Comparison of INSTI vs PI - PowerPoint Presentation

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Comparison of INSTI vs PI - PPT Presentation

FLAMINGO GS2360103 ACTG A5257 WAVES Lennox JL Ann Intern Med 201416146171 ACTG A5257 Design Objective Evaluate regimen equivalence regarding virologic efficacy and tolerability over 96 weeks by intentiontotreat analysis Equivalence 2sided 975 CI on the ID: 759281

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Slide1

Comparison of INSTI vs PI

FLAMINGO

GS-236-0103

ACTG A5257

WAVES

Slide2

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

Design

Objective

Evaluate regimen equivalence regarding

virologic efficacy and tolerability over 96 weeks, by intention-to-treat analysis. Equivalence = 2-sided 97.5% CI on the pairwise difference in 96-week cumulative incidence of each individual or composite endpoint falling between - 10% and 10%, 90% power. If equivalence was not shown, superiority was defined as exclusion of 0 from the 97.5% CI

*Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) at screening, participation in cardiovascular sub-study, and 10-year Framingham risk score

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Randomisation*

1 : 1 : 1

Open label

N = 603

N = 605

W96

N = 601

18 years

ARV-naïve (< 10 days of ART)

HIV RNA

> 1,000 c/mLAny CD4 cell countNo resistance to NRTI or PI

ATV/r 300/100 mg QD + TDF/FTC

RAL 400 mg BID + TDF/FTC

DRV/r 800/100 mg QD + TDF/FTC

Slide3

EndpointsVirologic failure: confirmed HIV-1 RNA > 1,000 c/mL at or after W16, or > 200 c/mL at or after W24Tolerability failure: time from randomisation to discontinuation of the randomised regimen component for toxicity (substitution of TDF or FTC not considered as tolerability failure)Composite endpoint: virologic or tolerability failure, whichever occurred firstITT-TLOVR, with HIV-1 RNA threshold of 200 c/mLHIV-1 RNA < 50 c/mL at W96 by ITT, snapshotSensitivity analysis: as-treated (virologic failure including treatment discontinuation as a competing event)Key toxicity secondary endpoint: time from initiation of treatment to the first grade 2, 3, or 4 sign or symptom (grade 3 or 4 if after week 48) or any grade 3 or 4 laboratory abnormality while the patient was receiving the randomized treatment (as-treated)Prespecified sensitivity analysis excluded hyperbilirubinemia and elevated CK levelsFurther sensitivity analysis included all qualifying adverse events regardless of status on randomized treatment (ITT analysis)

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Slide4

ATV/r + TDF/FTCN = 605DRV/r + TDF/FTCN = 601RAL + TDF/FTCN = 603Median age, years373736Female24%24%25%HIV RNA (log10 c/mL), median4.604.614.66HIV RNA > 100,000 c/mL32%27.8%32%HIV RNA > 500,000 c/mL6.9%6.0%8.3%CD4 cell count (/mm3), mean309310304CD4 < 200 per mm328.9%29%31%Hepatitis B / hepatitis C coinfection2.5% / 7.8%3% / 7.5%2.7% / 8.1%Never started ART, N544Discontinuation by W968.1%9.1%7.1%Death10136Lost to follow-up293423

Baseline characteristics and patient disposition

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Slide5

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Cumulative incidence of

virologic

failure (primary end point)

Virologic failure (ITT)

Virologic failure (as-treated)

Equivalence of the 3 regimens

ATV/r

RAL

DRV/r

Cumulative probability of

virologic

failure by W96

ATV/r

12.6%

DRV/r 14.9%RAL 9.0%

112

128

144

0.00

0.25

0.50

0.75

1.00

-20

-10

ATV/r (12.6%) vs. RAL (9.0%)

3.4% (-0.7% to 7.4%)

DRV/r (14.9%) vs. RAL (9.0%)

5.6% (1.3% to 9.9%)

ATV/r (12.6%) vs. DRV/r (14.9%)

-2.2% (-6.7% to 2.3%)

Week

578

574

585

605

603

601

541

552

530

493

517

484

369

390

364

ATV/r

RAL

DRV/r

≠ (97.5% CI)

112

128

144

0.00

0.25

0.50

0.75

1.00

-20

-10

ATV/r (10.7%) vs. RAL (8.0%)

2.4% (-1.4% to 6.2%)

DRV/r (13.1%) vs. RAL (8.0%)

4.7% (0.7% to 8.7%)

ATV/r (10.7%) vs. DRV/r (13.1%)

-2.3% (-6.5% to 2.0%)

Week

536

574

559

605

603

601

494

545

520

427

511

470

317

387

358

ATV/r

RAL

DRV/r

≠ (97.5% CI)

Slide6

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Greater tolerability benefit of

RAL

vs ATV/r in patients with baseline HIV RNA < 100,000 c/mLRAL vs DRV/r in women

RAL equivalent to DRV/rRAL superior to ATV/rDRV/r superior to ATV/r

ATV/r

RAL

DRV/r

Cumulative incidence of

tolerability

failure

(

primary end point)

Favors

RAL

Favors

DRV/r

112

128

144

0.00

0.25

0.50

0.75

1.00

Week

548

585

576

605

603

601

522

562

553

467

534

517

349

411

392

ATV/r

RAL

DRV/r

-10

-20

ATV/r (13.9%) vs. RAL (0.9%)

12.7% (9.4% ; 16.1%)

DRV/r (4.7%) vs. RAL (0.9%)

3.6% (1.4% ; 5.8%)

ATV/r (13.9%) vs. DRV/r (4.7%)

9.2% (5.5% ; 12.9%)

≠ (97.5% CI)

Slide7

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ATV/r +

TDF/FTC

N = 605DRV/r +TDF/FTCN = 601RAL +TDF/FTCN = 603Any toxicity/discontinuations95 (15.7%)32 (5.3%)8 (1.3%)Jaundice or hyperbilirubinemia4700Nausea or other gastrointestinal toxicities25142Hepatic toxicity451Skin toxicity75 (1 Stevens-Johnson)2Metabolic toxicity620Renal toxicity400Abnormal chemistry/hematology findings020Other243

Discontinuations of

randomised

antiretroviral therapy for toxicity

Slide8

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ATV/r inferior to DRV/r and to RAL

DRV/r inferior to RAL

Cumulative incidence of

virologic or tolerability failure (preplanned composite failure)

112

128

144

0.00

0.25

0.50

0.75

1.00

Week

536

574

559

605

603

601

494

545

520

427

511

470

317

307

358

ATV/r

RAL

DRV/r

Participants in the

risk

set,

Favors

RAL

Favors

DRV/r

Favors

RAL

-20

-10

ATV/r (24.1%) vs. RAL (8.6%)

14.9% (10.2% ; 19.6%)

DRV/r (16.6%) vs. RAL (8.6%)

7.5% (3.2% ; 11.8%)

ATV/r (24.1%) vs. DRV/r (16.6%)

7.5% (2.3% ; 12.7%)

ATV/r

RAL

DRV/r

≠ (97.5% CI)

Slide9

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ATV/r

RAL

DRV/r

HIV-1 RNA

level

≤ 50 copies/

regardless

of ART change

(ITT analysis)

HIV-1 RNA level ≤ 50 copies/mL andreceiving randomized ART(ITT, snapshot analysis)

605

603

601

605

603

601

605

603

601

605

603

601

471

483

468

ATV/r

RAL

DRV/r

Participants

contributing

data,

0.0

1.0

0.8

0.6

0.4

0.2

120

144

Week

79.8%

72.7%

62.6%

120

144

0.0

1.0

563

566

564

605

603

601

553

555

542

515

526

518

394

410

387

ATV/r

RAL

DRV/r

Participants

contributing

data,

0.8

0.6

0.4

0.2

Week

93.9%

89.4%

88.3%

Slide10

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Genotypic analysis for resistance at

virologic

failure

ATV/r + TDF/FTCN = 605DRV/r + TDF/FTCN = 601RAL + TDF/FTCN = 603Virologic failure9511585Genotype available759965Any resistance detected9418PI resistance000NRTI-only resistance837 - FTC - TDF - FTC and TDF521300700INI-only resistance111NRTI and INI resistance0010 - FTC and RAL - FTC, TDF and RAL73

Patients may not have been on their randomised treatment at time of failure

Slide11

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Grade 2 or higher adverse events in ≥ 5% of participants in either group

ATV/r + TDF/FTC

N = 605

DRV/r + TDF/FTC

N = 601

RAL + TDF/FTC

N = 603

Grade, N

Total

Grade, N

Total

Grade, N

Total

Diarrhea

46 (7.6)

52 (8.6)

36 (6.0)

Nausea

45 (7.4)

41 (6.8)

33 (5.5)

Vomiting

30 (5.0)

32 (5.3)

24 (4.0)

Abdominal pain

31 (5.1)

29 (4.8)

17 (2.8)

Headache

35 (5.8)

44 (7.3)

42 (7.0)

Pain in extremity

42 (6.9)

32 (5.3)

45 (7.5)

Arthralgia

25 (4.1)

28 (4.7)

22 (3.6)

Back pain

18 (3.0)

21 (3.5)

31 (5.1)

Fatigue

39 (6.4)

33 (5.5)

31 (5.1)

Cough

42 (6.9)

36 (6.0)

40 (6.6)

Dyspepsia

26 (4.3)

23 (3.8)

28 (4.6)

Pyrexia

26 (4.3)

27 (4.5)

35 (5.8)

Hyperbilirubinemia

217

286 (47.3)

4 (< 1)

5 (< 1)

Hypophosphatemia

34 (5.6)

37 (6.2)

29 (4.8)

Hyperglycemia

26 (4.3)

27 (4.5)

26 (4.3)

Slide12

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

ACTG A5257 Study: (ATV/r

DRV/r vs RAL) + TDF/FTC

Other safety data

ATV/r +TDF/FTCN = 605DRV/r +TDF/FTCN = 601RAL +TDF/FTCN = 60396-week cumulative incidence of the 1st clinical or laboratory AEAny AE80.3%64.9%59.5%Excluding bilirubin and CK62.3%64.9%59.3%Fasting LDL-cholesterol increasep ≤ 0.001*p ≤ 0.001*-Fasting triglycerides increasep ≤ 0.001*p ≤ 0.001*-Grade 3-4 elevation in creatinineN = 7N = 12N = 4Substitution of TDF and/or FTCN = 20N = 23 N = 9

* vs RAL

Slide13

Ofotokun I, CID 2015;60:1842-51

Mean (95% CI) changes from baseline in fasting lipids, mg/dL

LDL-cholesterol

Triglycerides

HDL-cholesterol

ATV/r

RAL

DRV/r

ACTG A5257 Study: (ATV/r

DRV/r

RAL) + TDF/FTC

5,0

144

7,5

2,5

p>0.05

weeks

p<0.001

-5

144

596

593

581

529

518

508

512

531

486

480

493

468

360

395

346

weeks

<0.001

-20

144

602

600

595

542

527

528

522

542

507

490

505

490

364

397

363

weeks

144

weeks

-20

602

600

595

541

527

529

521

542

507

490

505

490

364

397

363

Total cholesterol

p<0.001

ACTG A5257

Slide14

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ACTG A5257

Mean percentage change in bone mineral density over 96 weeks

3.9

3.7

3.4

2.4

-5

-4

-3

-2

-1

ATV/r vs DRV/r

PI/

r vs RAL

Total hip

p=0.36

p=0.005

Lumbar

spine

4.0

3.8

3.6

1.8

-5

-4

-3

-2

-1

ATV/r vs DRV/r

PI/

r vs RAL

p=0.42

p<0.001

Total body

Brown TT, JID 2015; 212:1241-9

ATV/

r (N = 109)

RAL (N = 106)

DRV/

r (N = 113)

Combined

PI/r

2.9

1.7

1.6

-4

-3

-2

-1

ATV/r vs RAL vs DRV/r

p=0.004

p=0.72

p=0.001

Slide15

Effect of Baseline CD4 count and HIV RNA Load on Bone LossAfter adjustment for age, sex, race/ethnicity, baseline HIV RNA and BMI : no associations between lower baseline CD4 count and bone loss at the lumbar spine or total hipAfter multivariable adjustment, higher baseline HIV RNA was associated with bone loss at both sites (spine, −1.53% [95% CI: −2.28% to − 0.77%] for each log10 c/mL increase [p < 0.001]; total hip, −0.82% [95% CI, −1.51% to − 0.14%] for each log10 cmL increase [p = 0.02])Multivariable analyses of BMD loss at W96Baseline factors associated with total hip BMD losshigher baseline concentrations of hsCRP, IL6, and sCD14Baseline factors associated with lumbar spine BMD lossMarkers of CD4+ T-cell senescence and exhaustion (CD4+CD28−CD57+PD1+)Markers of CD4+ T-cell activation (CD4+CD38+HLA-DR+)

ACTG A5257

Brown TT, JID 2015; 212:1241-9

ACTG A5257 Study: (ATV/r

DRV/r

RAL) + TDF/FTC

Slide16

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Larger increases in waist circumference were observed with the RAL arm compared to DRV/r arm at weeks 48 and 96 (all p ≤ 0.023) but not compared with the ATV/r arm (p ≥ 0.07)

ACTG A5257

Mean (97.5%) % of body composition change at W96, ITT : limb fat, trunk fat and lean mass (DXA scan), visceral and subcutaneous abdominal fat (CT abdomen)

Comsey

GA, CROI 2015, Abs. 140 ; Ofotokun I, CID 2015;60:1842-51

Baseline

W96

109

105

113

Number of subjects

ATV/r : 11 %

RAL : 20 %

DRV/r : 14 %

Limb fat

Baseline

W96

108

103

113

Number of subjects

ATV/r : 16 %

RAL : 29 %

DRV/r : 21 %

Trunk fat

Baseline

W96

108

104

112

Number of subjects

ATV/r : 23 %

RAL : 25 %

DRV/r : 20 %

SAT

Baseline

W96

108

105

112

Number of subjects

ATV/r : 31 %

RAL : 33 %

DRV/r : 29 %

VAT

ATV/r

RAL

DRV/r

All p values (ATV/r vs DRV/r, PI/r vs RAL) not significant

Slide17

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Effect of baseline HIV RNA onfat changes at W96 in the 3 groups

Changes in central fat correlated with changes in peripheral fat (r = 0.67 ; p < 0.001)No change in VAT:TAT ratio within or between regimensGreater gains in VAT associated with :Lower baseline leptinHigher baseline adiponectinHIV RNA levelGreater gains in SAT associated with the same baseline factors , with in addition higher IL-6Greater gains in lean body mass associated with :Higher HIV RNA, IL-6 and D-dimer, and lower CD4 at baseline

ACTG A5257

SAT

VAT

100

DRV/r

Change

from

baseline

(%)

SAT

VAT

100

ATV/r

SAT

VAT

100

RAL

SAT

VAT

100

DRV/r

Change

from

baseline

(%)

SAT

VAT

100

ATV/r

SAT

VAT

100

RAL

HIV-1 RNA > 100 000 c/ml

HIV-1 RNA < 100 000 c/ml

Comsey

GA, CROI 2015, Abs. 140

Slide18

Changes in Inflammation and Immune activationSubstudy A5260S (328 patients) : 234 included (HIV RNA < 50 c/mL at W24) : 68 on ATV/r, 84 on DRV/r and 82 on RALPlasma biomarkers of inflammation and coagulation : hsCRP, IL-6, GlycA, D-dimer, sCD14, sCD163, and sIL-2rBlood cellular markers : %CD38+DR+ of T-cell subsets and %CD14+CD16+ and%CD14(dim)CD16+ monocyte subsetsChanges in biomarkers varied by regimen during the 96 weeks of follow-up :hsCRP declined with ATV/r and RAL IL-6 declined only with RAL GLycA decreased in all groups D-dimer declined with ATV/r and DRV/r and was unchanged with RALMarkers of T-cell activation and sCD163 (but not sCD14 and CD14-+CD16+) declined in all groupsConclusion : no consistent evidence that the reduction of inflammation and immune activation with ART initiation was different between RAL and PI-based regimens

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ACTG A5257

Kelesidis

T. CID 2015;61:651-60

Slide19

ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ConclusionATV/r, RAL, and DRV/r were equivalent for virologic efficacy, when given with TDF/FTCATV/r + TDF/FTC was less-well tolerated than DRV/r + TDF/FTC or RAL + TDF/FTCA composite assessment of virologic efficacy and tolerability found that RAL + TDF/FTC was superior to both PI-containing regimensDRV/r + TDF/FTC was superior to ATV/r + TDF/FTCTolerability result was caused primarily by jaundice for ATV/r and gastrointestinal toxicity for both PI/rATV/r was less tolerated than DRV/r and RAL across all sub-groupsRAL tolerability benefit over DRV/r was greater in womenLimitations: open-label design, switch to another arm for tolerability or toxicity allowedWhen tolerability and virologic response are considered together, RAL + TDF/FTC was superior overall to both PI-based therapies and DRV/r was superior to ATV/r. An advantage of PI/r over RAL is the reduced likelihood of drug resistance if virologic failure occurs

Lennox JL. Ann Intern Med 2014;161:461-71

ACTG A5257

Comparison of INSTI vs PI - PowerPoint Presentation

Comparison of INSTI vs PI - PPT Presentation

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