Transcript LPV/r + NVP

Switching to a Thymidine Analog-Sparing or a
Nucleoside-Sparing Regimen Improves
Lipoatrophy: 24 Week Results of a Prospective
Randomized Clinical Trial: AACTG A5110
Robert Murphy, Jiameng Zhang, Richard Hafner,
Abby Shevitz, Karen Tashima, Kevin Yarasheski,
Baiba Berzins, Susan Owens, Jodi Forand, Scott Evans,
Pablo Tebas and the AACTG A5110 Study Team
Objectives
• Primary Objectives:
– To investigate effects of change in peripheral fat wasting of
thymidine-sparing regimen and NRTI-sparing regimen
• Secondary Objectives:
– To investigate the effect of changes on subcutaneous and
visceral fat tissue distribution in the abdomen
– To investigate the effect of change on safety and virologic
activity.
– To investigate the effect of change on glucose and lipid
metabolism
– To investigate the effect of change on serum and urine markers
of bone mineral metabolism
– To investigate the effect of treatment change on quality of life
Inclusion criteria
•
HIV-1 infection
•
Self-reported peripheral fat wasting including atrophy of the
extremities, since starting ARV therapy
•
Fat wasting confirmed on a physical examination
•
On HAART including either ZDV or d4T, for  24 weeks
•
Plasma HIV-1 RNA < 500 copies/mL
•
CD4+ cell count  100 cells/mm3
•
Labs
–
–
–
Creatinine  3 x ULN
AST (SGOT) and ALT (SGPT)  5x ULN
Lipase  1.5 x ULN
Exclusion criteria
•
•
•
•
•
•
•
•
•
•
Initiation of oral hypoglycemic agents,
Use of insulin, megestrol, rhGrowth hormone, supraphysiologic
doses of corticosteroids, or hydroxyurea *
Initiation of androgen therapy*
Hyperthyroidism or hypothyroidism *
Systemic chemotherapy within 6 months
Pregnancy and breast-feeding
Drug abuse that could interfere with adherence to study
Serious illness
Current use of investigational agents
Documented or suspected acute hepatitis within 60 days of entry
* Stable physiologic replacement was allowed
A5110 Schema
A1: Thymidine-sparing
n=37
Switch d4T or ZDV to ABC
Clinical Lipoatrophy
>24 wks ZDV or d4T
HIV RNA <500 c/ml
“Readable” CT
N = 101
15 ACTG sites
n=40
A2: Nucleoside-sparing
Switch to
LPV/r + NVP
Secondary endpoint (combined arms)
n=11
n=13
B1: Delayed
Switch d4T or ZDV to ABC
B2: Delayed
Switch to
O
24w
LPV/r + NVP
48w
72w
Primary endpoint
 Original 2:2:1:1 randomization. Delayed arms were discontinued after MITOX was presented
 Patients restrictively randomized based on ARV history and genotype; 80% eligible for all arms
Stratification by current d4T or ZDV use
Primary endpoint
• Primary: Change in thigh subcutaneous (SQ) adipose
tissue at 24 weeks for all 3 arms
• Secondary:
– Change in thigh SQ adipose tissue after 24 weeks of
intervention (combined arms)
– Change in abdominal visceral adipose tissue (VAT),
subcutaneous adipose tissue (SAT), glucose, lipid,
bone, quality of life at 24 and 48 weeks
Power: 50 patients per group, 80% to detect a 30% difference within arms
SQ thigh adipose tissue
• All CTs
centrally
analyzed at
Tufts
Subcutaneous thigh
adipose tissue
Week 0
Week 48
Abdominal VAT and SAT
• All CTs
centrally
analyzed at
Tufts
Subcutaneous adipose
tissue (SAT)
Visceral adipose tissue
(VAT)
Week 0
Week 48
Baseline characteristics
Delayed
(n=24)
ABC
(n=37)
LPV/r +
NVP
(n=40)
Male %
92
81
85
NS
White %
71
70
68
NS
Hx IVDU %
21
5
8
NS
Age y (median)
46
48
45
NS
572
598
645
NS
4
3
6
NS
88
78
68
NS
CD4/ml (median)
% HIV RNA >200 c/ml
% on D4T
p value
Baseline characteristics
median (IQR)
Delayed
(n=24)
ABC
(n=37)
LPV/r +
NVP
(n=40)
19 (7, 27)
15 (7, 29)
20 (11, 29)
ns
SAT(cm2)
78 (34,111)
60 (39,170)
85 (53,121)
ns
VAT(cm2)
94 (50,146)
142
(82,195)
115
(71,160)
0.04
VAT:TAT ratio
0.53
(0.45, 0.70)
0.64
(0.46, 0.77)
0.57
(0.44, 0.68)
ns
Thigh SQ adipose
tissue (cm2)
p value
SQ thigh adipose tissue
median (IQR)
Primary EP 24 wk
ABC
LPV/r+NVP
Delayed
25
20
% change from baseline
Combined arms 24 wk
ABC (n=48)
LPV/r+NVP (n=53)
15
p=0.02*
p=0.06*
10
5
0
-5
-10
-15
-20
0
* within arm change
24
0
Weeks
24
Abdominal SQ adipose tissue
median (IQR)
Primary EP 24 wk
50
Delayed
ABC
LPV/r+NVP
40
% change from baseline
Combined arms 24 wk
30
ABC
LPV/r+NVP
p<0.01*
p<0.01*
p<0.01*
20
p=0.04*
10
0
†
-10
-20
-30
-40
0
*Within arm change
† Between arm p<0.01
24
0
Weeks
24
Visceral adipose tissue (VAT)
median (IQR)
Primary EP 24 wk
Combined arms 24 wk
50
% change from baseline
ABC
LPV/r+NVP
Delayed
ABC
LPV/r+NVP
40
30
20
10
0
-10
p<0.01*
p<0.01*
-20
-30
-40
0
24
0
Weeks
* Within arm change
24
VAT:TAT ratio
median (IQR)
Primary EP 24 wk
Combined arms 24 wk
25
Delayed
ABC
LPV/r+NVP
% change from baseline
20
15
ABC
LPV/r+NVP
10
p=0.08*
5
0
-5
†
-10
p<0.01*
p<0.01*
p<0.01*
p<0.01*
-15
-20
-25
0
* Within arm change
† Between arms p<0.01
24
0
Weeks
24
CD4 and HIV RNA
at 24 weeks
ABC
(n=37)
LPV/r +
NVP
(n=40)
100
92
93
2.4
-7,26
-4.8
-15,11
8.0
-9,25
NS
NS
P=0.03
Delayed
(n=24)
% HIV RNA <200c/ml
(486, 946, 706,
15211, 96805)
CD4 count
Median % change
IQR
NS
Early Discontinuation Reasons
ABC
Study discontinuations
Unable to contact patient
1
Patient withdrawal
1
Severe debilitation, unable to continue 0
LPV/+NVP
0
2
1
Study drug discontinuations
6
6
ABC: fever, nausea, hepatitis, rash/allergic reaction (3)
LPV/r+NVP: rash/allergic reaction, hyperlipidemia (3),
hepatitis (2)
Conclusions
• Switching d4T or ZDV to lopinavir/r + nevirapine, an NRTI-sparing
regimen. is associated with significant improvement in SQ extremity
fat at 24 weeks.
• Switching d4T or ZDV to abacavir, a non-thymidine analog, or
lopinavir/r + nevirapine, an NRTI-sparing regimen, is associated with
significant improvements in abdominal SAT, VAT and VAT:TAT
• Both interventions appear safe immunologically and virologically, the
NRTI-sparing increased CD4 counts significantly
• Longer follow up is needed to better understand the long term
implications of both interventions
• Central lipid, glucose, bone metabolism and quality of life studies
and 48 week analyses are ongoing
Acknowledgments
• Team members
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Robert L. Murphy, M.D.
Pablo Tebas, M.D.
Richard Hafner, M.D.
Mira Madans
Scott Evans, Ph.D.
Jiameng Zhang, Ph.D.
Susan Owens, R.N., M.S.
Paul Tran, R.Ph.
Robert W. Coombs, M.D., Ph.D.
Karen T. Tashima, M.D.
Kevin E. Yarasheski, Ph.D.
Abby Helen Shevitz, M.D., M.P.H.
Jane Baum, B.S.N.,
Baiba Berzins, M.P.H.
Carolyn Schnizlein-Bick, Ph.D.
Melvin Littles. A.A.
•
•
•
•
Participants
Sites
Quest Diagnostics
Pharmaceutical Partners
– Abbott
• Kevin Garren
• Scott Brun
– Boehringer-Ingelheim
• Doug Ferriman
• Pete Piliero
– GlaxoSmithKline
• Irene Gray
• Gary Pakes
• Tufts reading center
–
–
Jodi Lee Forand, B.S.
Abby Shevitz, M.D.