-0.2

-0.1

0

0.1

0.2

0 48 96

TDF-FTC ABC-3TC

ABC-3TC N=176 165 168TDF-FTC N=176 167 172

P<0.0001 P<0.0001

Right hip t-score

ABC-3TC N=175 162 158TDF-FTC N=174 168 164

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0 24 48 72

TDF-FTC ABC-3TC

P=0.025

Ch

ang

e

Figure 2: Total:HDL cholesterol

96

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

A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIALA RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIALDavid A CooperDavid A Cooper11, Mark Bloch, Mark Bloch22, Allison Humphries, Allison Humphries11, Janaki Amin, Janaki Amin11, David Baker, David Baker33, Sean Em, Sean Emeryery11, Andrew Carr, Andrew Carr44** on behalf of the STEAL study group on behalf of the STEAL study group

11National Centre in National Centre in HIV Epidemiology and Clinical Research, UniversityHIV Epidemiology and Clinical Research, University of New South Wales; of New South Wales; 22Holdsworth House Medical Practice; Holdsworth House Medical Practice; 33East Sydney DoctorsEast Sydney Doctors; ; 44St Vincent’s Hospital, Sydney, NSW, AustraliaSt Vincent’s Hospital, Sydney, NSW, Australia

Conclusion

Methods

Introduction Results

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 AsherSTEAL 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 YeungSTEAL DSMB members – Dr Alan Winston, Prof Steve Wesselingh, Dr Deborah Black STEAL Independent SNAE Reviewer – Dr Gail MatthewsWe extend our grateful thanks to all the participants and the Victorian Red Cross Blood Bank for HLA-B*5701 testingNCHECR is funded by the Australian Government Department of Health & Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales.

• 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.

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

• 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.

Acknowledgements

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/TDF-FTC (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 t-score -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.

FACULTY OF MEDICINETHE UNIVERSITY OF NEW SOUTH WALESLevel 2, 376 Victoria StDarlinghurst NSW, 2010 AustraliaTelephone: +61 (2) 8382 3707Facsimile : +61 (2) 8382 2090Email: acarr@stvincents.com.auwww.med.unsw.edu.au/nchecr

Poster 576Poster 576

Table 1: Baseline participant characteristics

HCV +ve

25 ± 425 ± 3BMI (kg/m2)

8686White ethnicity (%)

9798Male (%)

44 ± 846 ± 9 Age (years)

TDF-FTCABC-3TCDemographics

599 ± 257627 ± 306CD4+ count (cells/mm3)

10 ± 610 ± 6HIV duration (years)

1617Prior AIDS (%)

8988MSM transmission (%)

HIV History

2940Current smoker (%)

01Ischaemic stroke (%)

24Ischaemic heart disease (%)

1113Hypertension (%)

Non-HIV History

7 ± 58 ± 7Framingham CVD risk (%)

35Diabetes mellitus (%)

2324Protease Inhibitor (%)

3030TDF (%)

2120 ABC (%)

Antiretroviral Therapy

Table 3: Serious non-AIDS events (SNAEs)  ABC-3TC TDF-FTC Hazard ratio

(TDF/ABC)95%CI P

  n Rate n Rate

Total 14 4.4 4 1.2 0.26 0.08, 0.79 0.018*Cardiovascular disease 8 2.2 1 0.3 0.13 0.02, 0.98 0.046

Cancer 5 2

Major fracture 0 1

Cirrhosis 1 0

Deaths (all cancer) 3 1

End-stage renal disease 0 0

Ch

ang

e

-0.20

-0.10

0.00

0.10

0.20

0 48 96

TDF-FTC ABC-3TC

Spine t-score

P=0.002 P=0.023

N=175 164 167N=176 167 172

Changes in Bone Mineral Density

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

Table 2: Virological failures through week 96Analysis Treatment n % Difference (%) 95% CI PITT missing equal failure ABC-3TC 10 5.6 1.7 -2.8, 6.1 0.62

TDF-FTC 7 3.9

ITT non-completer equal failure ABC-3TC 23 12.8 3.3 -3.3, 9.9 0.40TDF-FTC 17 9.6

Available data ABC-3TC 3 1.7 0 -2.7, 2.7 1.00TDF-FTC 3 1.7

On-treatment ABC-3TC 2 1.1 0 -2.2, 2.2 1.00TDF-FTC 2 1.1

Table 4: Categorical secondary endpointsEndpoint n ABC-3TC

Rate/100 pt years (95% CI)

n TDF-FTCRate/100 pt years

(95% CI)

Hazard Ratio P

Lipid (new cholesterol >6.5 or increase >2mmol/L; new HDL<0.9 or decrease>0.5mmol/L; or new therapy)

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; phosphate<0.65mmol/L)

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 therapy)

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; new BMD therapy)

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

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

0

1

2

3

4

5

6

7

8

9

Qtr1/06 Qtr2/06 Qtr3/06 Qtr4/06 Qtr1/07 Qtr2/07 Qtr3/07 Qtr4/07 Qtr1/08 Qtr2/08

Nu

mb

er o

f p

arti

cip

ants

ABC/3TC

TDF/FTC

P=0.98

STEAL Protocol Steering Committee – Janaki Amin, David Baker, Mark Bloch, Andrew Carr, David Cooper, Sean Emery, Allison HumphriesSTEAL 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.

Assessed for eligibility

441

Randomized 360

Not randomized 81Ineligible70* 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 1Eligible 11 patient choice 9 physician choice 1 exceeded screening period 1

Allocated ABC-3TC 180Participant withdrew 1

Allocated TDF-FTC 180Participant withdrew 2

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 178Ceased TDF-FTC 19 adverse event 8 lost to follow-up 2 patient choice 3 died 1 virological failure 1 other 4

Analysed 179 Analysed 178

P=ns