38
Metabolic Outcomes of ACTG 5142: A Prospective, Randomized, Phase III Trial of NRTI-, PI-, and NNRTI-sparing Regimens for Initial Treatment of HIV-1 Infection
Richard H. Haubrich*1, S Riddler2, G DiRienzo3, L Komarow3, W Powderly4, K Garren5, T George6, J Rooney7, J Mellors2, D Havlir8, and the AIDS Clinical Trials Group 5142 Study Team
1Univ of California, San Diego, US; 2Univ of Pittsburgh, PA, US; 3Harvard Sch of Publ Hlth, Statistical and Data Analysis Ctr, Boston, MA, US; 4Univ Coll Dublin, Ireland; 5Abbott Labs, Abbott Park, IL, US; 6Bristol-Myers Squibb, Plainsboro, NJ, US; 7Gilead Sci, Foster City, CA, US; and 8Univ of California, San Francisco, US
Background: The metabolic
effects of lopinavire (LPV)-
or efavirenz (EFV) -based regimens + 2 nucleoside
reverse transcriptase inhibitors (NRTI) have not been compared nor has the role
of an NRTI-sparing regimen in preventing lipoatrophy
been tested.
Methods: This open-label,
randomized trial compared class-sparing regimens for naïve subjects: LPV+EFV vs LPV+2
NRTI (LPV soft-gel twice daily) vs EFV+2 NRTI. NRTI
were selected before randomization from zidovudine (ZDV),
stavudine (d4T XR), or tenofovir
(TDF) (each plus lamivudine [3TC]). Metabolic
objectives included evaluation of changes in fat (DEXA) and fasting lipids.
DEXA and lipids were performed at baseline, and 48 and 96 weeks. Lipoatrophy was defined as ≥20% loss of limb fat from
baseline. All analyses were intent to treat without adjustment for multiple
comparisons or regimen changes. Pairwise comparisons
used non-parametric tests.
Results: We enrolled 753
subjects (median CD4 182 cells/mm3, median HIV-1 RNA 100,000 copies/mL) who were followed for a median 112 weeks. The NRTI of choice
was ZDV 42%, d4T XR 24%, and TDF 34%. Median baseline values were not different
by arm: trunk fat 8.2 kg, extremity fat
7.0 kg, total cholesterol (TC) 154 mg/dL, HDL 35 mg/dL, non-HDL 117 mg/dL, and
triglycerides (TG) 116 mg/dL. By week 96, 10%, 12%,
and 26% of EFV, LPV, and LPV/EFV subjects used a lipid-lowering agent. Week-96
results (see the table) were similar to other time points. Lipoatrophy
in the EFV or LPV+NRTI was predominately seen in the d4T- or ZDV-containing regimens;
there was no significant difference (p
>0.5) in lipoatrophy between TDF- containing and NRTI-sparing
regimens.
Conclusions: A NRTI-sparing
regimen (LPV+EFV) increased lipids significantly more than EFV or LPV+2 NRTI regimens.
Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but
cholesterol changes were not significantly different. Compared to EFV, LPV had
less lipoatrophy when given with NRTI. The frequency
of lipoatrophy was lowest in NRTI-sparing and TDF-containing
regimens.
|
Week 96 Result
|
Primary Randomized
Arm
|
NRTI (LPV and
EFV Arms)
|
|
|
N
|
EFV
|
LPV
|
LPV/EFV
|
p ≤ 0.01
|
N
|
d4T
|
TDF
|
ZDV
|
p ≤ 0.05
|
|
|
|
Median value
or %
|
|
|
Median value
or %
|
|
|
% D extremity fat
|
498
|
0.3
|
9.9
|
18
|
a,b,c
|
329
|
–11
|
17
|
2.0
|
d,e,f
|
|
% D trunk fat
|
498
|
12
|
19
|
17
|
--
|
329
|
11
|
23
|
16
|
d
|
|
lipoatrophy
|
498
|
32%
|
18%
|
8%
|
a,b,c
|
329
|
43%
|
10%
|
27%
|
d,e,f
|
|
D TC (mg/dL)
|
517
|
33
|
33
|
57
|
b,c
|
343
|
41
|
21
|
33
|
d
|
|
D HDL (mg/dl)
|
508
|
9
|
8
|
16
|
b,c
|
334
|
8
|
8
|
9
|
--
|
|
D non-HDL (mg/dL)
|
506
|
21
|
26
|
43
|
b,c
|
333
|
26
|
17
|
26
|
d
|
|
D TG (mg/dL)
|
518
|
14
|
47
|
63
|
a,b*,c
|
344
|
47
|
21
|
24
|
d
|
Pairwise comparisons: a = EFV vs
LPV; b = LPV vs LPV/EFV; c = EFV vs
LPV/EFV; d = d4T vs TDF; e = TDF vs
ZDV; f = ZDV vs d4T. b*= 0.025.
If not listed, p >0.05
|
