Transcript ARV-trials 2015

Comparison of INSTI vs PI
 FLAMINGO
 GS-236-0103
 ACTG A5257
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
 Design
Randomisation*
1:1
Open-label
> 18 years
ARV-naïve
HIV RNA > 1,000 c/mL
Any CD4 cell count
No primary resistance
in RT or protease
W48
N = 243
DTG 50 mg QD + 2 NRTI**
N = 245
DRV/r 800/100 mg QD + 2 NRTI**
W96
*Randomisation (DTG vs DRV/r) was stratified by HIV RNA (< or > 100,000 c/mL) at screening and NRTI
backbone
**NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) was selected by investigator
 Objective
– Non inferiority of DTG at W48: % HIV RNA < 50 c/mL by intention to treat,
snapshot analysis (1-sided significance level of 2.5%, lower margin of the 95%
CI for the difference = -12%, 90% power)
FLAMINGO
Clotet B. Lancet 2014;383;2222-31; Molina JM. Lancet HIV 2015, 2:e127-136
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Baseline characteristics
DTG + 2 NRTI
N = 242
DRV/r + 2 NRTI
N = 242
34
34
Female
13%
17%
HIV RNA (log10 c/mL), median
4.49
4.48
HIV RNA > 100,000 c/mL
25%
25%
CD4 cell count (/mm3), median
390
400
CD4 < 200 per mm3
10%
10%
4% / 7%
2% / 7%
67% / 33%
67% / 33%
Median age, years
Hepatitis B / hepatitis C coinfection
Dual NRTI on day 1 : TDF/FTC / ABC/3TC
FLAMINGO
Clotet B. Lancet 2014;383;2222-31
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Patient disposition, n (%)
DTG + 2 NRTI
N = 242
DRV/r + 2 NRTI
N = 242
18 (7.4%)
29 (12.0%)
2
2
3/1
9/1
6
10
3/1
3/1
34 (14%)
52 (21.5%)
For lack of efficacy / AE / LTFU / Withdrew consent
3
4
For adverse event
6
13
Lost to follow-up
15
18
Withdrew consent
2
8
Discontinuation by W48
For lack of efficacy
For adverse event / For liver stopping criteria
Lost to follow-up
Protocol deviation / Withdrew consent
Discontinuation by W96
FLAMINGO
Clotet B. Lancet 2014;383;2222-31; Molina JM. Lancet HIV 2015, 2:e127-136
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Response to treatment at week 48
HIV RNA < 50 c/mL
%
DTG + 2 NRTI
DRV/r + 2 NRTI
Primary analysis
100
91.1
89.7
82.6
83.8
Protocol-defined virologic failures
(2 consecutive HIV RNA > 200 c/mL
on or after W24)
• 2 on DTG + NRTI (TDF/FTC)
• 2 on DRV/r + NRTI (ABC/3TC)
• No resistance emergence in the 4 cases
75
50
25
0
ITT, snapshot
Per protocol
Adjusted difference
(95% CI) =
7.1% (0.9 ; 13.2)
Adjusted difference
(95% CI) =
7.4% (-1.4 ; 13.3)
FLAMINGO
Median CD4/mm3 increase at W48 :
+ 210 in both groups
Clotet B. Lancet 2014;383;2222-31
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Response to treatment at week 96
DTG + 2 NRTI
DRV/r + 2 NRTI
HIV RNA < 50 c/mL
%
Kaplan Meier proportion
without failure
97.9
100
98.7
98.1
83
80
75
94.7
68
70
50
25
0
ITT, snapshot
Per protocol
TRDF*
ERDF**
Adjusted difference
(95% CI) =
12.4% (4.7 ; 20.1)
Adjusted difference
(95% CI) =
12.9% (5.3 ; 20.6)
Adjusted difference
(95% CI) =
3.3% (-0.3 ; 6.7)
Adjusted difference
(95% CI) =
0.6% (-1.7 ; 2.9)
* Protocol-defined virological failure or withdrawal for drugrelated AE, safety stopping criteria, or lack of efficacy .
** PDVF or withdrawal because of lack of efficacy
FLAMINGO
Molina JM. Lancet HIV 2015, 2:e127-136
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
HIV-1 RNA < 50 c/mL at week 48 by stratification factors
(HIV-1 RNA and background NRTI)
DTG + 2 NRTI
N = 242
DRV/r + 2 NRTI
N = 242
Difference in %
(95% CI)
DTG – DRV/r
Number of Responders/N Assessed
HIV RNA ≤ 100,000 c/mL
160/181(88%)
157 / 181 (87%)
1.7 (-5.1, 8.5)
HIV RNA > 100,000 c/mL
57/61 (93%)
43/61 (70%)
23.0 (9.9, 36.0)
ABC/3TC
71/79 (90%)
68/80 (85%)
4.9 (-5.4, 15.1)
TDF/FTC
146/163 (90%)
132/162 (81%)
8.1 (0.5, 15.7)
ABC/3TC ; ≤ 100,000 c/mL
59/66 (89%)
60/68 (88%)
ABC/3TC ; > 100,000 c/mL
12/13 (92%)
8/12 (67%)
TDF/FTC ; ≤ 100,000 c/mL
101/115 (88%)
97/113 (86%)
45/48 (94%)
35/49 (71%)
TDF/FTCTC ; > 100,000 c/mL
FLAMINGO
Clotet B. Lancet 2014;383;2222-31
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
HIV-1 RNA < 50 c/mL at week 96 by stratification factors
(HIV-1 RNA and background NRTI)
DTG + 2 NRTI
DRV/r + 2 NRTI
Unadjusted difference
in % (95% CI) DTG – DRV/r
Number of Responders/N Assessed
HIV RNA ≤ 100,000 c/mL
144/181(80%)
132/181 (73%)
6.6 (-2.1, 15.4)
HIV RNA > 100,000 c/mL
50/61 (82%)
32/61 (52%)
29.5 (13.7, 45.3)
ABC/3TC
65/79 (82%)
60/80 (75%)
7.3 (-5.4, 20.0)
TDF/FTC
129/163 (79%)
104/162 (64%)
14.9 (5.3, 24.6)
 Median CD4/mm3 increase at W96 :
– + 260 (IQR 185 – 400) in the DTG group
– + 250 (IQR 130-400) in the DRV/r group
 Protocol-defined virologic failures (2 consecutive HIV RNA > 200 c/mL
on or after W24)
•
•
FLAMINGO
2 on DTG + NRTI (TDF/FTC) ; 4 on DRV/r + NRTI
No resistance emergence in the 6 cases
Molina JM. Lancet HIV 2015, 2:e127-136
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Adverse events occurring in > 5% in either group at week 48
Any adverse event
Diarrhea
Nausea
Headache
Nasopharyngitis
Upper respiratory tract infection
Insomnia
Cough
Vomiting
Fatigue
Pyrexia
Dizziness
Rash
Back pain
Pharyngitis
Bronchitis
Sinusitis
Depression
Arthralgia
FLAMINGO
DTG + 2 NRTI
DRV/r + 2 NRTI
85%
17%
16%
15%
9%
5%
7%
5%
6%
6%
5%
6%
4%
4%
3%
2%
2%
5%
2%
85%
29%
18%
10%
8%
10%
6%
7%
6%
5%
6%
5%
6%
5%
5%
5%
5%
2%
5%
Clotet B. Lancet 2014;383;2222-31
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Safety at week 48
DTG + 2 NRTI
DRV/r + 2 NRTI
N = 26 (11%)
N = 13 (5%)
Infections and infestations
N=5
N=8
Gastrointestinal disorders
N=6
N=2
Psychiatric disorders
N=4
N=1
Injury, poisoning and procedural complications
N=4
0
Nervous system disorders
N=4
0
Cardiac disorders
N=1
N=1
Articular disorders
N=2
0
Renal and urinary disorders
N=1
N=1
Cholelithiasis
N=1
0
0
N=1
Hodgkin’s disease
N=1
0
Asthma
N=1
0
N = 9 (4%)
N = 6 (2%)
N=1
N=4
Any serious adverse event
Drug hypersensitivity
Emergent ALT increase > 3 ULN
Protocol liver stopping criteria (all related to other causes)
Mean difference in increase in fasting LDL-cholesterol, mmol/L
Grade > 2 LDL-cholesterol
FLAMINGO
-0.30 (95% CI: -0.42 ; -0.19 ;p<0.0001)
2%
7% (p=0.0001)
Clotet B. Lancet 2014;383;2222-31
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
Safety at week 96
DTG + 2 NRTI
DRV/r + 2 NRTI
N = 36 (15%)
N = 21 (9%)
14 in 10 patients
9 in 8 patients
6 (3 / 1)
1 (0 / 0)
7 (3%)
15 (6%)
Gastrointestinal disorders
2
3
Nervous system disorders
2
3
1 (acute)
2 (1 acute)
1/0
0/2
General disorders
0
2
Aminotransferase increased
0
2
Renal colic
0
1
Renal failure
1
0
Rash
0
1
Drug hypersensitivity
1
1
Lipodystrophy
0
1
Gynaecomastia
0
1
Hodgkin’s disease
1
0
Any serious adverse event
Between W48 and W96
Psychiatric disorders (including suicide attempt / completed suicide)
Adverse event leading to discontinuation of study drug
Hepatitis C
Completed suicide / Psychiatric disorders
FLAMINGO
Molina JM. Lancet HIV 2015, 2:e127-136
FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD
+ 2 NRTI
 Conclusion at week 48
– DTG 50 mg QD achieved higher virologic success at week 48,
than DRV/r QD, when combined with either TDF/FTC or ABC/3TC
– In patients with high baseline viral load, the response rate was higher for DTG
– No resistance mutations were detected through 48 weeks in the 2 groups
– Adverse events leading to discontinuation occurred less frequently in the DTG
group
– No specific trends in adverse events
• With the exception of 2 patients reporting suicide attempt and overdose on DTG
– No discontinuation due to renal events
– Mean increases in creatinine with accompanying decreases in estimated
glomerular filtration rate occurred by week 4, and stabilized up to week 48
– Once-daily DTG in combination with fixed-dose NRTIs represents an effective
treatment option for HIV-1-infected, treatment-naive patients
 Conclusion at week 96
– Durable suppression of viral replication with DTG 50 mg + 2 NRTIs with no
new cases of virological failure after 48 weeks
FLAMINGO
Clotet B. Lancet 2014;383;2222-31; Molina JM. Lancet HIV 2015, 2:e127-136