Transcript ARV-trials 2014

Comparison of NNRTI vs PI/r
 EFV vs LPV/r vs EFV + LPV/r
– A5142
– Mexican Study
 NVP vs ATV/r
– ARTEN
 EFV vs ATV/r
– A5202
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
 Design
Randomisation*
1:1:1
Open-label
> 18 years, ARV-naïve
CD4 cell count
< 400/mm3 for males,
<250/mm3 for females
Creatinine clearance
> 50 mL/min
W48
W144
N = 188 NVP 400 mg QD** + TDF/FTC
N = 188
NVP 200 mg BID** + TDF/FTC
N = 193
ATV/r 300+100 mg QD + TDF/FTC
* Randomisation stratified by HIV RNA (< or > 100,000 c/mL) and CD4 (> or < 50/mm3) at screening
** Lead-in of NVP 200 mg QD for the first 2 weeks
 Objective
– Non inferiority of NVP (combined groups) compared to ATV/r for primary
endpoint: % HIV RNA < 50 c/mL at W24, W36 and W48 by intention to treat
with non completers equals failures, (2-sided significance level of 5%, lower
margin of the 95% CI for the difference = -12%, 80% power)
ARTEN
Soriano V. Antiviral Therapy 2011;16:339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
Baseline characteristics and patient disposition
NVP QD
N = 188
NVP BID
N = 188
ATV/r
N = 193
38
40
38
Female
19%
13%
16%
HIV RNA (log10 c/mL), mean
5.1
5.1
5.1
62.8%
62.8%
65.8%
CD4 cell count (/mm3), mean
177
187
188
CD4 < 50 per mm3
7.4%
9.0%
6.2%
3% / 9%
4% / 7%
3% / 9%
Discontinuation by W48
43 (22.9%)
56 (29.8%)
18 (9.3%)
For adverse event
N = 20
N = 27
N=5
For lack of efficacy
N = 11
N = 21
N=3
Lost to follow-up
N=6
N=2
N=4
Other reasons
N=6
N=6
N=6
Mean age
HIV RNA > 100,000 c/mL
Hepatitis B / hepatitis C coinfection
ARTEN
Soriano V. Antiviral Therapy 2011;16:339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
Response to treatment at week 48
HIV RNA < 50 c/mL
%
100
75
NVP (QD + BID) + TDF/FTC
ATV/r + TDF/FTC
Primary analysis
(W24, W36 and W48)
67
65
70
74
ITT, snapshot : response rate
• NVP : 67.3%
• ATV/r : 78.8%
difference – 11.1%
(95%CI : -18.4 ; - 3.9 ; P = 0.003)
50
25
0
ARTEN
Treatment response similar for NVP BID
(66.5%) and QD (67%)
ITT, NC=F
ITT, TLOVR
Adjusted difference
(95% CI) = 1.9%
(-5.9% ; 9.8%)
Adjusted difference
(95% CI) = - 2.9%
(-10.4% ; 4.5%)
Mean CD4/mm3 increase at W48 :
+ 170 for NVP
+ 186 for ATV/r
Soriano V. Antiviral Therapy 2011;16:339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
 Adverse events through week 48
NVP QD
N = 188
NVP BID
N = 188
ATV/r
N = 193
Adverse event, any
85.9%
86.5%
Drug-related adverse event
34.6%
48.7%
Discontinuation for adverse event
13.6%
3.6%
Serious adverse event
9.6%
8.8%
Rash
Any grade
14.9%
17.0%
12.4%
Grade 3
1.6%
1.6%
0
Leading to discontinuation
3.7%
6.4%
0
Any grade
1.6%
2.1%
0
Grade 3-4
1.0%
1.6%
0
Leading to discontinuation
1.6%
2.1%
0
Hepatitis
The majority of rash in NVP groups occurred during the lead-in phase
No Grade 4 rashes
ARTEN
Soriano V. Antiviral Therapy 2011;16:339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
 Grade 3 and 4 adverse events and liver enzyme increases
Combined NVP
N = 376
ATV/r
N = 193
Overall
9.0%
13.5%
Increased bilirubin
0.3%
6.2%
Increased ALT
1.3%
0.5%
Jaundice
0
3.1%
Hyperbilirubinemia
0
2.6%
Rash
1.6%
0
Hypertriglyceridemia
0.3%
1.0%
Grade 3 / Grade 4 ALT
3.7% / 3.5%
1.6% / 0
Grade 3 / Grade 4 AST
4.0% / 2.1%
2.1% / 0.5%
Grade 3/ Grade 4 total bilirubin
1.6% / 1.6%
44.6% / 8.8%
Drug-related Grade 3-4 AE in > 1% in either group, any
Grade 3-4 liver related laboratory abnormalities
ARTEN
Soriano V. Antiviral Therapy 2011;16:339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
 Mean lipid values at baseline, W48 (LOCF) and change from
baseline (LOCF)
Baseline
ATV/r
W48
Combined
NVP
(N = 376)
(N = 193)
Combined
NVP
(N = 376)
TC (mg/dL)
155.68
153.84
180.05
TG (mg/dL)
131.61
132.46
HDL-c (mg/dL)
38.79
LDL-c (mg/dL)
Change to W48
ATV/r
Combined
NVP
(N = 376)
(N = 193)
173.46
24.37
19.62
0.0382
131.63
160.26
0.02
27.80
0.0001
39.00
48.45
42.89
9.66
3.89
< 0.0001
91.57
88.83
106.32
99.26
14.98
10.43
0.0110
TC/HDL-c ratio
4.25
4.15
4.01
4.28
-0.24
0.13
0.0001
ApoA1 (gL)
1.15
1.15
1.33
1.23
0.18
0.08
< 0.0001
ApoB (g/L)
0.76
0.76
0.77
0.77
0.02
0.02
-
ApoB/A1 ratio
0.68
0.68
0.61
0.64
-0.07
-0.03
0.0080
(N =
193)
ATV/r
p*
Combined
NVP vs ATV/r
* ANCOVA controlling for screeening viral load and CD4 cell count
ARTEN
Podzamczer D. HIV Medicine 2011;12:374-82
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
Mean change in lipid parameters (mg/dL)
at week 48 (LOCF)
p < 0.0001
NVP
ATV/r
30
P = 0.041
25
28.1
24.3
20
19.6
15
P = 0.011
P < 0.0001
15.0
10
10.5
5
9.7
3.9
0
Total
cholesterol
-5
LDL-C
HDL-C
-0.2
Triglycerides
0.2
Mean change in TC:
HDL ratio at week 48
(LOCF)
ARTEN
0.1
0.13
0
 Safety
– Incidence of discontinuation due to
adverse event: 13.6% NVP vs 3.6%
ATV/r
– Rash: 16% NVP vs 12.4% ATV/r
(discontinuation due to rash :
5.1% vs 0%)
– Hepatitis: 1.9% NVP vs 0% ATV/r
– Grade 3-4 liver enzyme elevations:
4% NVP vs 1.5% ATV/r
– Grade 3-4 hyperbilirubinemia:
3.2% NVP vs 54.4% ATV/r
– No cases of Stevens-Johnson, toxic
epidermal necrolysis, or death due
to liver or skin toxicity
-0.1
-0.2
-0.25
-0.24
P = 0.0001
Soriano V, Antivir Ther. 2011;16(3):339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
 Resistance data
– Virologic failure : 2 consecutive HIV RNA > 50 copies/mL at least 2 weeks apart
Virologic failure
NVP QD
N = 188
NVP BID
N = 188
ATV/r
N = 193
N = 20
N = 24
N = 28
N=9
N = 15
-
NNRTI resistance mutations
Y181C/I/V/S
Other NNRTI mutations
N=5
NRTI resistance mutations
N=2
M184V/I
N = 10
N = 15
0
K65R
N=4
N=8
0
-
-
0
Protease resistance mutations
ARTEN
Soriano V. Antiviral Therapy 2011;16:339-48
ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC
 Conclusion
– NVP demonstrated at week 48 non-inferior antiviral efficacy
compared with ATV/r when given along with TDF/FTC, despite more
drug-related discontinuations with NVP than ATV/r
– NVP BID and QD had similar efficacy and tolerability
– The application of the recommended CD4+ T-cell thresholds when
initiating first-line NVP therapy probably explain relative low rate of
liver enzymes increases and discontinuations for liver toxicity
– NVP was associated with a lower atherogenic lipid profile than ATV/r
– At virologic failure, there was a high rate of resistance mutations
selected by NVP and none with ATV/r
ARTEN
Soriano V. Antiviral Therapy 2011;16:339-48