Comparison of INSTI vs PI FLAMINGO GS-236-0103 ACTG A5257 WAVES.

Comparison of INSTI vs PI

FLAMINGO GS-236-0103 ACTG A5257 WAVES

DeJesus E. Lancet 2012;379:2429-38

Design

Objective– Non inferiority of EVG/c/FTC/TDF at W48: % HIV RNA < 50 c/mL by intention

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

EVG/c/FTC/TDF 150/150/200/300 mg QDATV/r + TDF/FTC placebo

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

EVG/c/FTC/TDF placebo

Randomisation*1 : 1

Double-blind

Randomisation*1 : 1

Double-blind

> 18 yearsARV-naïve

HIV RNA > 5,000 c/mLAny CD4 cell counteGFR> 70 mL/min

> 18 yearsARV-naïve

HIV RNA > 5,000 c/mLAny CD4 cell counteGFR> 70 mL/min

*Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) at screening

Study GS-236-0103: EVG/c/FTC/TDF QD vs ATV/r + FTC/TDF QD

N = 355

N = 353

W48W48 W192W192

GS-236-0103

EVG/c/FTC/TDFN = 353

ATV/r + FTC/TDFN = 355

Mean age, years 38 39

Female 8% 11%

HIV RNA (log10c/mL), mean 4.8±0.61 4.8±0.62

HIV RNA > 100,000 c/mL 42% 40%

CD4 cell count (/mm3), median 351 366

CD4 < 200 per mm3 15% 11%

Hepatitis B / hepatitis C coinfection 1% / 5% 2% / 3%

Discontinuation by W48 9.3% 11.3%

For lack of efficacy N = 4 N = 1

For adverse event N = 13 N = 18

Lost to follow-up N = 7 N = 7

Non-compliance N = 5 N = 5

Discontinuation by W96 14% 15%

Baseline characteristics and patient disposition

DeJesus E. Lancet 2012;379:2429-38 ; Rockstroh JK, JAIDS 2013;62:483-6GS-236-0103


Response to treatment at week 48


GS-236-0103

Mean CD4/mm3 increase at W48 :+ 207 (EVG/c/FTC/TDF) vs+ 211 (ATV/r + FTC/TDF)

Viral suppression was high in both treatment arms, for varioussubgroups including patientswith HIV RNA > 100 000 c/mLat baseline

25

50

100

75

89.5 86.8

Adjusted difference(95% CI)=

3.0 % (- 1.9; 7.8)

97.5 97.7


= -0.1 % (- 2.6; 2.4)

ITT, snapshot Per protocol

EVG/c/FTC/TDFATV/r + FTC/TDF

HIV RNA < 50 c/mLPrimaryanalysis

%

0


DeJesus E. Lancet 2012;379:2429-38 GS-236-0103

ARN VIH < 50 c/ml


20

60

80

Weeks

0

40

100

0 2 4 8 12 16 24 32 40 4828 36 4020


353 353 353 353 353 353 353 353 353

355 355 355 355 355 355 355 355 355

EVCG/c/FTC/TDF

ATV/r + FTC/TDF

Number of patients

%

Response to treatment at week 96 and week 144

Rockstroh JK, JAIDS 2013;62:483-6 ; Clumeck N, JAIDS 2014;65:e121-4GS-236-0103

25

50

100

75

83.3 82.3

%


1.1 % (- 4.5 ; 6.7)

86.7 85.4


1.4 % (- 3.8 ; 6.5)

ITT, snapshot ITT, M = F


HIV RNA < 50 c/mL at week 96

0

25

50

100

7577.6

74.6

%


3.1 % (- 3.2; 9.4)


2.3 % (- 3.6 ; 8.2)

ITT, snapshot ITT, M = F

81.0 78.9

HIV RNA < 50 c/mL at week 144


0


Response to treatment at week 144

EVG/c/FTC/TDF ATV/r + FTC/TDF

Virologic failure 7.9 % 7.3 %

Mean CD4/mm3 increase + 280 + 293

No treatment difference in virologic success for various subgroups, including patients with HIV RNA > 100,000 c/mL at baseline, except for adherence > 95 % (favoring EVG/c/FTC/TDF)

EVG/c/FTC/TDF ATV/r + FTC/TDF

W48 W96 W144 W48 W96 W144

Lumbar spine - 2.63 % - 1.96 % - 1.43%* - 3.33 % - 3.54 % -3.68%*

Hip - 3.06 % - 3.16 % - 2.83% - 3.88 % - 4.19 % -3.77%

* p = 0.018

DeJesus E. Lancet 2012;379:2429-38 ; Rockstroh JK, JAIDS 2013;62:483-6 ; Clumeck N, JAIDS 2014;65:e121-4 GS-236-0103

Mean decrease in bone mineral density

Secondary outcomes


Virologic failure definition– Suboptimal virologic response : 2 consecutive visits with HIV RNA ≥ 50 c/mL

and <1 log10 c/mL below baseline at or after week 8– Virologic rebound (2 consecutive visits with HIV RNA either ≥ 400 c/mL after achieving

HIV RNA < 50 c/mL, or >1 log10 c/mL increase from nadir) – HIV RNA ≥ 400 c/mL at their last visit (at or after week 8)

Criteria for resistance testing– Virological failure or HIV RNA > 400 c/mL at study discontinuation

(at or after W8 and taking study drug)



Analysed for the development of resistance 12 (3.4%) 8 (2.3%)

Emergent primary integrase mutations 4*, ** -

Emergent reverse transcriptase resistance 4 0

M184V

K65R

4

1

-

-

Emergent primary protease mutation - 0

* Q148R, N = 2, N155H, N = 1, T66I + E92Q + N155H, N = 1 ; ** 1 had also M184V + K65R and 2 M184V


GS-236-0103

Resistance data at week 48




TotalD0-W48

W48-W96

W96-W144

TotalD0-W48

W48-W96

W96-W144

Emergent resistance, n 8 5* 1 2** 2 0 0 2

INSTI resistance 6 4 1 1 -

E92Q 2 1 1 0

N155H 2 2 0 0

Q148R 2 2 0 0

T66I 1 1 0 0

T97A 1 0 0 1

NRTI resistance 7 4 1 2 2 0 0 2

M184V/I 7 4 1 2 2

K65R 1 1 0 0 0

Protease mutation - 0

Resistance data at week 144

Rockstroh JK, JAIDS 2013 62:483-6 ; Clumeck N, JAIDS 2014;65:e121-4

* INSTI + NRTI resistance, N = 3, ** INSTI + NRTI resistance, N = 1

GS-236-0103


EVG/c/FTC/TDF ATV/r + FTC/TDFTotal at week 48 13 (3.7%) 18 (5.1%)

Ocular icterus/Jaundice 0 / 0 4 / 2

Gastro-intestinal disorder 4 5

General disorder 3 2

Drug hypersensitivity 1 0

Infection 1 2

Overdose 0 1

Aminotransferase increased 2 0

Creatinine increased 1 0

Nephropathy toxic 0 1

Limb discomfort or rhabdomyloysis 2 0

Neoplasm 1 1

Neuropsychiatric disorder 4 3

Rash, drug eruption 2 4

Other 3 0

Total at week 96 15 (4.2%) 21 (5.9%)

Total at week 144 21 (5.9%) 30 (8.5%)

DeJesus E. Lancet 2012;379:2429-38 ; Rockstroh JK, JAIDS 2013;62:483-6 ; Clumeck N, JAIDS 2014;65:e121-4 GS-236-0103

Treatment-emergent adverse events leading to premature discontinuation of study drugs


EVG/c/FTC/TDF ATV/r + FTC/TDFDiarrhoea 77 (22%) 97 (27%)

Nausea 70 (20%) 69 (19%)

Upper respiratory tract infection 54 (15%) 58 (16%)

Headache 53 (15%) 44 (12%)

Fatigue 50 (14%) 45 (13%)

Ocular icterus 2 (1%) 51 (14%)

Treatment-emergent adverse events occurring in > 10% of patients in either group (week 48)


EVG/c/FTC/TDF ATV/r + FTC/TDF PTriglycerides (mg/dL), median change 0.09 0.26 0.006

Creatinine (mo/L), median change (IQR) 11 (5 ; 18) 7 (1 ; 15) < 0.001

eGFR (mL/min), median change (IQR) - 12.7 (- 21.8 ; 4.3) - 9.5 (- 17.9 ; 0.2) < 0.001

Graded ALT abnormality 15.3% 21.6% 0.041

Severe/life threatening bilirubin abnormality 0.6% 58.2% < 0.001

Laboratory test results at week 48

GS-236-0103


Discontinuations due to renal eventEVG/c/FTC/TDF ATV/r + FTC/TDF

W48 W96 W144 W48 W96 W144

Discontinuation for renal event 2 1 2 1 1 6

Proximal renal tubulopathy 0 0 0 0 0 3

DeJesus E. Lancet 2012;379:2429-38 ; Rockstroh JK, JAIDS 2013; 62:483-6 ; Clumeck N, JAIDS 2014;65:e121-4 GS-236-0103

Median change in serum creatinine (mol/L) concentration from baseline

EVG/c/FTC/TDF ATV/r + FTC/TDF-5

5

20

10

Weeks-10

0

15

0 2 4 8 12 16 24 32 40 48


Summary (W48 results)– EVG/c/FTC/TDFQD was virologically non inferior to ATV/r + FTC/TDF– Similar virologic reponse of the 2 regimens in different subgroups of patients,

including those with high HIV RNA at enrolment– Discontinuation because of adverse events was lower with EVG/c/FTC/TDF :

3.7% vs 5.1%– Development of major resistance mutations occurred in

• 5 patients on EVG/c/FTC/TDF : 4 with integrase mutations (3/4 had also NRTI mutations), 1 with only RT mutation (M184V)

• none on ATV/r + FTC/TDF

– Incidence of adverse events was similar except for jaundice/icterus– Median increases in creatinine with accompanying decreases in estimated

glomerular filtration rate • occurred in both study groups by week 2• generally stabilized by week 8 and did not change up to week 48 • median change : + 11 μmol/L vs + 7 μmol/L ; P < 0.001


GS-236-0103


Comparison of INSTI vs PI FLAMINGO GS-236-0103 ACTG A5257 WAVES.

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Transcript of Comparison of INSTI vs PI FLAMINGO GS-236-0103 ACTG A5257 WAVES.