Transcript ARV-trials 2014

Comparison of NRTI combinations
 ZDV/3TC vs TDF + FTC
– Study 934
 ABC/3TC vs TDF/FTC
– HEAT Study
– ACTG A5202 Study
– ASSERT Study
 Comparison of TAF vs TDF
– Studies GS-US-292-0104 and GS-US-292-0111
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
 Design
Randomisation*
1:1
Open-label
> 18 years
ARV-naïve
HIV RNA > 1,000 c/mL
Any CD4 cell count
HLA-B*5701 allele negative
W48
N = 195
ABC/3TC + EFV
N = 197
TDF/FTC + EFV
W96
* Randomisation was stratified by screening eGFR (MDRD), race (black or non black), and BMI
 Primary analysis
– Intention to treat, exposed analysis : 2-sided significance level of 5%, with 90%
power to detect a difference of 10 mL/min in eGFR (MDRD) change from
baseline between arms
ASSERT
Post FA. JAIDS 2010;55:149-57
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
Baseline characteristics and patient disposition
ABC/3TC + EFV
N = 192
TDF/FTC + EFV
N = 197
38
36
Female
17%
20%
Black
14%
16%
BMI (kg/m2) < 25 / > 25
66% / 33%
67% / 33%
eGFR (mL/min/1.73m2) < 90 / > 90
32% / 68%
33% / 67%
HIV RNA (log10 c/mL), median
5.01
5.12
CD4 cell count (/mm3), median
240
230
10-year coronary heart disease risk
(Framingham score), median
2.97
2.90
63 (33%)
44 (23%)
For lack of efficacy
N =11
N=2
For adverse event
N = 25
N = 20
Lost to follow-up
N=5
N=5
N=5/N=6
N=1/N=4
N = 11
N = 12
Median age, years
Discontinuation by W48
Protocol deviation / Withdrew consent
Other reasons
ASSERT
Post FA. JAIDS 2010;55:149-57
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
8
4
P = 0.435
0
ABC/3TC + EFV
TDF/FTC + EFV
-4
-8
0
Subjects at visit
ABC/3TC + EFV
TDF/FTC + EFV
4
192 172
193 181
12
158
176
24
36
Week
155
173
144
167
48
135
159
Treatment Difference
at week 48
4
0
-4
Treatment difference
(ml/min/1.73 m²)
8
ABC/3TC EFV QD TDF/FTC EFV QD
Better Better
Change from BL in GFR by MDRD
(ml/min/1.73 m²)
Adjusted mean change from baseline in eGFR by MDRD
(ml/min/1.73 m2), ITT-e population
-8
Mean change in eGFR
at week 96 :
+ 1.48 (ABC/3TC)
- 1.15 (TDF/FTC)
Repeated measures mixed model analysis
ASSERT
Post FA. JAIDS 2010;55:149-57 ; Moyle GJ, Antiviral Therapy 2013;18:905-13
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
 Secondary renal endpoints
– No differences between arms in proportion with significant declines in eGFR
or with renal failure
– Percentage change from baseline at week 48
• Urinary retinol-binding protein/creatinine ratio : TDF/FTC = + 50% vs ABC/3TC = 0%
(p < 0.0001)
• Urinary b2-microglobulin/creatinine ratio : TDF/FTC = + 24% vs ABC/3TC = - 47%
(p < 0.0001)
Changes in bone density (DXA) at week 48
ABC/3TC + EFV
TDF/FTC + EFV
p
Mean change in total hip loss
- 1.9%
- 3.6%
< 0.001
Mean change in lumbar spine
- 1.6%
- 2.4%
0.036
3% / 5%
13% / 10%
BMD loss > 6% in the hip / in the spine
 Bone turnover markers : increased in both groups over the first 24 weeks
(significantly greater with TDF/FTC), stabilizing or decreasing thereafter
ASSERT
Post FA. JAIDS 2010;55:149-57 ; Moyle GJ, Antiviral Therapy 2013;18:905-13 ; Stellbrink HJ. CID 2010;51:963-72
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
Efficacy at week 48
HIV RNA < 50 c/mL
%
ABC/3TC + EFV
TDF/FTC + EFV
100
71.0
75
59.4
50
25
0
Protocol-defined virologic failure (< 1 log10 c/mL reduction in
HIV RNA by W4, confirmed rebound ≥ 400 c/mL after
confirmed HIV RNA < 400 c/mL by W24 or confirmed HIV RNA
> 400 c/mL after W24)
• 6 on ABC/3TC + EFV
– Emergence of resistance : 3/6
– 2 patients with NNRTI mutations
–1 patient with NNRTI mutation and K65R + D67N
• 2 on TDF/FTC + EFV = no resistance emergence
ITT, TLOVR
Adjusted difference
95% CI = 11.6% (2.2 ; 21.1)
ASSERT
Median CD4/mm3 increase at W48 : + 150 in both groups
Post FA. JAIDS 2010;55:149-57
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
 Safety at W48
Drug-related adverse events
Grade 2-4
ABC/3TC + EFV
N = 192
TDF/FTC + EFV
N = 197
51%
47%
29%
20%
Most common grade 2-4 AEs : dizziness, abnormal dreams, drug hypersensitivity
Drug hypersensitivity
N = 12 (6%)
N = 1 (< 1%)
N=6
-
Total cholesterol, mg/dL
1.36
0.66
Triglycerides, mg/dL
0.23
0.05
LDL-cholesterol, mg/dL
0.81
0.39
HDL-cholesterol, mg/dL
0.38
0.28
- 0.559
-0.934
Clinically suspected ABC hypersensitivity
Median changes in fasting lipids from baseline at W48
Total cholesterol/HDL-cholesterol ratio
ASSERT
Post FA. JAIDS 2010; 55:149-57
ASSERT Study: ABC/3TC + EFV vs TDF/FTC + EFV
 Conclusion
– No difference in estimated glomerular filtration rate between ABC/3TC
+ EFV and TDF/FTC + EFV
• However, increases in markers of tubular dysfunction in the TDF/FTC arm
• No differences in markers of glomerular dysfunction over 96 weeks
– Significant higher virologic efficacy for TDF/FTC + EFV
• Emergence of resistance to NNRTI and NRTI on virological failure with
ABC/3TC + EFV but not with TDF/FTC + EFV
– Incidence of grade 4 adverse events and serious adverse events was
higher in the ABC/3TC arm, mainly because of drug hypersensitivity
or hypersensitivity
– Smaller increases in serum lipids with TDF/FTC
– Greater increases in bone turnover and decreases in hip and vertebral
bone mineral density with TDF/FTC + EFV compared to ABC/3TC
+ EFV
ASSERT
Post FA. JAIDS 2010; 55:149-57 ; Moyle GJ, Antiviral Therapy 2013;18:905-13