Poster 576 SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITAINE OR ABACAVIRLAMIVUDINE

Poster 576 SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITAINE OR ABACAVIRLAMIVUDINE

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

National Centre in HIV Epidemiology and Clinical Research, University of New South Wales; 2Holdsworth House Medical Practice; 3East Sydney Doctors; 4St Vincents Hospital, Sydney, NSW, Australia

1

Assessed for
eligibility
441

Not randomized
Ineligible
70*
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 26 19 17 8 2 1 1 1 Eligible Randomized 360 Allocated ABC-3TC Participant withdrew 11 patient choice physician choice exceeded screening period 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.

81

180
1

9
1
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

ABC-3TC

TDF-FTC

46 9

44 8

Male (%)

98

97

White ethnicity (%)

86

86

25 3

25 4

Age (years)

BMI (kg/m2)
MSM transmission (%)

88

89

Prior AIDS (%)

17

16

10 6

10 6

627 306

599 257

CD4+ count (cells/mm3)

%
5.6
3.9
12.8
9.6
1.7
1.7
1.1
1.1

Difference (%)
1.7
3.3
0

95% CI
-2.8, 6.1
-3.3, 9.9
-2.7, 2.7

P
0.62

Endpoint

n

11

Ischaemic heart disease (%)

4

2

Ischaemic stroke (%)

1

0

Current smoker (%)

40

29

Diabetes mellitus (%)

5

3

Framingham CVD risk (%)

87

75

TDF-FTC
n
Rate
4
1.2
1
0.3
2
1
0
1
0

20

21

TDF (%)

30

30

Protease Inhibitor (%)

24

23

8

0.1

0.40
1.00

P=0.025

-2.2, 2.2

1.00

-0.1
TDF-FTC

95%CI

P

0.26
0.13

0.08, 0.79
0.02, 0.98

0.018*
0.046

Hazard Ratio

P

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

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 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 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 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

phosphate<0.65mmol/L) therapy) Rate/100 pt years (95% CI) Rate/100 pt years (95% CI) P=0.98 7 6 5 ABC/3TC TDF/FTC 4 3 2 1 0 Qtr1/06 Qtr2/06 Qtr3/06 Qtr4/06 Qtr1/07 Qtr2/07 Qtr3/07 Qtr4/07 Qtr1/08 Qtr2/08 24 48 72 162 168 96 158 164 Changes in Bone Mineral Density Right hip t-score 0.2 P<0.0001 0.1 TDF-FTC ABC-3TC -0.3 0 Hazard ratio (TDF/ABC) P=ns 0 Spine t-score 0.20 P<0.0001 0.10 0 0.00 -0.1 -0.10 -0.2 -0.20 48 TDF-FTC n >2mmol/L; new HDL<0.9 or decrease>0.5mmol/L; or new therapy)

ABC-3TC N=176
TDF-FTC N=176

165
167

96

0

ABC-3TC

P=0.002

P=0.023

48

96

TDF-FTC
168
172

N=175
N=176

164
167

ABC-3TC
167
172

Conclusion
In this population, TDF-FTC and ABC-3TC had similar virological efficacy.
However, ABC-3TC was associated with more SNAEs (particularly
cardiovascular disease) and lipid endpoints, and TDF-FTC caused more
BMD loss.

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, 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.

Acknowledgeme
nts
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,

Antiretroviral Therapy
ABC (%)

9

ABC-3TC N=175
TDF-FTC N=174

ABC-3TC

new BMD therapy)
13

0.2

-0.2

0

Figure 3: Calendar period at
commencement of lipid-lowering therapy

0.3

Table 4: Categorical secondary endpoints

Non-HIV History
Hypertension (%)

Figure 2: Total:HDL cholesterol

0

HIV History

HIV duration (years)

Table 3: Serious non-AIDS events (SNAEs)
ABC-3TC
n
Rate
Total
14
4.4
Cardiovascular disease
8
2.2
Cancer
5
Major fracture
0
Cirrhosis
1
Deaths (all cancer)
3
End-stage renal disease
0

n
10
7
23
17
3
3
2
2

* This association remained significant when adjusted for baseline smoking or time on randomized ART

Table 1: Baseline participant characteristics
Demographics

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

Number of participants

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

Change

Introduction

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.

HCV

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
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
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
+ve
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.

Recently Viewed Presentations

  • ROBOTC for IFI - FIRST

    ROBOTC for IFI - FIRST

    RobotC Programming for LEGO Mindstorms NXT SOURCES: Carnegie Mellon Dacta Lego Timothy Friez Miha Štajdohar [email protected] Loading Firmware Robots require "Operating Systems" to run properly ROBOTC has it's own Operating System, called Firmware.
  • Due Diligence: Failures and Remedies

    Due Diligence: Failures and Remedies

    The Nonprime Mortgage Crisis and Positive Feedback Lending Bernard Black Northwestern (Law School and Kellogg, Finance Dep't) Bar Ilan (December 2012)
  • Slide 27

    Slide 27

    If a pill is more than 3 hours late, a backup method of contraception should be used for at least the next 48 hours. Inform women about emergency contraception. ... Bracken MB. Oral contraception and congenital malformations in offspring: a...
  • Internet2 IPv6 Workshop

    Internet2 IPv6 Workshop

    Will set the wheels in motion If you connect to a gigaPoP you should obtain your address block from that gigaPoP— talk to them first. Remember the minimum you should receive is a /48. More is OK if you can...
  • Begley School Vision

    Begley School Vision

    In keeping with the Provincial Code of Conduct, the Greater Essex County District School Board Code of Conduct, Begley Public School adopts as a framework the following guiding principles of the Code: 1. To ensure that all members of the...
  • Session 8 Exchange Rates Disclaimer: The views expressed

    Session 8 Exchange Rates Disclaimer: The views expressed

    Quantity of Dollars Traded. S. 1 D. 1 1. D. 2 2. 1. 2. Increasing demand for dollars. Leads to a rising price (value) A stronger U.S. dollar means … U.S. can buy foreign goods more cheaply and U.S. imports...
  • The Value of Disease Management: Stakeholder Perspectives

    The Value of Disease Management: Stakeholder Perspectives

    "Rules of the Game" model Disease management Case management for high risk participants "Skin in the game" model Tiered co-pays Coinsurance High Deductible Health Plans Tiered networks: hospitals, specialists, PCPs Consumer Directed Plans "Brain in the game" model Healthy lifestyles...
  • Promoting physical activity

    Promoting physical activity

    Active living programs. Search online for some examples of school, community and workplace physical activity intervention programs or initiatives designed to promote active living. Summarise your research. For each setting, answer the following. Provide at least 2 example programs