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Introduction

Tenofovir DF + Efavirenz (TDF+EFV) vs Tenofovir DF + Efavirenz + Lamivudine (TDF+EFV+3TC) Maintenance Regimen in Virologically Controlled Patients: COOL Trial.

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Introduction

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  1. Tenofovir DF + Efavirenz (TDF+EFV) vs Tenofovir DF + Efavirenz + Lamivudine (TDF+EFV+3TC) Maintenance Regimen in Virologically Controlled Patients: COOL Trial PM Girard,1 A Cabié,2 C Michelet,3 R Verdon,4 C Katlama,5 P Mercié,6L Morand Joubert,1 G Chêne,7 P Pétour,8 and A Trylesinski8 1Hop. St Antoine, Paris, France; 2Hop. Zobda Quitman, Fort de France, France; 3Hop. Pontchaillou, Rennes, France; 4Hop. Caen, Caen, France; 5Hop. Pitie Salpêtrière, Paris, France; 6Hop. St André, Bordeaux, France; 7INSERM U593, Bordeaux, France; 8Gilead Sciences, Inc., Paris, France

  2. Introduction • HIV-1 infection is a long term illness requiring long term therapy • Antiretroviral therapy may induce metabolic abnormalities and fat tissue redistribution • Nucleoside reverse transcriptase inhibitors (NRTIs) are associated with such toxicity • A 48 week randomized study (the COOL Study) enrolled 143 virologically controlled (BLQ) patients who were switched to 2 simplified new regimens TDF+3TC+EFV vs TDF+EFV

  3. Objectives • Primary objective: Evaluation of the efficacy of TDF+3TC+EFV versus TDF+EFV QD to maintain plasma HIV-1 RNA BLQ (< 50 copies/mL) (c/mL) at 48 weeks (W48) • Main Secondary objectives: • – Comparison of the two arms for genotypic resistance profile in case of virological failure – CD4 changes from baseline– Evolution of the lipid profile and morphological changes in fat distribution, and safety • Efficacy and genotypic profile data, results of lipid markers, morphological changes and main biological parameters are presented

  4. Methods • Main Eligibility Criteria: • Stable HAART ≥ 3 months • HIV-1 RNA < 50 c/mL ≥ 6 months • No HAART failure history • Weight > 45 kg • No CD4+ cell count criteria • No significant laboratory or clinical abnormalities • Creatinine Clearance > 60 mL/min • Follow-up was performed at Week 4, 12, 24, 36 and 48 including clinical examination, adverse events assessment, CD4 cell count, HIV-1 RNA level, metabolic parameters and morphologic evaluation. Creatinine Clearance was calculated according to the Cockcroft-Gault equation • Success rate was defined as maintained VL BLQ (< 50 c/mL) without study drug modification at W48 • Non inferiority limit:14% • L4 CT-Scans were performed at baseline and Week 48 (SAT and VAT measurement) • Two DSMB meetings were scheduled for formal unblinded statistical review of the first 40 and 80 patients at Week 12 for HIV-1 RNA, CD4, and AE • Clinical and biological data were collected via an Electronic Data Capture system (eCRF) allowing a tight follow-up by DSMB in a timely manner • Statistical analysis was performed with SAS, version 8.2 • Intent To Treat (ITT) Population defined as all included patients having received at least one dose of study treatment • As Treated (AT) Population defined as all included patients having received at least one dose of study treatment, with at least one evaluation at baseline and after baseline and with no major deviation to the protocol

  5. Study Design A 48 Week, pilot, open label, multicenter, randomised clinical trial W 4 8 S ta ble H A A R T § T D F + EF V M o n t h s VL < 50 c / mL § randomization 1: 1 W 4 .. W1 2 … … W 2 4 … … W 36 ….. M o n t h s N = 143 patient s N o h i st o r y o f § Vi r o l o g i c F a ilu r e W 4 8 T D F + EF V + 3 T C D S M B da t a rev i e w

  6. Baseline Characteristics of the ITT Population

  7. % of Patients with Viral Load < 50 c/mL (ITT / AT Populations) 1 0 0 : 1 0 % 1 0 0 9 7 : 1 5 . 5 % 95 % C I a : 15 . 5 % 95 % CIa : 23 . 7 % 9 0 8 2 T D F + 3 T C + E F V 5 0 N = 7 0 N = 5 8 N = 7 0 N = 5 4 T D F + E F V 0 I T T A T N= 72 71 7 0 6 0 a. Upper bound of 95% CI

  8. Main Reasons for Failure at W48 (ITT Population) a. Except study drug discontinuation of patients with HIV-1 RNA > 50 c/mL b. 1 SAE: « Suicide Attempt »c. 2 SAE and 1 AE: « Transaminases Increase », « Vertigo » and « Transaminases Increase » respectively

  9. RT Mutations Emergence from Baseline a. Pre-existing at baseline

  10. T D F + E F V [N = 3 / 71 ] a A R V modification 10000 0 0 00 9 - 0 0 7 01 5 - 0 1 1 1000 0 0 b A R V modification 01 6 - 0 0 5 ] L 100 0 0 m / c ( Log HIV-1 RNA (c/mL) 10 0 0 A RN 1 0 0 1 - V I 1 0 H g Lo 1 Baseline W 4 W 1 2 W 2 4 W 3 6 W 4 8 Patients with Virological Failure (Only TDF / EFV Arm): Evolution of HIV-1 RNA through W48 a. ZDV + 3TC + ATVb. ZDV + 3TC + IDV + RTVNote: For patient 016-005, a decrease of study drug compliance was observed (based on drug returns at study visits) to reach < 50% at W36. For patients 009-007 and 015-011, compliance evaluation was not possible since no bottle returns were recorded

  11. “Blips” through W48 Follow-Up: Viral Load > 50 c/mL and Subsequently BLQ Note: Patient # 001-008 displayed a K103N mutation at W24 and VL BLQ at W48 with no ARV modification

  12. Biological Parameters: W48 Change from Baseline a. Wilcoxon test (TDF + 3TC + EFV vs TDF + EFV); significant for p < 0.05 b. Wilcoxon Rank-Sum test on overall TDF switched population (Baseline vs W48); significant for p < 0.05 c. According to the Cockcroft-Gault equation

  13. T r i g l yc e r i d e s T o ta l C h o l e s te r o l T D F + 3 T C + EF V T D F + EF V A l l P opul a ti o n T D F + 3 T C + EF V T D F + EF V A l l P opul a ti o n 2 . 5 6 . 5 6 2 A l l popul at io n * A l l popul at io n * 5 . 5 mmol/l mmol/l 1 . 5 - 0 . 3 1 mm ol/ l : -0 . 2 5 mm ol/ l 5 1 p < 0 . 0001* * p < 0 . 001 * * 4 . 5 0 . 5 4 B a s e lin e W 4 8 B a s e l i n e W 4 8 LDL Chole ste ro l HDL Chol e s te ro l T D F + 3 T C + EF V T D F + EF V A l l P opul a ti o n T D F + 3 T C + EF V T D F + EF V A l l P opul a ti o n 4 . 5 3- d r u g A r m 2 : -0 . 20mm o l/l 4 p = 0 . 015* * A l l popul at io n * 2- d r u g A r m 3 . 5 mmol/l mmol/l 1 . 5 : +0.05 mmol/l : +0.15 mmol/l p = 0 . 0041* * p = 0 . 50* * 3 A l l popul at io n : -0 . 0 2 mm ol/ l 1 2 . 5 p = 0 . 15* * B a s e lin e W 4 8 B a s e lin e W 4 8 Lipids: W48 Change from Baseline (As Treated Population) *W48 change from baseline for Total, HDL cholesterol and Triglycerides were not significantly different between arms. **Wilcoxon signed rank test, Significant when p < 0.05

  14. Su b c u t a n e o u s A bd o m i n a l F a t (S A T ) V i s c e r a l A bd o m i n a l F a t (V A T ) T D F + 3 T C + E F V T D F + EF V A l l P opul a ti o n T D F + 3 T C + E F V T D F + EF V A l l P opul a ti o n 2 5 0 1 5 0 2 0 0 1 2 0 9 0 1 5 0 A l l popul at io n * A l l popul at io n * - 1 . 5 c m + 9 . 0 c m 2 2 1 0 0 6 0 p = 0 . 84* * p = 0 . 017* * 5 0 3 0 0 0 B a s e lin e W 4 8 B a s e lin e W 4 8 V A T / SA T R a ti o T o ta l A bd o m i n a l F a t (T A T ) [( V A T + SA T ) ] T D F + 3 T C + E F V T D F + EF V A l l P opul a ti o n T D F + 3 T C + E F V T D F + EF V A l l P opul a ti o n 1 . 5 3 5 0 3 0 0 1 2 5 0 A l l popul at io n * A l l popul at io n * + 1 4 c m - 0 . 0 5 2 2 0 0 p = 0 . 10* * p = 0 . 06* * 0 . 5 1 5 0 1 0 0 0 B a s e lin e W 4 8 B a s e lin e W 4 8 L4 CT Scans: Visceral and Subcutaneous Abdominal Fat[Patients Subgroup of AT Population for Whom Baseline and W48 Data were Available (N = 79)] cm/2 cm/2 2 2 m m c c cm/2 2 o i t cm/2 m a c R *W48 change from baseline for VAT, SAT,TAT and VAT/SAT ratio were not significantly different between arms **Wilcoxon signed rank test, significant when p < 0.05

  15. Conclusions • TDF + 3TC + EFV demonstrates an optimal success rate (97%) as a maintenance regimen when compared to TDF + EFV (82%) • TDF + EFV demonstrated lower efficacy due to: • Virological Failure: 4% • Study Drug Discontinuation: 14% • Switching to a QD tenofovir based regimen can significantly improve lipid profile even when lipids are within the median normal range at baseline • Other improvements in biological parameters were observed following a switch from BID HAART to QD TDF-based HAART • No glomerular filtration rate decrease or hypophosphatemia was observed

  16. Acknowledgements • French COOL Investigators and Experts • Dr BENTATA, Hôpital Avicennes, Bobigny; Pr BESNIER, CHU Tours; Dr CABIÉ, Hôpital Paul Zobda Quitman, Fort de France; Pr CHÊNE, Inserm U593, Bordeaux; Pr DELFRAISSY, CHU Kremlin-Bicêtre; Dr DURANT, CHU de Nice; Pr GALLAIS, Hôpital La Conception, Marseille; Pr GIRARD, CHU Saint-Antoine, Paris; Pr HOEN, Hôpital Saint Jacques, Besançon; Pr KATLAMA, CHU Pitié-Salpêtrière; Dr LIVROZET, Hôpital Edouard Herriot, Lyon; Pr MAY, CHU de Nancy; Pr MERCIÉ, CHU de Bordeaux; Pr MICHELET, CHU de Rennes; Dr MORAND-JOUBERT, CHU Saint-Antoine, Paris; Dr PARTISANI, Hôpital Civil de Strasbourg; Pr PELLEGRIN, Hôpital Haut-Lévêque, Pessac; Dr PRAZUCK, CHR d’Orléans; Pr ROZENBAUM, Hôpital Tenon Paris; Pr SALMON, Hôpital Cochin, Paris; Pr SERENI, Hôpital Saint-Louis, Paris; Dr SIMON, Hôpital Pitié-Salpêtrière, Paris; Dr STRADY, Hôpital de Reims; Pr VERDON, CHU de Caen; Pr VITTECOQ, Hôpital Paul Brousse, Villejuif; Pr WEISS, Hôpital Européen Georges Pompidou, Paris; Dr ZUCMAN, Hôpital Foch, Suresnes • Gilead Sciences, Inc. • Dr C. AUBRON-OLIVIER, A. FIREK; N. FORGET; Dr F. MONCHECOURT. • Study Sites Personnel and Patients

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