject Disposition at Week 12 a N (%) (N=79) Kivexa + Efavirenz (N=78) Subjects completing 12 weeks of study 78 (98.7%) 74 (94.9%) Treatment Discontinuation (Prior to Week 12) 1 (1.3 %) 4 (5.1%) Adverse Events b 1 (1.3%) 1 (1.3%) Pregnancy Protocol Violation 2 (2.5%) Withdrew Consent Investigator s Decision 1 (1.3%) a. Treated AnalysisSet b. Adverse Events leading to study drug discontinuation: ATR arm - anxiety / heartburn / night sweats / general body pain/ palpitations KVX arm - depression Fasting Metabolic Parameters: Week 12 - Change from Baseline MITT Analysis Set (LOCF) Excluding subjects who started / modified lipid lowering medications during the study Median Change from Baseline (mmol/l).1 -.1 -.2 -.3 -.4 -.5 -.6 -.7 -.8 -.9-1 N=76 N=74 N=76 N=74 6.6 6.19 4.5 3.92 N=75 N=74 1.4 1.44 N=76 N=74 N=75 N=73 4.8 4.4 1.84 1.66 p <.1* p <.1* p <.1* p <.1* p=.3* LDL Cholesterol Total Cholesterol HDL Cholesterol Triglycerides TC: HDL ratio Kivexa + Efavirenz * P values for between arm differences Median value at baseline (mmol/l) LDL measured directly
Coronary Heart Disease Risk by Framingham Risk Score: Week 12 Median (IQR) Change from Baseline Median (IQR) Kivexa + Efavirenz Baseline 8. (4., 13.) 8. (4., 13.) Week 12 8. (3., 13.) Change from BL to Week 12 a. (-3.,.) 8. (4., 1.). (-1.,.) a. p=.37 for ATR vs KVX +EFV comparison Viral Suppression Change by Visit ITT Analysis Set (Missing = Excluded) % Subjects with HIV RNA < 5 c/ml CD4 count Week 12 Change from Baseline % % 1 9 8 7 6 5 4 3 Kivexa + Efavirenz 92.2% 9.3% 2 1 time Baseline Week 4 Week 12 Median CD4 count (cells/m m 3) (IQR) 3 2 1-1 -2-3 459 45 p=.13* (-36, 77) time (-96, 49) Kivexa + Efavirenz Virological failure [Subjects with 2 consecutive post-baseline value 4 copies/ml]: ATR /79 (%), KVX+EFV /78 (%) Median value at baseline (cells/mm3) * p values for between arm differences
Renal Function Creatinine Clearance - Median (IQR) Cockroft Gault (ml/min) and MDRD (ml/min/1.73m 2 ) 15 Creatinine Clearance: Cockroft Gault (ml/min) - Median (IQR) 15 Estimated GFR: MDRD (ml/min/1.732 m2) - Median (IQR) 125 125 ml/min 1 75 5 ATR ml/min/1.73 m 2 1 75 5 ATR 25 KVX + EFV Normal boundary 25 KVX + EFV Normal boundary 4 Weeks 12 4 12 Weeks No subject experienced a grade 3 or 4 renal abnormality in either arm Conclusions Switching from Kivexa + Efavirenz to in subjects with hypercholesterolaemia: Significantly reduces lipid parameters Maintains virological control Switching from Kivexa + Efavirenz to is beneficial in suitable hypercholesterolaemic patients
Acknowledgements 4 The ROCKET I Study Group Greater London: J Ainsworth, A Waters (North Middlesex, London) J Anderson, L Morumba (Homerton University, London) G Brook, M Chikohora (Central Middlesex, London) P Hay, A Adebiyi, M Cockerill, M Ndoro (St. Georges, London) M Johnson, A Carroll, F Turner (Royal Free, London) G Moyle, C Fletcher, J Osorio (Chelsea & Westminster, London) C Orkin, J Hand, C Desouza (Barts & Royal London) South East England: M Fisher, N Perry, T Maher, A Bray (Brighton & Sussex University) South West England: A de Burgh Thomas, M Bunting, L Jones (Gloucester Royal) Midlands: North England: Scotland: Northern Ireland: D White, J Groves (Birmingham Heartlands) J Ross, L Brown, K Hood (Selly Oak, Birmingham) J Dhar, S Johnson (Leicester Royal Infirmary) E Morgan, R Hewart (Royal Bolton) E Ong, J Wotherspoon (Newcastle General) E Wilkins, E Stockwell, A Robertson (North Manchester General) C Leen, S Morris, L Ellis (Western General, Edinburgh) R Maw, S McKernan (Royal Victoria, Belfast) C Herath, J Ewan, M (Hui) Wang, R Ebrahimi (Gilead Sciences Limited, Cambridge) We wish to thank all the patients that participated in the study.