the slides - ARV

Comparison of INSTI vs EFV
 STARTMRK
 GS-US-236-0102
 SINGLE
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
 Design
Randomisation*
1:1
Double-blind
> 18 years
ARV-naïve
HIV RNA > 1,000 c/mL
Any CD4 cell count
HBsAg negative
No genotypic resistance
HLA-B*5701 negative
N = 422
W96
DTG 50 mg + ABC/3TC FDC QD
TDF/FTC/EFV placebo
N = 422
W144
Open-label
TDF/FTC/EFV QD
DTG placebo + ABC/3TC placebo
*Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) and CD4/mm3 (< or > 200) at screening
 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 = -10%, 90% power)
SINGLE
Walmsley S. NEJM 2013;369:1807-18
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
Baseline characteristics and patient disposition
DTG + ABC/3TC
N = 414
TDF/FTC/EFV
N = 419
36
35
Female
16%
15%
HIV RNA (log10 c/mL), median
4.67
4.70
HIV RNA > 100,000 c/mL
32%
31%
CD4 cell count (/mm3), median
335
339
CD4 < 200 per mm3
14%
15%
Hepatitis C coinfection
7%
7%
Discontinuation by W48
51 (12.3%)
84 (20.0%)
For lack of efficacy
N = 14
N = 13
For adverse event
N = 10
N = 42
Lost to follow-up
N = 14
N=9
N=7/N=5
N = 7 / N = 11
Median age, years
Protocol deviation / Withdrew consent
SINGLE
Walmsley S. NEJM 2013;369:1807-18
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
Response to treatment at week 48
HIV RNA < 50 c/mL
%
100
DTG + ABC/3TC
TDF/FTC/EFV
Primary
analysis
87.9
89.8
80.7
81.3
75
50
Differences in viral suppression were
also seen in key demographic
subgroups including race, sex,
age and patients with
HIV RNA > 100,000 c/mL at baseline
25
0
ITT, snapshot
Per protocol
Adjusted difference
(95% CI) = 7% (2; 12)
Adjusted difference
(95% CI) = 9% (4; 13)
Adjusted mean CD4/mm3 increase
at W48 :
+ 267 for DTG + ABC/3TC
+ 208 for TDF/FTC/EFV (p<0.001)
 Superiority of DTG + ABC/3TC
SINGLE
Walmsley S. NEJM 2013;369:1807-18
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
HIV-1 RNA < 50 c/mL at week 48 by stratification factors
DTG + ABC/3TC
Baseline Plasma HIV-1 RNA
TDF/FTC/EFV
Number of Responders/Number Assessed
≤100,000 c/mL
253/280 (90.4%)
238/288 (82.6%)
>100,000 c/mL
111/134 (82.8%)
100/131 (76.3%)
> 200/mm3
319/357 (89.4%)
290/357 (81.2%)
< 200/mm3
45/57 (78.9%)
48/62 (77.4%)
Baseline CD4+ T cell count
SINGLE
Walmsley S. NEJM 2013;369:1807-18
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
Response to treatment at week 96
HIV-1 RNA < 50 c/ml (ITT, snapshot)
DTG + ABC/3TC
TDF/FTC/EFV
%
100
DTG : 80%
80
EFV : 72%
60
Adjusted difference at W96 (95 % CI) :
+ 8.0 % (+ 2.3 % ; + 13.8 %) ; P = 0.006
40
20
0
0
4 8 12 16
24
32
40
48
60
72
84
96
Weeks
SINGLE
Walmsley S, CROI 2014, Abs. 543
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
 Virologic failure definition
– 2 consecutive plasma HIV-1 RNA > 50 c/mL, on or after W24
 Criteria for resistance testing
– All patients with protocol defined virologic failure (PDVF)
– Genotype of RT and integrase on baseline and suspected virologic failure samples
Resistance data at PDVF
DTG + ABC/3TC , N = 414
PDVF
Integrase genotype results at baseline
and time of PDVF
Emergent integrase-resistance mutations
Reverse transcriptase genotype results
at baseline and time of PDVF
Emergent NRTI-resistance mutations
Emergent NNRTI-resistance mutations
TDF/FTC/EFV, N = 419
D0-W48
W48-W96
D0-W48
W48-W96
18 (4.3%)
7
17 (4.1%)
8
7
-
7
-
0*
0
0
0
9
-
9
-
0
0
0
0
1 (K65R)
4**
0
2***
* E157Q/P polymorphism in 1 patient with no change in phenotype
** N = 1 with K101E, N = 1 with K103N, N = 1 with G190A, N = 1 with K103N + G190A ; **** N = 2 with K103K/N
SINGLE
Walmsley S, ICAAC 2012, Abs.H556b ; Walmsley S. NEJM 2013;369:807-18 ; Walmsley S, CROI 2014, Abs.543
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
Adverse events and laboratory abnormalities at week 48
Adverse event leading to discontinuation of study drug
Psychiatric disorder, N
Nervous system disorder, N
Skin and subcutaneous-tissue disorder, N
Gastrointestinal disorder, N
General disorder or administration-site condition, N
Adverse event of grade 2-4 in > 3% in either group
Bronchitis
Diarrhoea
Nausea
Insomnia
Anxiety
Depression
Headache
Dizziness
Rash
Grade 2-4 elevation of ALT
Grade 2-4 elevation of AST
SINGLE
DTG + ABC/3TC
TDF/FTC/EFV
10 (2.4%)
2
0
2
0
0
42 (10.0%)
15
13
8
8
7
2%
5%
2%
4%
2%
2%
3%
< 1%
1%
2%
2%
3%
4%
3%
4%
3%
3%
3%
5%
5%
5%
5%
Walmsley S. NEJM 2013;369:1807-18
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
 Insomnia was more frequent in DTG group (15% vs 10%)
 Serious adverse events related to study drug at week 48
– DTG + ABC/3TC, N = 1
• Suspected drug hypersensitivity
– TDF/FTC/EFV, N = 8
•
•
•
•
Psychiatric event, N = 4
Drug hypersensitivity, N = 2
Cerebrovascular accident, N = 1
Renal failure, N = 1
 Mean change in creatinine at W48 on DTG: + 0.12 to 0.15 mg/dL
(10.56 to 13.2 mmol/L), peak at W2, then stable
SINGLE
Walmsley S. NEJM 2013;369:1807-18
SINGLE Study: DTG + ABC/3TC vs TDF/FTC/EFV QD
 Conclusion
– DTG + ABC/3TC QD had a better safety profile and was superior
through 48 weeks to TDF/FTC/EFV for first-line antiretroviral therapy
• Superior virologic response with DTG + ABC/3TC also seen in key
demographic subgroups and in patients with low or high baseline viral load
• Statistical superiority in CD4 response for DTG + ABC/3TC
• Virologic superiority of DTG + ABC/3TC confirmed at W96
– No INSTI major mutations were detected through 96 weeks with DTG
– Lower occurrence of adverse events leading to discontinuation
with DTG : 2% vs 10%
– Significant lower reported rates of neuro-psychiatric and rash events
with DTG + ABC/3TC
• Except for insomnia (15% vs 10%)
SINGLE
Walmsley S. NEJM 2013;369:807-18 ; Walmsley S, CROI 2014, Abs.543
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