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from TDF to TAF GSUS2920109 Study GSUS3111089 Study Design Endpoints Primary proportion of patients maintaining HIV RNA lt 50 cmL at W48 ITT snapshot noninferiority if lower margin of a twosided 95 CI for the difference 10 gt 95 power ID: 541817 Download Presentation

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Presentation on theme: "Switch"— Presentation transcript

Slide1

Switch from TDF to TAF

GS-US-292-0109 Study

GS-US-311-1089 Study

Slide2

Design

Endpoints

Primary: proportion of patients maintaining HIV RNA < 50 c/mL at W48 (ITT, snapshot) ; non-inferiority if lower margin of a two-sided 95% CI for the difference = -10%, > 95% power

Secondary with multiple adjustments: percentage change in hip and spine bone mineral density

F/TAF * + F/TDF placebo + 3rd agent unchanged

F/TDF + F/TAF * placebo + 3rd agent unchanged

GS-US-311-1089

Randomisation

1 : 1Double blind

HIV+ ≥ 18 yearsOn F/TDF + 3rd agent HIV RNA < 50 c/ml > 6 monthseGFR (Cockroft-Gault) > 50 mL/min

N = 330

N = 333

W48

GS-US-311-1089

Study

: Switch TDF to TAF

W96

Randomisation stratified on 3

rd

agent (boosted PI or other)

* F/TAF: 200/10 mg if boosted PI, 200/25 mg if other

Gallant J. Lancet HIV. 2016;3:e158-65,

Raffi

F. J

Acquir

Immune

Defic

Syndr

. 2017;75:226-31Slide3

F/TAF

N = 333

F/TDF

N = 330

Median age, years

4849

Female14%16%

Race: white / black / other

73% / 21% / 6%77% / 20% / 3%

CD4/mm3, median663624

eGR

(Cockroft-Gault

), mL/min, median99.4100.2

3rd agent: PI/r / otherDRV/r / ATV/r / LPV/rNVP/ RAL / DTG / other

47% / 53%

25% / 16% / 5%

22% / 20% / 8% / 4%

45% / 55%

25% / 15% / 5%

20% / 22% / 7% / 5%

Discontinuation by W48, N (%)

Adverse eventInvestigator decisionConsent withdrawalLost to follow-up / Non compliance

Pregnancy / Protocol violation

Discontinuation by W96, N (%)

21 (6%)71101 / 11 / 036 (11%)21 (6%)31101 / 20 / 439 (12%)

Baseline characteristics and outcome

GS-US-311-1089

GS-US-311-1089 Study: Switch TDF to TAF

Gallant J. Lancet HIV. 2016;3:e158-65,

Raffi

F. J

Acquir

Immune

Defic

Syndr

. 2017;75:226-31Slide4

F/TAF

(N = 333)

F/TDF

(N = 330)

N tested for resistance *

- D0 to W48

- W48 to W962212

Emergence of resistance

1 (M184V (isolated at W36)0Resistance data* Confirmed HIV-1 RNA ≥ 50 c/mL at any visit or unconfirmed > 400 c/mL at endpoint or discontinuation

Virologic outcome (ITT, snapshot)

GS-US-311-1089

GS-US-311-1089

Study: Switch TDF to TAF

F/TAF + 3rd agent (N = 333)

F/TDF + 3

rd

agent (N = 330)

W48

W48

W96

Difference (95% CI)

W48 = 1.3% (-2.5 to 5.1)

W96 = -0.5% (- 5.3 to 4.4)

Success

HIV RNA< 50 c/mLVirologic failureNo virologic data

W96%94.30.35.4931.5

5.5020406080100

88.6

89.1

2.4

0.6

9.0

10.3

Gallant J. Lancet HIV. 2016;3:e158-65,

Raffi

F. J

Acquir

Immune

Defic

Syndr

. 2017;75:226-31Slide5

HIV-1 RNA < 50 c/mL at W48 according to 3

rd

agent, %

Virologic success was similar between treatment groups for the subgroups of age, sex, race, and study drug adherence

Mean changes in CD4 at W48+ 20/mm3 F/TAF+ 21/mm3 F/TDF

GS-US-311-1089GS-US-311-1089 Study: Switch TDF to TAF

Gallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65AllBoosted PIOther 3rd agent

0

20

406080100949392

93

97

93333330155151178179% N =

F/TDF

F/TAFSlide6

Adverse events, N (%)

F/TAF

N = 333

F/TDF

N = 330

Adverse events related to study drug (D0 to W48)Leading to discontinuation

Adverse events leading to study discontinuation by W969%N = 2 (0.6%)N = 8 (2%)

12%

N = 3 (0.9%)N = 4 (1%)Serious adverse event (D0 to W48)18 (5%)

14 (4%)Serious adverse event related to study drug at W4801 (< 1%)

Most common adverse events (D0 to W48)

Upper respiratory tract infection

DiarrheaHeadacheNasopharyngitisCoughBronchitis

Back painArthralgiaFatigueSinusitis

9%9%

8%

8%6%

6%

6%

6%

5%

4%14%10%4.5%

6%

5%

5%5%3%4%7%GS-US-311-1089GS-US-311-1089 Study: Switch TDF to TAFGallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65,Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31Slide7

F/TAF (N = 333)

F/TDF (N = 330)

Discontinuation for adverse event

Insomnia / Mood altered

Dysphagia Atrial fibrillation

Diarrhea Peripheral edema Overdose Lymphoma Acquired lipodystrophy

/affective disorder Increased serum creatinine Rectal tenesmus Feeling abnormal / Headache Renal tubular disorder

8 (2.4%)

11111111

00004 (1.2%)000

0

0

000111

1Laboratory abnormalities grade 3-4 ≥ 2 % (no treatment discontinuation), %

LDL

Total bilirubin

CK

Total cholesterol

Gamma GT

Glycosuria

Hematuria

AST / ALTAmylaseLipase107

5

4

2322 / 222566132< 1< 1 / < 141Discontinuation for adverse event, laboratory abnormalities grade 3-4 (D0-W96)

GS-US-311-1089GS-US-311-1089

Study: Switch TDF to TAFGallant J, CROI 2016, Abs. 29, Gallant J. Lancet HIV. 2016;3:e158-65,Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31Slide8

321

310

300

320

310

306

294

297

287

292

321

309

300

317

305

303

293

296

288

289

FTC/TAF, N

FTC/TDF, N

Spine

Hip

-1

0

1

2

3

0

24

48

72

96

Week

2.2

-0.2

p < 0.001

1.7

-0.1

-1

0

1

2

3

0

24

48

72

96

Week

1.9

-0.3

p < 0.001

1.2

-0.1

GS-US-311-1089

Study

: Switch TDF to TAF

GS-US-311-1089

Mean

change

in

bone

mineral

density

through

W96 (%, 95% CI)

Gallant J, CROI 2016, Abs. 29,

Gallant J. Lancet HIV.

2016;3:e158-65,

Raffi

F. J

Acquir

Immune

Defic

Syndr

. 2017;75:226-31Slide9

The distribution of the bone mineral density status (normal, osteopenia, osteoporosis) adjusted for baseline status was significantly different between treatment groups at W48 at the hip (p = 0.012)

and at the spine (p = 0.037)

Driven by a higher percentage of subjects in the F/TAF group with an improvement in BMD status (i.e. osteopenia to normal, osteoporosis to normal or osteopenia), and correspondingly, a lower percentage of subjects in the F/TAF with worsening BMD status (i.e. normal to osteopenia or osteoporosis, or osteopenia to osteoporosis)

GS-US-311-1089

Bone mineral density status changes through W48

Gallant J. Lancet HIV. 2016;3:e158-65

0

20

40

60

80

100

Normal

Osteopenia

Osteoporosis

6.2

4.0

5.6

5.6

0.9

0.7

0.9

1.3

39.5

38.7

34.0

35.0

33.030.3

33.8

35.3

54.2

57.3

60.3

59.5

66.0

69.0

65.3

63.4

BL

W48

BL

W48

BL

W48

BL

W48

F/TAF

N = 321

F/TDF

N = 320

F/TAF

N = 321

F/TDF

N = 317

Patients (%)

Spine

Hip

GS-US-311-1089

Study

: Switch TDF to TAFSlide10

Change in renal biomarkers at W96

GS-US-311-1089

Discontinuation for renal adverse event

F/TAF = 0F/TDF = 2 (creatinine increase = 1, renal tubular disorder = 1)

Urine protein to creatinine ratio (% median change)eGFRMedian Change (mL/min)*10.04.0

* p < 0.001

- 26.0

3.4

- 4.1

- 29.7

2.7

27.0

42.6

46.8-30-20-10010

2030

P/Cr

Alb/CrRBP/Cr

b2MG/Cr

Cr: creatininuria*

*

*

*4050GS-US-311-1089 Study: Switch TDF to TAF

F/TAF

F/TDF

Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31Slide11

Safety by 3

rd

Agent

GS-US-311-1089 Study: Switch TDF to TAF

GS-US-311-1089

Boosted PI

Other 3rd Agent

FTC/TAF

N = 155FTC/TDFN = 151

FTC/TAFN = 178FTC/TDFN = 179Renal safety (Changes at W96)

eGFR

(mL/min)

+ 9.3

+ 4.2

+ 10.6

+ 3.3

Urine protein/Cr (%)

- 27.2

- 1.8

-25.6

+ 7.8

Urine albumin/Cr (%)

- 1.3

+ 21.7+ 5.0+ 29.2 Urine RBP/Cr (%)- 5.5

+ 36.5- 2.0+ 49.9

Urine β2MG/Cr (%)- 28.2

+ 41.8

- 31.9

+

51.5

Bone safety (Changes at W96)

Spine BMD (%)

+ 2.03

- 0.49

+ 2.26

+ 0.10

Hip BMD (%)

+ 1.82

- 0.28

+ 1.88

- 0.38

Raffi

F. J

Acquir

Immune

Defic

Syndr

. 2017;75:226-31Slide12

Median fasting lipids W48 versus baseline (mg/

dL

)

F/TAF

F/TDF

Patients initiating lipid-lowering agents

4%

4%

F/TAF

F/TDF

Week 48

Baseline

GS-US-311-1089

GS-US-311-1089

Study

: Switch TDF to TAF

Gallant J. Lancet HIV. 2016;3:e158-65

Total

Cholesterol

LDL

HDL

Triglycerides

p = 0.073

128

118

112

110

p = 0.02

51

49

50

49

p < 0.001

125

112

114

110

p < 0.001

201

187

183

182

0

50

100

150

200

250

TC: HDL Ratio

p = 0.094

3.7

3.6

3.6

3.6

0

1

2

3

4Slide13

Conclusion

In this

randomised

double-blind study, switch of patients on F/TDF + 3rd agent with suppressed viral load for F/TAF + continuation of 3rd agent Is non-inferior at W48 and W96 for maintaining virologic suppression (HIV-1 RNA < 50 c/mL)in rare cases of virologic failure, the risk of resistance emergence is low (1 case of M184V on F/TAF), none after W48Is associated with a similar clinical and biological toleranceLeads to improvement of renal parameters: increase in eGFR and decrease in proteinuria, no renal discontinuations or renal tubulopathy in F/TAF group Improves bone mineral density: increase on F/TAF with significant difference of changes at W48 vs F/TDF and continuing increase in hip and spine BMD after W48Increases lipid parameters, with no change in the total cholesterol total: HDL-cholesterol ratio

Similar safety findings by 3rd agent

GS-US-311-1089GS-US-311-1089 Study: Switch TDF to TAF

Gallant J. Lancet HIV. 2016;3:e158-65; Raffi F. J Acquir Immune Defic Syndr. 2017;75:226-31