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

1
Tenofovir DF Efavirenz (TDFEFV) vs Tenofovir
DF Efavirenz Lamivudine (TDFEFV3TC)
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,6 L 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 TDF3TCEFV vs TDFEFV

3
Objectives

• Primary objective Evaluation of the efficacy of
  TDF3TCEFV versus TDFEFV QD to maintain plasma
  HIV-1 RNA BLQ (lt 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 lt 50 c/mL 6 months
• No HAART failure history
• Weight gt 45 kg
• No CD4 cell count criteria
• No significant laboratory or clinical
  abnormalities
• Creatinine Clearance gt 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 (lt
  50 c/mL) without study drug modification at W48
• Non inferiority limit14
• 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
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Baseline Characteristics of the ITT Population
TDF 3TC EFV n 72 TDF EFV n 71 TDF EFV n 71 All N 143
Demographics Demographics Demographics Demographics Demographics
Median Age (years) range 42 22 to 73 42 22 to 73 39.5 22 to 70 40 22 to 73
Mean Weight (kg) SD 68 12 68 12 70 10 69 11
Female () 29 29 27 28
HIV Infection HIV Infection HIV Infection HIV Infection HIV Infection
CDC stage C in 35 35 35 35
Median CD4 (cells/mm3) range 497.5 78 to 1775 410 104 to 1332 410 104 to 1332 473 78 to 1775
Median HIV RNA (c/mL) range 50 20 to 88 50 20 to 4700 50 20 to 4700 50 20 to 4700
HAART history prior to switch HAART history prior to switch HAART history prior to switch HAART history prior to switch HAART history prior to switch
Median Duration (years) range 3.6 0.5 to 7.5 3.7 1.0 to 7.7 3.7 1.0 to 7.7 3.7 0.5 to 7.7
HAART types before randomisation () 2 NRTI 1 NNRTI 2 NRTI 1 PI Others 39 49 12 48 42 10 48 42 10 43.5 45.5 11
3TC / ZDV as part of the Combination () 69 73 73 71
7
of Patients with Viral Load lt 50 c/mL (ITT /
AT Populations)
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a. Upper bound of 95 CI
8
Main Reasons for Failure at W48 (ITT Population)
TDF 3TC EFV N 72 TDF EFV N 71
HIV-1 RNA gt 50 c/mL HIV-1 RNA gt 50 c/mL HIV-1 RNA gt 50 c/mL
of patients (N) Patients with emergent NNRTIs Mutations 0 (0) 4.2 (3)
of patients (N) Patients with emergent NNRTIs Mutations 0 100
Study Drug Regimen Discontinuationa Study Drug Regimen Discontinuationa Study Drug Regimen Discontinuationa
of patients (N) 2.7 (2) 14.0 (10)
AE/SAE (N) Unrelated to Study Drugs Related to Study Drugs
AE/SAE (N) Unrelated to Study Drugs Related to Study Drugs - 1.4 (1)b
AE/SAE (N) Unrelated to Study Drugs Related to Study Drugs - 4.2 (3)c
lost to follow-up / Patient request (N) 2.7 (2) 8.4 (6)
a. Except study drug discontinuation of patients
with HIV-1 RNA gt 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
Patient ID Time to Emergence (Weeks) Viral Load (c/mL) Major RT Mutation(s) Emergence from Baseline Major RT Mutation(s) Emergence from Baseline Major RT Mutation(s) Emergence from Baseline
Patient ID Time to Emergence (Weeks) Viral Load (c/mL) NRTIs NNRTIs PIs
TDF EFV (N 3)
009-007 W 24 1490 - Y188L -
015-011 W 25 257,720 - K101E K103Ra G190A -
016-005 W 48 1600 - G190E -

TDF 3TC EFV (N 0) - - - - -
a. Pre-existing at baseline
10
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 lt 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 gt 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
Baseline W48 Change from Baseline W48 Change from Baseline W48 Change from Baseline W48 Change from Baseline W48 Change from Baseline
Both Arms TDF 3TC EFV TDF EFV pa Both Arms pb
CD4 Median IQR (cells/mm3) N 137 N 71 N 66 N 137
CD4 Median IQR (cells/mm3) 473 345 663 35 -62 101 14 -59 96 p 0.94 24 -59 96 p 0.007
Hemogoblin Median IQR (g/dl) N 139 N 71 N 68 N 139
Hemogoblin Median IQR (g/dl) 13.6 12.70 14.40 0.80 0.10 1.30 0.45 -0.05 0.90 p 0.14 0.60 0.00 1.30 p lt 0.001
Lactatemia Median IQR(ml/min) N 111 N 59 N 52 N 111
Lactatemia Median IQR(ml/min) 1.49 1.02 2.00 -0.2 -0.60 0.20 -0.05 -0.43 0.28 p 0.32 -0.14 -0.5 0.24 p 0.006
Creatinine Clearancec Median IQR (ml/min) N 130 N 68 N 62 N 130
Creatinine Clearancec Median IQR (ml/min) 100.8 86.9 115.9 -3.3 -11.3 4.5 1.7 -11.3 12.2 p 0.17 -1.3 -11.2 8.2 p 0.31
Phosphatemia Median IQR (mmol/l) N 109 N 57 N 52 N 109
Phosphatemia Median IQR (mmol/l) 1.10 0.84 1.10 0.03 -0.14 0.13 -0.02 -0.14 0.14 p 0.70 0.00 -0.14 0.14 p 0.97
a. Wilcoxon test (TDF 3TC EFV vs TDF EFV)
significant for p lt 0.05 b. Wilcoxon Rank-Sum
test on overall TDF switched population (Baseline
vs W48) significant for p lt 0.05 c. According
to the Cockcroft-Gault equation
13
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 lt 0.05
14
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
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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 lt 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 dOrléans 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