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 A5202 Study: ABC/3TC vs TDF/FTC
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC
Multicenter, randomized, blinded equivalence study in 1858 HIV-1 infected patients
Comparison of antiviral activity, safety and tolerability of ABC/3TC and TDF/FTC, given with EFV or ATV/r
Scheduled interim review by the DSMB of the NIAID: inferior virologic efficacy of ABC/3TC in patients with a screening HIV RNA > 100,000 c/mL
Report of data from the 797 patients with screening HIV RNA > 100,000 c/mL
Inclusion criteria: HIV-1 infection, > 16 years, < 7 days of prior antiretroviral therapy, acceptable laboratory values
Design: randomized, partially blinded study comparing 4 once-daily regimens for the initial treatment of HIV-1 infection:
EFV 600 mg or ATV/r 300/100 mg, in combination with ABC/3TC or TDF/FTC (double-blinding for the NRTIs)
Randomisation was stratified on screening HIV RNA (> or < 100,000 c/mL)
Planned study duration was 96 weeks after enrolment of the last patient
Genotypic resistance test was required in patients with recent HIV-1 acquisition
Testing for HLA-B*5701 was permitted but not required
A5202
Sax PE. NEJM 2009;361: 2

3. ACTG A5202 Study: ABC/3TC vs TDF/FTC
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC
Statistical analysis
Primary efficacy endpoint: time to virologic failure (confirmed HIV RNA > 1,000 c/mL at or after W16 and before W24, or > 200 c/mL at or after W24)
Primary hypotheses:
Equivalence of ABC/3TC and TDF/FTC (for each regimens with ATV/r and EFV)
Equivalence of ATV/r and EFV (for each NRTI regimen)
Equivalence if the two-sided 95% CI for the hazard ratio was between 0.71 and 1.40 (power of 89.8%)
Pre specified early-stopping rules for inferiority at annual efficacy review by DSMB
Analyses of efficacy by ITT, stratified according to the screening HIV RNA
Kaplan-Meier estimation of time-to-event, with comparison by two-sided log-rank tests. Hazard ratios estimated by Cox models
Primary safety endpoint: time to the first grade 3 or 4 sign, symptom, or laboratory abnormality at least 1 grade higher than at baseline (except isolated unconjugated bilirubin and creatine kinase) while on randomly assigned treatment
A5202
Sax PE. NEJM 2009;361: 3

4. ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Baseline characteristics of the patients with screening HIV RNA > 100,000 c/mL
ABC/3TC
N = 398
TDF/FTC
N = 399
Total
N = 797
Median age, years 38 40 39
Female
17%
14%
15%
White/Black/Other
43% / 28% / 30%
51% / 24% / 25%
47% / 26% / 27%
History of AIDS
26%
22%
24%
HIV RNA, log10 c/mL, median (IQR) *
5.0 (4.7–5.6)
HIV RNA > 100,000 c/mL
HIV RNA 50,000–99,999 c/mL
49%
30%
50%
27%
28%
CD4 count/mm3, median (IQR) **
138 (36–282)
146 (45–294)
145 (41–285)
CD4 < 200/mm3
CD4 < 50/mm3
61%
31%
58%
59%
HBsAg+ or HCV Ab+ 9% 8%
Genotype tested at screening
44%
42%
43%
* Geometric mean of screening and entry visits; ** mean of screening and entry visits
A5202
Sax PE. NEJM 2009;361: 4

5. Time to virologic failure
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Time to virologic failure
100
TDF/FTC (26 events)
Median follow-up = 60 weeks
Discontinuation: 10% = 41 patients on ABC/3TC and 38 on TDF/FTC
Risk of subsequent virologic failure among 448 patients with > 2 consecutive HIV RNA < 50 c/mL = 12 in ABC/3TC group vs 9 in TDF/FTC group (p = 0.25)
Median CD4/mm3 increase at W48: 194 (ABC/3TC) vs 199 (TDF/FTC) 80
ABC/3TC (57 events) 60
Probability of No Virologic Failure (%)
p < 0.001, log-rank test 40
Hazard ratio : 2.33 (95% CI : ) 20 4 16 24 36 48 60 72 84 96
108
Weeks since randomisation
No. at risk
ABC/3TC
398
363
313
267
222
188
137 87 49 20
TDF/FTC
399
361
321
284
236
204
160
104 65 23
Early and late virologic failure according to the protocol-defined criteria by treatment group
ABC/3TC
N = 57
TDF/FTC N = 26
HIV RNA > 1,000 c/mL at W16 to < W24 without previous level < 200 c/mL 19 9
HIV RNA > 200 c/mL at or after W24 without previous level < 200 c/mL 2
HIV RNA > 200 c/mL at or after W24 with previous level < 200 c/mL 29 15
A5202
Sax PE. NEJM 2009;361: 5

6. ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Time to regimen failure*
Time to safety endpoint
100
100
TDF/FTC (68 events)
TDF/FTC (78 events) 80 80 60 60
Probability of No Regimen Failure (%)
ABC/3TC (114 events)
Primary Safety Event (%)
Probability of No
ABC/3TC (130 events) 40 40
p < 0.001, log-rank test
Hazard ratio: 1.87 (95% CI: )
p < 0.001, log-rank test
Hazard ratio: 1.89 (95% CI: ) 20 20 4 16 24 36 48 60 72 84 96
108 4 16 24 36 48 60 72 84 96
108
Weeks since randomisation
Weeks since treatment dispensation
No. at risk
No. at risk
ABC/3TC
396
341
290
247
206
173
124 78 46 19
ABC/3TC
397
258
219
177
148
118 82 49 27 5
TDF/FTC
397
355
316
281
235
204
158
101 63 21
TDF/FTC
397
299
272
233
188
156
112 71 35 12
* Regimen failure: virologic failure or NRTI modification (time to first event)
A5202
Sax PE. NEJM 2009;361: 6

7. % of patients with HIV-1 RNA < 50 c/mL * Weeks since randomisation
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
% of patients with HIV-1 RNA < 50 c/mL *
100
TDF/FTC 80
ABC/3TC 60
p = 0.20, chi-square test at week 48 40 20
Weeks since randomisation 4 16 24 36 48 60 72 84 96
108
No. with RNA value
ABC/3TC
388
357
324
293
245
212
163
114 59
TDF/FTC
393
352
325
285
244
211
169
109 69
* ITT analysis involving all patients, regardless of prior NRTI discontinuation or virologic failure
This analysis represents the aggregate success of both initial (randomly assigned) and subsequent therapy
A5202
Sax PE. NEJM 2009;361: 7

8. Events per 100 person-year
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Estimated effect of ABC/3TC (N=398) vs TDF/FTC (N=399) on the hazard of virologic failure
Subgroup
Events per 100 person-year
Hazard Ratio (95% CI)
p for interaction
Overall
57/398 (14.82)
26/399 (6.34)
2.33 (1.46–3.72)
< 0.001
Sex
0.04
Male
50/331 (15.41)
18/345 (5.24)
3.00 (1.74–5.17)
Female
7/67 (11.63)
8/54 (11.97)
0.85 (0.30–2.39)
Age
0.07
30 yr
3.24 (1.73–6.08)
40 yr
2.08 (1.28–3.39)
Race or ethnic group
0.55
White
18/170 (10.33)
8/202 (3.63)
2.82 (1.22–6.53)
Black
26/112 (26.71)
12/94 (13.93)
1.94 (0.96–3.90)
Hispanic
9/103 (8.87)
6/93 (6.59)
1.35 (0.48–3.83)
HIV-1 RNA
0.20
5.5 log10 c/mL
2.64 (1.58–4.40)
6.0 log10 c/mL
3.39 (1.60–7.22)
CD4 count
0.007
50 cells/mm3
3.54 (1.97–6.36)
200 cells/mm3
1.68 (0.98–2.88)
Genotype tested at screening
0.02
Yes
22/175 (14.05)
3/166 (1.99)
7.21 (2.15–24.2) No
35/223 (15.35)
23/233 (8.88)
1.71 (1.00–2.91)
0.04 1 25
ABC/3TC better
TDF/FTC better
A5202
Sax PE. NEJM 2009;361: 8

9. ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Grade 3 or 4 signs, symptoms or laboratory abnormalities at least 1 grade higher than the grade at baseline, during the initial regimen
ABC/3TC N = 397
TDF/FTC N = 397
Any lab. abnormality or clinical adverse event, N (%)
130 (33)
78 (20)
Metabolic abnormality, N (%)
41 (10)
11 (3)
Triglycerides elevation, N 15 3
Total cholesterol elevation, N 20 2
LDL-cholesterol elevation, N 13 4
ALT, N 7 5
AST, N 12
Diarrhoea or loose stool, N
Nausea or vomiting, N
General signs or symptoms, N (%)
58 (15)
38 (10)
Pain or discomfort, N 24 14
Rash, N 8
Pruritus, N 9
Fever, N 10
Asthenia, N 6
Headache, N
A5202
Sax PE. NEJM 2009;361: 9

10. Selected clinical and laboratory events
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Selected clinical and laboratory events
ABC/3TC
TDF/FTC p
Median change in fasting lipids at W48 (mg/dL)
Total cholesterol
+ 34
+ 26
< 0.001
HDL-cholesterol
+ 9
+ 7
0.05
Triglycerides
+ 25
+ 3
0.001
Ratio of total cholesterol to HDL-cholesterol
- 0,2
0.5
Suspected study drug-related HSR, N (%)
27 *, ** (7%)
27 ** (7%)
Renal failure, N 2
Median change in calculated creatinine clearance at W48 (mL/min)
+ 4
+ 2
0.10
Myocardial infarction, N
Bone fractures, N 7 10
AIDS events, N (%)
26 (7%)
17 (4%)
HIV-related cancers, N 8 4
* 1 death after restarting ABC-containing study medication
** subsequent viriologic failure among patients with suspected HSR = 4 in ABC/3TC group, 3 in TDF/FTC group
A5202
Sax PE. NEJM 2009;361: 10

11. ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC (screening HIV RNA > 100,000 c/mL)
Summary - Conclusion
For initial treatment of HIV-1 infection, patients with a screening HIV RNA > 100,000 c/mL whose regimen contains TDF/FTC as compared with ABC/3TC were significantly less likely
to experience virologic failure: TDF/FTC superiority in virologic outcome was observed throughout the duration of the study and in multiple sensitivity analyses
to experience tolerability failure
Possible explanation: ABC/3TC is less potent than TDF/FTC
Difference in virologic failure between NRTIs significantly increased with a lower CD4 count
Differences in virologic failure persisted after adjustement for multiple baseline covariates
Occurrence of suspected hypersensitivity reactions did not influence study outcomes: equal number in both groups, virologic failure infrequent
Important implications for clinical practice of this double-blind, randomized, prospective study
Patients with high HIV RNA have a risk of virologic failure twice higher with ABC/3TC as compared with TDF/FTC
Treatment guidelines recommend to consider results of this study when selecting NRTIs for first-line antiretroviral therapy in patients with high HIV RNA
A5202
Sax PE. NEJM 2009;361: 11

12. Patients characteristics at screenning
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients)
Patients characteristics at screenning
ABC/3TC
TDF/FTC
Total
n = 1,857
EFV
n = 465
ATV/r
n = 463
n = 464
Median age, years 37 38 39
Female
21%
16 %
15%
17%
History of AIDS
19%
18 %
HIV RNA (log10 c/ml), median
4.7
4.6
CD4 cell count (/mm3), median
225
236
234
224
230
HCV Ab+ 6% 7% 9%
Genotype at screening
43%
48%
47%
40%
45%
Results in the 797 patients with screening HIV RNA > 100,000 c/mL :
at DSMB action, time to virologic failure was significantly shorter with ABC/3TC as compared with TDF/FTC, independently of 3rd drug
[HR (95% CI)]: 2.33 ( ) (Sax PE, NEJM 2009;361: )
with EFV: 2.46 ( )
with ATV/r: 2.22 ( )
A5202
Sax PE, NEJM 2009;361: ) ; Daar ES. CROI 2010; Abs. 59LB 12

13. Time to virologic failure
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients)
Time to virologic failure
HR (95% CI)
Probability of absence of virologic failure at W96
Screening HIV RNA < 100,000 c/ml (n = 1,060)
ABC/3TC vs TDF/FTC (+ ATV/r)
1.26 ( )
88.3% vs 90.3%
ABC/3TC vs TDF/FTC (+ EFV)
1.23 ( )
87.4% vs 89.2%
Overall, all patients (n = 1,857)
ATV/r vs EFV (+ ABC/3TC)
1.13 ( )
83.4% vs 85.3%
ATV/r vs EFV (+ TDF/FTC)
1.01 ( )
89% vs 89.8%
In patients with screening HIV RNA < 100,000 c/ml, ABC/3TC and TDF/FTC have similar time to virologic failure, with ATV/r and EFV
Overall, ATV/r and EFV have similar time to virologic failure, with both NRTIs
A5202
Sax PE, NEJM 2009;361: ) ; Daar ES. CROI 2010; Abs. 59LB 13

14. Time to primary safety endpoint (Grade 3-4 event)
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients)
Time to primary safety endpoint (Grade 3-4 event)
Time to tolerability endpoint (modification of originally randomized regimen)
HR (95% CI) p
Screening HIV RNA < 100,000 c/ml (n = 1,060)
ABC/3TC vs TDF/FTC + ATV/r
1.13
( )
0.44
1.43
( )
0.018
ABC/3TC vs TDF/FTC + EFV
1.38
( )
0.03
1.48
( )
0.005
Overall, all patients (n = 1,857)
ATV/r vs EFV + ABC/3TC
0.81
( )
0.05
0.69
( )
0.0008
ATV/r vs EFV + TDF/FTC
0.91
( )
0.84
( )
0.17
A5202
Daar ES. CROI 2010; Abs. 59LB 14

15. ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC: final results (screening HIV RNA < 100,000 c/ml )
In patients with screening HIV RNA < 100,000 c/ml: ABC/3TC compared with TDF/FTC
Similar time to virologic failure with ATV/r and EFV
Shorter time to safety event with EFV
Shorter time to modification with ATV/r and EFV (difference driven by suspected hypersensitivity reactions in ABC/3TC arms)
Greater increase in CD4 with EFV
Greater increase in total cholesterol, LDL- and HDL-cholesterol with both ATV/r and EFV; greater increase in triglycerides with ATV/r
Increase (ABC/3TC) versus modest decline (TDF/FTC) in creatinine clearance with ATV/r
A5202
Daar ES, CROI 2010, Abs. 59LB
Daar ES. CROI 2010; Abs. 59LB 15

16. ATV/r compared with EFV (all patients)
ARV-trial.com
ACTG A5202 Study: ABC/3TC vs TDF/FTC, in combination with EFV vs ATV/r - Final results (all patients)
ATV/r compared with EFV (all patients)
Similar time to virologic failure with both NRTIs
Pre-specified equivalence boundary on HR was not met, as observed W96 event rate was lower than projected (~15% vs 32%)
Difference and CIs for probability of being failure free at W96 were within + 10% criteria often used for defining equivalence (post hoc analysis)
Longer time to safety event and to 3rd drug modification with ABC/3TC
Among virologic failures there was less resistance with both NRTIs
Greater increase in CD4 with TDF/FTC
Smaller increases in total cholesterol, LDL- and HDL-cholesterol with both NRTIs
Modest decline in creatinine clearance with TDF/FTC vs increase with ABC/3TC
A5202
Daar ES, CROI 2010, Abs. 59LB
Daar ES. CROI 2010; Abs. 59LB 16