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SIMPLIFICATION WITH FI XED-DOSE TENOFOVIR-EMTRICITAINE OR ABACAVIR-LAMIVUDINE IN ADULTS WITH SUPPRESSED HIV REPLICATION (THE STEAL STUDY): A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIAL. P=0.98. Poster 576. FACULTY OF MEDICINE THE UNIVERSITY OF NEW SOUTH WALES

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SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITAINE OR ABACAVIR-LAMIVUDINE IN ADULTS WITH SUPPRESSED HIV REPLICATION (THE STEAL STUDY):

A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIAL

P=0.98

Poster 576

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: acarr@stvincents.com.au

www.med.unsw.edu.au/nchecr

David A Cooper1, Mark Bloch2, Allison Humphries1, Janaki Amin1, David Baker3, Sean Emery1, Andrew Carr4* on behalf of the STEAL study group

1National 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

Introduction

Results

  • 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.

Assessed for eligibility

441

Not randomized 81

Ineligible 70*

HLA-B*5701-positive 26

HIV RNA >50 copies/ml plasma 19

eGFR <70 ml/min/kg 17

medical contra-indication 8

antiretroviral contra-indication 2

creatinine clearance <50 ml/min 1

prior abacavir hypersensitivity 1

unboosted atazanavir 1

Eligible 11

patient choice 9

physician choice 1

exceeded screening period 1

Figure 2: Total:HDL cholesterol

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

P=0.025

P=ns

Change

Randomized 360

Methods

96

Allocated ABC-3TC 180

Participant withdrew 1

ABC-3TC N=175 162 158

TDF-FTC N=174 168 164

Allocated TDF-FTC 180

Participant withdrew 2

  • 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 weeksbody 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 two-tailed 95% confidence interval of 15% around a 0% difference between treatment arms in virological failure rates.

Changes in Bone Mineral Density

Received ABC 179

Ceased ABC-3TC 25

adverse event 12

lost to follow-up 4

patient choice 3

died 3

cardiac risk 1

other 2

Received TDF-FTC 178

Ceased TDF-FTC 19

adverse event 8

lost to follow-up 2

patient choice 3

died 1

virological failure 1

other 4

Right hip t-score

Spine t-score

P<0.0001

P<0.0001

P=0.002

P=0.023

Change

Analysed 179

Analysed 178

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

Table 1: Baseline participant characteristics

ABC-3TC

Demographics

TDF-FTC

46 ± 9

Age (years)

44 ± 8

N=175 164 167

N=176 167 172

ABC-3TC N=176 165 168

TDF-FTC N=176 167 172

98

Male (%)

97

86

White ethnicity (%)

86

25 ± 3

BMI (kg/m2)

25 ± 4

Conclusion

HIV History

88

MSM transmission (%)

89

17

Prior AIDS (%)

16

10 ± 6

HIV duration (years)

10 ± 6

  • 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.

627 ± 306

CD4+ count (cells/mm3)

599 ± 257

Non-HIV History

13

Hypertension (%)

11

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, 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.

Acknowledgements

40

Current smoker (%)

29

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, 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

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.

8 ± 7

Framingham CVD risk (%)

7 ± 5

Antiretroviral Therapy

20

ABC (%)

21

30

TDF (%)

30

HCV +ve

24

Protease Inhibitor (%)

23