Transcript ARV-trials 2010

Comparison of PI vs PI
 ATV vs ATV/r
BMS 089
 LPV/r mono vs LPV/r + ZDV/3TC
MONARK
 LPV/r QD vs BID
M02-418
M05-730
A5073
 LPV/r + 3TC vs LPV/r + 2 NRTI
GARDEL
 ATV/r vs FPV/r
ALERT
 FPV/r vs LPV/r
KLEAN
 SQV/r vs LPV/r
GEMINI
 ATV/r vs LPV/r
CASTLE
 DRV/r vs LPV/r
ARTEMIS
Study M02-418: LPV/r QD vs BID,
in combination with TDF + FTC
 Design
Randomisation
3:2
Open-label
Adults > 18 years
ARV-naïve or < 7 days prior ART
HIV RNA > 1,000 c/mL
Any CD4 cell count
N = 115
LPV/r 800/200 mg QD +
TDF 300 mg + FTC 200 mg QD
N = 75
LPV/r 400/100 mg BID +
TDF 300 mg + FTC 200 mg QD
 Objective
– Primary endpoint: HIV RNA < 50 c/mL at W48 (ITT, NC = F)
– Non-inferiority of LPV/r QD vs BID if lower margin of the 95% CI
for the difference = - 15% (> 60% power)
M02-418
Johnson MA. JAIDS 2006;43:153-60
Study M02-418: LPV/r QD vs BID,
in combination with TDF + FTC
Patient disposition and baseline characteristics
LPV/r QD
LPV/r BID
Randomized, N
118
78
Treated eligible patients, N
115
75
39.2 + 11.1
37.7 + 9
19%
25%
57% / 27% / 16%
51% / 36% / 13%
HIV RNA (log10 c/mL), median
4.8
4.6
HIV RNA > 100,000 c/mL
44%
29% (p = 0.047 vs QD)
CD4 cell count (/mm3), median
214
232
CD4 < 200/mm3
44%
47%
HBsAg+ and/or HCV Ab+
17%
20%
23 (20%)
22 (29%)
For adverse event
14
6
For virologic failure
0
2
Mean age, years
Female
White/Black/Other
Discontinuation before W48, n (%)
Note: LPV/r was administered as soft-gel capsules
M02-418
Johnson MA. JAIDS 2006;43:153-60
Study M02-418: LPV/r QD vs BID,
in combination with TDF + FTC
Response to treatment at week 48
%
100
80
M02-418
Primary
efficacy
endpoint
70
64
QD (N = 115)
BID (N = 75)
/mm3
200
71
p = 0.67
185
196
160
65
60
120
40
80
20
40
0
0
ITT, NC = F
TLOVR
95% CI
for the difference
= - 7; 20
95% CI
for the difference
= - 8; 20
Mean CD4
increase
Johnson MA. JAIDS 2006;43:153-60
Study M02-418: LPV/r QD vs BID,
in combination with TDF + FTC
Pharmacokinetics and resistance
W4 steady-stade
LPV PK

Genotyping and phenotyping were performed
in all specimens with HIV RNA > 500 c/mL
from W12 through W48
BID group (N = 24) vs QD (N = 13)
– Cmax and AUC24 not significantly
different
– Significantly lower Ctrough and Cmin
for QD group (p < 0.003)
– Median Ctrough: 4.37 µg/mL for QD
vs 6.64 µg/mL for BID
– Median IQ (Ctrough/IC50*) significantly
lower for QD group (48.1) vs BID
(86.5; p < 0.001)
*Protein-binding adjusted IC50
for wild-type HIV-1 = 0.07 mg/mL
M02-418
LPV/r QD
LPV/r BID
Met criteria for
resistance testing
N = 11
N = 11 *
Testing failure **
N=3
N=3
LPV/r ***
0
0
TDF
0
0
FTC
2
1
Emergence of resistance to
* No specimen in 1
** Median HIV RNA = 625 c/mL
*** Any primary or active site mutation in protease at
codons 8, 30, 32, 46, 47, 48, 50, 82, 84, 90, with
decrease in phenotypic susceptibility to LPV > 2.5 fold
Johnson MA. JAIDS 2006;43:153-60
Study M02-418: LPV/r QD vs BID,
in combination with TDF + FTC
Safety and adverse events
LPV/r QD (N = 115)
LPV/r BID (N = 75)
p
Adverse events of at least moderate severity related to study drugs *
Diarrhoea
18 (16%)
4 (5%)
0.036
Nausea
10 (9%)
6 (8%)
NS
Vomiting
4 (3%)
3 (4%)
NS
N = 111
N = 74
AST > 5 x ULN
5 (5%)
2 (3%)
NS
ALT > 5 x ULN
4 (4%)
2 (3%)
NS
Triglycerides > 750 mg/dL
5 (5%)
3 (4%)
NS
Amylase > 2 x ULN
8 (7%)
4 (5%)
NS
Grade 3-4 laboratory abnormalities *
* Occurring in > 3% of patients
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Discontinuation for gastro-intestinal adverse events: QD (N = 9) vs BID (N = 2)
1 death in BID group, unrelated to study drugs (adenocarcinoma)
W48 increase: LDL-cholesterol + 14 mg/dL in both groups; HDL-cholesterol: QD + 3 mg/dL vs BID + 6 mg/dL
LDL-cholesterol > 130 mg/dL: 14% at baseline vs 26% at W48 (2 groups combined)
HDL-cholesterol < 40 mg/dL: 58% at baseline vs 42% at W48 (2 groups combined)
GFR (MDRD [mL/min/1.73 m2)]: 112 at baseline, 104 at W48 (2 groups combined), p < 0.001, with no
differences between groups. 1 case of acute renal failure in each group.
M02-418
Johnson MA. JAIDS 2006;43:153-60
Study M02-418: LPV/r QD vs BID,
in combination with TDF + FTC
 Summary - Conclusion
– In previously untreated HIV-1 infected adults, LPV/r soft-gel capsule
800/200 mg QD was non inferior to LPV/r 400/100 mg BID, in combination with
TDF + FTC QD
– Virologic response rate at W48 (HIV RNA < 50 c/mL) was 70% in the QD group
and 64% in the BID group
– Immunologic recovery was similar in the 2 treatment arms
– There were greater number of discontinuations for adverse events (primarily
gastrointestinal) and a significantly higher rate of diarrhoea in the QD group
– No significant differences in lipid changes was seen between the 2 groups
• Most pronounced lipid effect was triglyceride elevation
• Lipid increases were less than observed with LPV/r + thymidine analogues
– Lack of LPV resistance emergence in either group
– Lower Ctrough with LPV/r QD, not associated with reduced virologic response
– Limitation of the study: only 60% power to determine non inferiority of LPV/r QD
M02-418
Johnson MA. JAIDS 2006;43:153-60