Download THE STEAL STUDY

Poster 576
SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITAINE OR ABACAVIRLAMIVUDINE IN ADULTS WITH SUPPRESSED HIV REPLICATION (THE STEAL STUDY):
A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIAL
David A Cooper1, Mark Bloch2, Allison Humphries1, Janaki Amin1, David Baker3, Sean Emery1, Andrew Carr4* on behalf of the STEAL study group
FACULTY OF MEDICINE
THE UNIVERSITY OF NEW SOUTH
WALES
Level 2, 376 Victoria St
Darlinghurst NSW, 2010 Australia
Telephone: +61 (2) 8382 3707
Facsimile : +61 (2) 8382 2090
Email: [email protected]
www.med.unsw.edu.au/nchecr
Centre in HIV Epidemiology and Clinical Research, University of New South Wales; 2Holdsworth House Medical Practice; 3East Sydney Doctors; 4St Vincent’s Hospital, Sydney, NSW, Australia
• Two once-daily, dual nucleoside analogue, reverse transcriptase
inhibitor (NRTI), fixed-dose-combination (FDC) tablets available:
* tenofovir 300mg-emtricitabine 200mg (TDF-FTC)
* abacavir 600mg-lamivudine 300mg (ABC-3TC)
• Which FDC is more effective and safe is uncertain.
• We hypothesized that switching to TDF-FTC would be virologically
non-inferior to ABC-3TC over 96 weeks in HIV-infected adults with
sustained suppression of HIV replication, but that TDF-FTC and
ABC-3TC would have different safety profiles.
Results
Assessed for eligibility
441
Not randomized
Ineligible
HLA-B*5701-positive
HIV RNA >50 copies/ml plasma
eGFR <70 ml/min/kg
medical contra-indication
antiretroviral contra-indication
creatinine clearance <50 ml/min
prior abacavir hypersensitivity
unboosted atazanavir
Eligible
Randomized
patient choice
physician choice
exceeded screening period
360
81
70*
26
19
17
8
2
1
1
1
11
9
1
1
Methods
• Eligible participants randomly allocated 1:1 to continue their
current NNRTI and/or PI and switch their NRTIs to either TDF-FTC
or ABC-3TC.
• Key eligibility criteria:
* Age ≥ 18 years
* on stable 2NRTI + NNRTI or PI ART ≥ 12 weeks
* HIV RNA <50 copies/mL plasma ≥12 weeks
* glomerular filtration rate (GFR) ≥ 70mL/min/1.73m2
* creatinine clearance ≥ 50 mL/min
* HLA-B*5701 negative (unless already on ABC)
* no prior hypersensitivity, intolerance or failure to study drugs
* no prior exposure to either study FDC drugs
* not on un-boosted atazanavir
* no previous non-traumatic fracture
• Study visits at 0, 4, 12, 24, 36, 48, 60, 72, 84 and 96 weeks.
• At each visit adverse events, concomitant medications,
adherence, weight, biochemistry and HIV viral load were assessed;
every 12 weeks blood count, liver function tests and CD4 count
performed and blood stored; every 24 weeks quality of life (SF-8)
and fasting metabolic measures conducted; every 48 weeks body
composition measured by dual-energy x-ray absorptiometry
• Primary endpoint was virological failure, defined by repeat viral
load >400 copies/mL by intention-to-treat, missing=failure (ITTM=F)
analysis. Secondary endpoints (ITT) included death, AIDS, serious
non-AIDS events, metabolic parameters and body composition
(bone/soft-tissue; ITT-LOCF).
• Exact statistics were used for differences in proportions, T-tests to
compare means and Cox regression for hazard ratios. A sample of
175 participants per group yielded a 90% probability to detect a twotailed 95% confidence interval of 15% around a 0% difference
between treatment arms in virological failure rates.
Allocated ABC-3TC
Participant withdrew
180
1
Allocated TDF-FTC
Participant withdrew
180
2
Received ABC
Ceased ABC-3TC
adverse event
lost to follow-up
patient choice
died
cardiac risk
other
179
25
12
4
3
3
1
2
Received TDF-FTC
Ceased TDF-FTC
adverse event
lost to follow-up
patient choice
died
virological failure
other
178
19
8
2
3
1
1
4
Analysed
179
Analysed
178
Table 2: Virological failures through week 96
Analysis
Treatment
ITT missing equal failure
ABC-3TC
TDF-FTC
ITT non-completer equal failure
ABC-3TC
TDF-FTC
Available data
ABC-3TC
TDF-FTC
On-treatment
ABC-3TC
TDF-FTC
Figure 2: Total:HDL cholesterol
n
10
7
23
17
3
3
2
2
%
5.6
3.9
12.8
9.6
1.7
1.7
1.1
1.1
3.3
0
95% CI
-2.8, 6.1
-3.3, 9.9
-2.7, 2.7
P
0.62
0.3
0.2
9
8
0.1
0.40
P=0.025
-0.1
1.00
-0.2
0
-2.2, 2.2
TDF-FTC
n
Rate
4
1.2
1.00
TDF-FTC
Cardiovascular disease
8
1
Cancer
Major fracture
Cirrhosis
Deaths (all cancer)
End-stage renal disease
5
0
1
3
0
0.3
95%CI
P
0.26
0.08, 0.79
0.018*
0.13
0.02, 0.98
0.046
2
1
0
1
0
* This association remained significant when adjusted for baseline smoking or time on randomized ART
ABC-3TC
P=0.98
7
6
5
ABC/3TC
TDF/FTC
4
3
2
1
0
-0.3
Qtr1/06 Qtr2/06 Qtr3/06 Qtr4/06 Qtr1/07 Qtr2/07 Qtr3/07 Qtr4/07 Qtr1/08 Qtr2/08
0
Hazard ratio
(TDF/ABC)
P=ns
0
ABC-3TC N=175
TDF-FTC N=174
Table 3: Serious non-AIDS events (SNAEs)
ABC-3TC
n
Rate
Total
14
4.4
2.2
Difference (%)
1.7
Figure 3: Calendar period at
commencement of lipid-lowering therapy
Number of participants
Introduction
Change
1National
24
48
72
162
168
96
158
164
Changes in Bone Mineral Density
0.2
Right hip t-score
P<0.0001
0.20
P<0.0001
0.1
0.10
0
0.00
-0.1
-0.10
-0.2
-0.20
Change
Background:
Two once-daily, dual-nucleoside, fixed-dose-combination (FDC)
tablets are used for adult HIV-1 infection: tenofovir 300mg+emtricitabine 200mg
(TDF-FTC); and abacavir 600mg+lamivudine 300mg (ABC-3TC). Which FDC is
more effective and safe is uncertain.
Methods: We compared TDF-FTC and ABC-3TC-based therapy over 96 weeks
when either FDC was substituted for current NRTIs in HLA-B*5701-negative adults
with plasma HIV viral load <50 copies/mL. The primary endpoint was virological
failure, defined by repeat viral load >400 copies/mL plasma by intention-to-treat,
missing=failure (ITTM=F) analysis. Secondary endpoints (ITT) included death, AIDS,
serious non-AIDS events (see table), metabolic parameters and body composition
(bone/soft-tissue; ITT-LOCF). We used exact statistics for differences in proportions,
T-tests to compare means and Cox regression for hazard ratios for ABC-3TC/TDFFTC (HR 95%CI).
Results: 360 patients were randomized from January to August 2006. Key baseline
characteristics of the 357 treated participants were: male 98%, mean age 45.1 years,
prior NRTI therapy 5.8 years, current TDF 30%, current ABC 20%, current PI 24%,
mean CD4 count 612 cells/mm3, eGFR 98 mL/min/1.73m2, limb fat 5.5kg, and hip tscore -0.49. Groups were well balanced, except smoking was more prevalent with
ABC-3TC (40%) than with TDF-FTC (29%). 1.7% were lost to follow-up with no
between-group difference. No patient developed AIDS or renal failure. TDF-FTC was
associated with more bone loss. There was no significant between-group, week-96
difference for limb fat, eGFR, CD4 count, insulin sensitivity, total:HDL cholesterol
ratio, or lactate.
Conclusions: In this population, TDF-FTC and ABC-3TC had similar virological
efficacy and protection against AIDS. ABC-3TC was associated with more serious
non-AIDS events.
Spine t-score
P=0.002
P=0.023
Table 1: Baseline participant characteristics
0
48
96
0
48
96
ABC-3TC
Demographics
TDF-FTC
Table 4: Categorical secondary endpoints
TDF-FTC
ABC-3TC
TDF-FTC
ABC-3TC
46 ± 9
44 ± 8
Age (years)
Endpoint
n
ABC-3TC
n
TDF-FTC
Hazard Ratio
P
N=175
164
167
ABC-3TC N=176
165
168
98
Male (%)
97
Rate/100 pt years
Rate/100 pt years
N=176
167
172
TDF-FTC N=176
167
172
(95% CI)
(95% CI)
86
White ethnicity (%)
86
Lipid (new cholesterol >6.5 or increase
40 13.9 (10.2, 19.0) 19
6.1 (3.9, 9.5)
0.4 (0.3, 0.8)
0.003
25 ± 3
25 ± 4
BMI (kg/m2)
>2mmol/L; new HDL<0.9 or
HIV History
decrease>0.5mmol/L; or new therapy)
Conclusion
88
MSM transmission (%)
89
Renal (eGFR<60ml/min.1.73m2;
5
1.6 (0.7, 3.7)
3
0.9 (0.3, 2.8)
0.6 (0.1, 2.5)
0.48
phosphate<0.65mmol/L)
17
Prior AIDS (%)
16
Glycaemic (new diabetes or diabetic
2
0.6 (0.2, 2.5)
2
0.6 (0.2, 2.4)
1.0 (0.1, 7.1)
1.00
10 ± 6
10 ± 6
HIV duration (years)
• In this population, TDF-FTC and ABC-3TC had similar virological efficacy.
therapy)
627 ± 306
599 ± 257
CD4+ count (cells/mm3)
• However, ABC-3TC was associated with more SNAEs (particularly
Bone (osteopenia or osteoporosis; fracture;
14
4.4 (2.6, 7.4)
27
8.5 (5.9, 12.5)
-7.3 (-14.0, 0.7) 0.032
Non-HIV History
new BMD therapy)
cardiovascular disease) and lipid endpoints, and TDF-FTC caused more
13
Hypertension (%)
11
Hepatic (lactate>5mmol/L; ALT>5 x ULN)
2
0.6 (0.2, 2.5)
2
0.6 (0.2, 2.5)
1.0 (0.1, 7.0)
0.98
BMD loss.
4
Ischaemic heart disease (%)
2
1
Ischaemic stroke (%)
0
STEAL Protocol Steering Committee – Janaki Amin, David Baker, Mark Bloch, Andrew Carr, David Cooper, Sean Emery, Allison Humphries
STEAL study investigators – Mark Bloch, David Cooper, Andrew Carr, David Baker, Robert Finlayson, Jennifer Hoy, Tim Read, Nicholas Doong, Norman Roth, Jonathan Anderson, Richard Moore, John Chuah, Alan Street, David Shaw, David Orth,
40
Current smoker (%)
29
Acknowledgements
Mark Kelly, David Smith, David Nolan, Mark Boyd, David Gordon, Nicholas Medland, Ban Kiem Tee, Dominic Dwyer, John Dyer, Ian Woolley, Michelle Giles, Stephen Davies, Linda Dayan, William Donohue, Darren Russell, Jeffrey Post, John Quinn,
Don Smith, Anthony Allworth.
5
Diabetes mellitus (%)
3
STEAL study coordinators – Shikha Agrawal, Kate Beileiter, Karen Macrae, Richard Norris, Robert Fielden, Robyn Vale, Robyn Richardson, Sophie Dinning, Isabel Prone, Christine Alveras, Rachel Liddle, Julie Silvers, Helen Kent, Jeff Hudson, Helen Lau, Kaye Lowe, Paul Cortissos, Sian Edwards,
Framingham CVD risk (%)
8±7
7±5
Denise Lester, Tammy Schmidt, Fiona Clark, Janine Roney, Lyndal Daly, David Youds, Paul Negus, Peita-Lee Ambrose, Denni Pearson, Cherie Mincham, Claire Forsdyke, Robyn Gilligan, Michelle Wall, Rachel Wundke, Maggie Piper, Jacqueline Kerth, Samantha Libertino, Pauline Galt, James Baber,
Victoria Hounsfield, Michael Curry, Joy Oddy, Christine Remington, Laura Foy, Debra Hayhoe, Bernie Monaghan, Nicky Cunningham, Suzanne Ryan, Helen Best, Catherine Magill, Jason Gao, Jega Sarangapany, Janelle Zillman, Anne Sleat, Holly Asher
Antiretroviral Therapy
STEAL study team – Sean Emery, Allison Humphries, Janaki Amin, Wilma Goodyear, Kymme Courtney-Vega, Simone Jacoby, Hila Haskelberg, Cate Carey, Allie MacDonald, Lina Safro, Maja Berilazic, Aurelio Vulcao, David Courtney-Rodgers, Maria Arriaga, Tian Erho, Kat Marks, Kate Merlin, Julie Yeung
20
21
ABC (%)
STEAL DSMB members – Dr Alan Winston, Prof Steve Wesselingh, Dr Deborah Black
STEAL Independent SNAE Reviewer – Dr Gail Matthews
We extend our grateful thanks to all the participants and the Victorian Red Cross Blood Bank for HLA-B*5701 testing
30
TDF (%)
30
NCHECR is funded by the Australian Government Department of Health & Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales.
HCV +ve
24
Protease Inhibitor (%)
23