1. Comparison of NNRTI vs PI/r
ARV-trial.com
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 1

2. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Design
Randomisation*
1:1:1
Open-label
W96
N = 250
EFV 600 mg QD + 3TC + [d4T XR or TDF or ZDV]
> 13 years
ARV-naïve
HIV RNA > 2,000 c/mL
Any CD4 cell count
N = 253
LPV/r SGC 400/100 mg BID
+ 3TC + [d4T XR or TDF or ZDV]
N = 250
LPV/r SGC 533/133 mg BID
+ EFV 600 mg QD
* Stratified according to :
HIV RNA < or > 100,000 c/mL
Chronic hepatitis coinfection (B and/or C)
NRTI selection
3TC = 300 mg QD or 150 mg BID, in all patients
2nd NRTI (d4T XR 100 mg BID [75 mg if < 60 kg] or TDF [300 mg QD] or ZDV 300 mg BID) selected by investigator before randomisation
Follow-up = 96 weeks after last patient’s enrolment
A5142
Riddler SA. NEJM 2008;358: 2

3. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Objectives
Time to virologic failure: lack of suppression of HIV RNA by 1 log10 c/mL or rebound before W32, or lack of suppression of HIV RNA < 200 c/mL, or rebound after W32. Confirmation of suspected virologic failure was required within 4 weeks. If confirmation sample was missing, case was included as failure
Time to regimen failure: first of either virologic failure or toxicity-related discontinuation of any component of the initial randomized treatment regimen
Analyses
ITT analyses stratified according to the 3 randomisation factors, including all patients who received at least one dose of study drug
If discontinuation for intolerance, follow-up continued for the occurrence of virologic failure
If no virologic nor regimen failure, data was censored at last study visit
Missing data due to missed evaluations, loss to follow-up, or censoring were ignored
Power of 85% to detect a 56% reduction in the risk of virologic failure
Power of 90% to detect a 52% reduction in the risk of regimen failure
Primary endpoints assessed with Kaplan-Meier (statistical significance of hazard ratios between study groups: p < 0.014)
A5142
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4. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Baseline characteristics
Variable
EFV + 2 NRTI N = 250
LPV/r + 2 NRTI N = 253
EFV + LPV/r N = 250
All patients N = 753
Median age, years 39 37 38
Female
19%
23%
18%
20%
White/Black/Other
40%/38%/22%
35%/46%/19%
35%/41%/24%
36%/42%/22%
CD4 count (/mm3), median *
195
190
189
191
CD4 < 200/mm3
51%
54%
52%
HIV RNA (log10 c/mL), median *
4.8
4.9
HIV RNA > 100,000 c/mL
36%
37%
42%
38%
HBsAg+ or HCV Ab+
14%
13%
Selected NRTI, in addition to 3TC
ZDV
d4T XR
24%
25%
TDF
34%
* Mean of 2 measurements obtained at visits before study entry and at entry
No significant differences among the study group in baseline characteristics
Median follow-up = 112 weeks; 78% of patients completed the protocol.
No differences among the study groups in follow-up duration nor reasons for loss to follow-up
A5142
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5. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Probability of no virologic failure (%)
All patients
Probability of no regimen failure (%)
All patients % %
100
100 90 90 80 80 70 70 60 60
p = EFV vs LPV/r 50 50
p non significant * = 0,03 EFV vs LPV/r 40 40
EFV + 2 NRTIs
EFV + 2 NRTIs 30
LPV/r + 2 NRTIs 30
LPV/r + 2 NRTIs
EFV + LPV/r
EFV + LPV/r
Weeks
Weeks 24 48 72 96
120
144 24 48 72 96
120
144
N =
250
210
186
173
142 73 19
250
188
160
142
113 55 13
N =
253
210
185
168
140 74 14
253
193
159
143
116 52 11
N =
250
215
189
181
149 73 17
250
195
169
155
126 59 14
* Level of significance of p value with adjustement for multiple comparisons = 0.014
A5142
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6. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Probability of no virologic failure (%)
HIV RNA > 100,000 c/mL at screening
HIV RNA < 100,000 c/mL at screening % %
100
100 90 90 80 80 70 70
p = 0.01 EFV vs LPV/r
p = 0.02 EFV vs EFV + LPV/r 60 60
p = 0.02 EFV + LPV/r vs LPV/r 50 50 40 40
EFV + 2 NRTIs
LPV/r + 2 NRTIs
EFV + LPV/r 30 30
Weeks
Weeks 24 48 72 96
120
144 24 48 72 96
120
144
N =
121
108 96 90 76 40 11
129
102 90 83 66 33 8
N =
128
105 90 81 67 32 6
130
105 95 87 73 42 8
N =
122
102 86 81 66 35 9
128
113
103
100 83 38 9
A5142
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7. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
HIV RNA < 50 c/mL %
100
89% (95% CI: 84-93) 90
83% (95% CI: 76-88) 80
77% (95% CI: 71-83) 70 60
p = EFV vs LPV/r 50 40
Efavirenz + 2 NRTIs 30
Lopinavir/r + 2 NRTIs 20
EFV + LPV/r 10
Weeks 4 8 16 24 32 40 48 56 64 72 80 88 96
N =
250
236
224
212
201
178
N =
253
235
226
217
201
177
N =
250
242
228
217
206
180
A5142
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8. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Virologic and immunologic outcomes
Virologic failure
% HIV RNA < 50 c/mL at W96 (95% CI)
Median (IQR) CD4 (/mm3) increase at W96
Efavirenz + NRTI
24%
89 (84-93)
230 ( )
p = 0.01 vs LPV/r or EFV + LPV/r
Lopinavir/r + NRTI
37%
77 (71-83)
p = vs EFV
287 ( )
Efavirenz + lopinavir/r
29%
83 (76-88)
273 ( )
Hazard ratios (95% CI) for time to virologic failure or to regimen failure
Time to virologic failure
Time to regimen failure
EFV vs LPV/r
0.63 ( )
0.75 ( )
EFV vs EFV + LPV/r
0.86 ( )
0.93 ( )
LPV/r vs EFV + LPV/r
1.30 (0.95-1,77)
1.21 ( )
Hazard ratios (95% CI) for virologic failure *
Female sex
1.38 ( )
Black race
1.57 ( )
Younger age
1.23 ( )
Lower CD4 cell count
1.14 ( )
* Multivariable Cox model stratified according to the 3 baseline factors
A5142
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9. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Grade 3 or 4 clinical events or laboratory abnormalities
EFV + 2 NRTIs (1) N = 250
LPV/r + 2 NRTIs (2)
N = 253
EFV + LPV/r (3)
N = 250 p
Any new sign or symptom, grade 3 or 4
17%
18%
Pain or discomfort 6% 8%
Diarrhoea or loose stools
< 1% 3%
< 0.05 (1 vs 2)
Nausea 2%
Macules, papules or rash 1%
Headache 4%
Grade 3 or 4 laboratory abnormality
Any abnormality
29%
32%
43%
< 0.05 (1 vs 3)
< 0.05 (2 vs 3)
Creatine kinase > 5 x ULN
Neutrophil count < 750/mm3 7% 5%
Fasting LDL-cholesterol > 190 mg/dL
Fasting triglycerides > 750 mg/dL
14%
Hepatic aminotransferase > 5 x ULN
Lipase > 2 x ULN 9%
Clinical lipoatrophy
Toxicity leading to discontinuation of one or more drugs = 18% (no significant difference among the 3 groups)
A5142
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10. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Resistance mutations at the time of virologic failure
EFV + 2 NRTIs (1) N = 250
LPV/r + 2 NRTIs (2) N = 253
LPV/r + EFV (3) N = 250 p
Virologic failure, N (%)
60 (24%)
94 (37%)
73 (29%)
Genotype available, N 46 78 56
> 1 major mutation, N (%)
22 (48%)
16 (21%)
39 (70%)
0.03 (1 vs 3)
< (3 vs 2)
0.002 (1 vs 2)
Any NRTI mutation, N (%)
14 (30%)
15 (19%)
6 (11%)
0.02 (1 vs 3)
M184V, N (%)
8 (17%)
13 (17%)
1 (2%)
0.01 (1 vs 3)
< 0.01 (3 vs 2)
K65R, N (%)
3 (7%)
0.05 (1 vs 2)
TAMs *, N (%)
2 (4%)
1 (1%) -
Any NNRTI mutation, N (%)
20 (43%)
2 (3%)
37 (66%)
K103N, N (%)
11 (24%)
31 (55%)
0.002 (1 vs 3)
Major protease mutation **, N (%)
Mutation associated with 2 drug classes, N (%)
12 (26%)
4 (7%)
< (1 vs 2)
* 41L, 67N, 70R, 210W, 215Y/F and 219Q/E; ** 30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V and 90M
A5142
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11. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
ARV-trial.com
ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r
Summary - Conclusions
96-week randomized trial comparing 3 regimens for initial therapy for HIV infection
Less virologic failure with EFV + 2 NRTIs than with LPV/r + 2 NRTIs
NRTI-sparing regimen of EFV + LPV/r: virologic efficacy similar to EFV + 2 NRTIs but more frequent NNRTI resistance and lipid abnormalities
Non-significant trend toward a shorter time to regimen failure with LPV/r + 2 NRTIs as compared with EFV + 2 NRTIs
No significant difference among the 3 groups in the time to treatment-limiting toxicity
Lower increases in CD4 count with EFV + 2 NRTIs compared to the 2 LPV/r groups
Resistance emergence: NRTI resistance frequency not significantly different between EFV + 2 NRTIs and LPV/r + 2 NRTIs; mutations to 2 drug classes significantly more frequent with EFV + 2 NRTIs; EFV + NRTI failure associated with high frequency of NNRTI resistance; failure of LPV/r + 2 NRTIs not associated with LPV resistance
This study shows moderate efficacy superiority of EFV + 2 NRTIs as compared with LPV/r + 2 NRTIs for initial therapy of HIV-1 infection
Results highlight the complexity of choosing initial therapy with the need to take into considerations many factors, including virologic and immunologic response, tolerability, short-term and long-term toxicity, and the resistance consequences associated with virologic failure
A5142
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