Phase 2 of new ARVs TAF (TFV prodrug) - Study 292-0102 - Study 299-0102.

Phase 2 of new ARVsTAF (TFV prodrug)

- Study 292-0102- Study 299-0102

Design

Objective– Primary endpoint : non inferiority of D/C/F/TAF at W24: % HIV RNA < 50 c/mL

by intention to treat, snapshot analysis (lower margin of the 2 sided 95% CI for the difference = -12%)

– Secondary endpoints : HIV RNA < 50 c/mL at W48, safety, tolerability

D/C/F/TAF STR 800/150/200/10 mg QD

DRV 400 mg x 2 + COBI + F/TDF placebos QD

DRV 400 mg x 2 + COBI 150 mg + F/TDF 200/300 mg QD

D/C/F/TAF STR QD placebo

Randomisation*2 : 1

Double-blind

Adults ≥ 18 yearsARV-naïve

HIV RNA > 5,000 c/mLCD4 cell count >

50/mm3

eGFR ≥ 70 mL/minSensitive to DRV,

FTC and TDF

* Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) and race (black or nonblack)

Study GS-US-299-0102: D/C/F/TAF QD STR vs DRV + COBI + F/TDF QD

N = 50

N = 100

W24 W48

Mills A, JAIDS 2015,epub ahead of printGS-US-299-0102

D = darunavir ; C = cobicistat ; F = FTC

D/C/F/TAFN = 103

DRV + COBI + F/TDFN = 50

Median age, years 31 36

Female 8% 6%

Black 35% 34%

HIV RNA (log10 c/mL), median 4.7 4.6

HIV RNA > 100,000 c/mL 22% 14%

CD4 cell count (/mm3), median 368 433

CD4 < 200 per mm3 10.7% 20%

eGFR (Cockroft-Gault), mL/min, median 116 110

Discontinuation by W48 19 (18%) 8 (16%)

For investigator’s discretion 1 0

For adverse event 2 2

Lost to follow-up / Withdrew consent 10 / 4 4 / 2

Non-compliance 2 0

Baseline characteristics and patient disposition

Study GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QD


Response to treatmentHIV RNA < 50 c/mL, ITT, snapshot analysis

D/C/F/TAF DRV + COBI + F/TDF

171/196

174/195

96/112

104/117

703/753

680/750

25

50

100

7574.8 74.0

%

Adjusted difference(95% CI) =

3.3% (- 11.4 ; 18.1)

76.784.0

Primary analysis, W24(Overall)

0

W48

Adjusted difference(95% CI) =

-6.2% (- 19.9 ; 7.4)

D/C/F/TAF DRV + COBI+ F/TDF

Virologic failure 16% 12%

No data 8% 4%

Outcome at W48

D/C/F/TAF DRV + COBI+ F/TDF

W24 + 186 + 139

W48 + 231 + 212

p : not significant

CD4/mm3 response




D/C/F/TAFN = 103

DRV + COBI + F/TDF N = 50

Virologic failure 6 (5.8%) 2 (4%)

No emergence of resistance to TDF, FTC or DRV

Criteria for resistance testing– Confirmed virologic failure : 2 consecutive HIV RNA > 50 c/mL and an HIV

RNA > 400 c/mL at or after W8– Second, confirmatory, sample, tested for resistance

Resistance data at week 48


D/C/F/TAF DRV + COBI + F/TDFGrade 3-4 AE 6.8% 8.0%

AEs (all grades) in ≥ 10% of patients in either group

Diarrhea 21.4% 26%

Upper respiratory tract infection 15.5% 14%

Fatigue 13.6% 18%

Nausea 12.6% 10%

Rash 11.7% 8%

Flatulence 4.9% 12%

Pain in extremity 7.8% 10%

Vitamin D deficiency 1.9% 10%

Vomiting 3.9% 10%

Serious AEs 4.9% 4.0%

AE leading to discontinuationN = 2Rash;

Substance dependance

N = 2Worsening of diarrhea ;

Proximal renal tubulopathy


Adverse events by W48


Renal outcome at W48D/C/F/TAF DRV + COBI + F/TDF P

Mean (95% CI) change from baseline in creatinine, mg/dL

+ 0.06 (0.04 - 0.08) + 0.09 (0.05 - 0.14) 0.053

Median decrease in eGFR (Cockroft-Gault), mL/min

-2.9 -10.6 0.017

Median change in urine retinol binding protein/creatinine ratio, mg/g

+ 9% + 54% 0.003

Median change in urine beta-2 microglobulin/creatinine ratio, mg/g

-42% +2.3% 0.002

Median change in urine albumin/creatinine ratio, mg/g

-13.1%-22.6%

0.17

Median change in urine protein/creatinine ratio, mg/g

-8.22% -27.52%0.19

Median change in fractional excretion of phosphates

+ 2.4% + 1.8% ns

Emergent dipstick proteinuria 32% 34% ns



Mean percentage change from baseline in bone mineral density (DEXA)Total hip Lumbar spine

-0.53-0.84

-2.09

-3.82

-5

-4

-3

-2

-1

0

P < 0.001 P < 0.001

W24 W48

-1.09-1.57-3.82

-3.62

-4

-3

-2

-1

0

P < 0.001 P = 0.003

W24 W48

Bone sub-study outcome at W48D/C/F/TAF DRV + COBI + F/TDF P

BMD decline > 3% in hip 18.3% 61.7% < 0.001

BMD decline > 3% in lumbar spine 32.5% 55.3% 0.002

P1NP (bone formation) increase + 4.7% + 52.5% < 0.001

CTx (bone resorption) increase + 23.2% + 74.4% < 0.001

P1NP : pro-collagen Type 1 N-terminal propeptide ; CTx : C-terminal telopeptide



D/C/F/TAFDRV + COBI + F/TDF

Median change in fasting metabolic parameters at Week 48

D/C/F/TAF DRV + COBI + F/TDF P

Total cholesterol, mg/dL + 40 + 5 < 0.001

LDL-cholesterol, mg/dL + 26 + 4 < 0.001

HDL-cholesterol, mg/dL + 7 + 3 0.009

Total cholesterol:HDL-cholesterol ratio 0.0 -0.2 0.15

Triglycerides, mg/dL + 29 -5 0.007

Serum glucose, mg/dL + 5 + 7 0.33

Initiation of lipid lowering agent by W48 6.8% 8%


Mills A, JAIDS 2015, epub ahead of printGS-US-299-0102



Conclusion– D/C/F/TAF had significantly improved renal and bone safety

parameters than DRV + COBI + F/TDF in antiretroviral-naïve, HIV-1 infected subjects :

• Less proteinuria• Less change in hip and spine BMD

– Study limitations• Small sample size• Each participant had to take 5 tablets (double-blind) not optimal for

patient’s adherence and retention in the study• Few women enrolled

– This D/C/F/TAF STR offers a promising option for initial HIV treatment, with

• The high barrier to resistance of DRV• And the potential for improved long-term renal and bone safety with TAF

Phase 2 of new ARVs TAF (TFV prodrug) - Study 292-0102 - Study 299-0102.

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