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12th Conference on Retroviruses and Opportunistic Infections February 22-25, Boston. - PowerPoint PPT Presentation
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A randomized open study comparing the impact of reducing stavudine dose vs. switching to tenofovir on mitochondrial function, metabolic parameters,
and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing
stavudine.
A randomized open study comparing the impact of reducing stavudine dose vs. switching to tenofovir on mitochondrial function, metabolic parameters,
and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing
stavudine.
Milinkovic A, López S, Miro O, Vidal S, Arnaiz JA, Blanco JL, Leon A, Larrousse M, Lonca M, Laguno
M, Mallolas J, Miro JM , Gatell JM, Martinez E.
Hospital Clínic, Barcelona
anamilinkovic@hotmail.com
12th Conference on Retroviruses and Opportunistic Infections
February 22-25, Boston
•Peripheral lipoatrophy and dyslipidemia may complicate stavudine-containing
antiretroviral therapy. Mitochondrial dysfunction has been suggested as at
least one potential underlying mechanism in the pathogenesis of peripheral
lipoatrophy and dyslipidemia associated with stavudine.
•Available data suggest that tenofovir has little effect on mitochondrial gamma
polymerase and a lower risk for peripheral lipoatrophy and dyslipidemia than
stavudine. Switching from stavudine to abacavir has shown an improvement
on peripheral lipoatrophy without significant effects on plasma lipids. To date,
the effects of switching from stavudine to tenofovir are unknown.
•Scarce data suggest that reducing stavudine dose may be as effective as
standard dose but less toxic, although the effects of reducing stavudine dose
on peripheral lipoatrophy and dyslipidemia are unknown.
•Peripheral lipoatrophy and dyslipidemia may complicate stavudine-containing
antiretroviral therapy. Mitochondrial dysfunction has been suggested as at
least one potential underlying mechanism in the pathogenesis of peripheral
lipoatrophy and dyslipidemia associated with stavudine.
•Available data suggest that tenofovir has little effect on mitochondrial gamma
polymerase and a lower risk for peripheral lipoatrophy and dyslipidemia than
stavudine. Switching from stavudine to abacavir has shown an improvement
on peripheral lipoatrophy without significant effects on plasma lipids. To date,
the effects of switching from stavudine to tenofovir are unknown.
•Scarce data suggest that reducing stavudine dose may be as effective as
standard dose but less toxic, although the effects of reducing stavudine dose
on peripheral lipoatrophy and dyslipidemia are unknown.
Background Background
Type of study Prospective, randomized, open-label study
Inclusion criteria Clinically stable HIV-infected patients receiving
antiretroviral therapy containing stavudine 40 mg bid with a plasma HIV
RNA <200 copies/mL for at least the previous 6 months .
Treatment arms (while preserving the remaining drugs unchanged)
d4T dose reduction to 30mg bid d4T 30 arm
Switch d4T to TDF TDF arm
Continue d4T 40mg bid d4T 40 arm
Type of study Prospective, randomized, open-label study
Inclusion criteria Clinically stable HIV-infected patients receiving
antiretroviral therapy containing stavudine 40 mg bid with a plasma HIV
RNA <200 copies/mL for at least the previous 6 months .
Treatment arms (while preserving the remaining drugs unchanged)
d4T dose reduction to 30mg bid d4T 30 arm
Switch d4T to TDF TDF arm
Continue d4T 40mg bid d4T 40 arm
Patients and methods Patients and methods
Follow up 6 months
Study visits:
• Baseline, 1, 3 and 6 months: glucose , triglycerides, total, HDL and
LDL cholesterol, plasma HIV–1 RNA, CD4 cells count and lactate.
• Baseline and 6 months: mitochondrial analysis and body
composition (DEXA).
• Statistical analysis: Kruskal-Wallis test , Bonferroni adjustment for
the significance level , McNemar test , Fisher Chi-square test .
MethodsMethods
Mitochondrial analysis in PBMCs
• Mitochondrial DNA content was determined by quantitative real time PCR.
• Mitochondrial Mass was determined through the measurement of Citrate Synthase
(CS) Activity by spectrophotometry.
• Oxidative activity of intact cells (spontaneous cellular oxidation) was determined by
polarography.
• Enzyme activity of the mtDNA-encoded complexes of the OXPHOS system (Complex
IV and Complex III activity) was determined by spectrophotometry.
• Results were expressed as absolute values and as percentages with respect to the
baseline value.
Methods - mitochondrial functionMethods - mitochondrial function
Baseline characteristicsBaseline characteristicsBaseline characteristicsBaseline characteristics
D4T-40 (n=22)D4T-40 (n=22) D4T-30 (n=19)D4T-30 (n=19) TDF (n=17) TDF (n=17) AgeAge (mean±SD)(mean±SD) 45 ± 1045 ± 10 43 ± 7 43 ± 7 46 ± 9 46 ± 9
CD4 (/mmCD4 (/mm33)) HIV diagnosisHIV diagnosis 174 ± 120 197 ± 199174 ± 120 197 ± 199 246 ± 207 246 ± 207Baseline studyBaseline study 568 ± 245 695 ± 317 568 ± 245 695 ± 317 529 ± 325 529 ± 325
PIs PIs (n, %)(n, %) 7(32) 7(32) 1(5) 1(5) 2(12) 2(12)NNRTIs NNRTIs (n, %)(n, %) 13 (59)13 (59) 17(89) 17(89) 13(76) 13(76)ddI ddI (n, %)(n, %) 6(27)6(27) 4(21) 4(21) 1(6) 1(6)
HIV-1 RNA (copies/mL) HIV-1 RNA (copies/mL) HIV diagnosis HIV diagnosis 278000 273000 202000278000 273000 202000
BaselineBaseline <20 copies/mL <20 copies/mL 22 (100%)22 (100%) 19 (100%) 19 (100%) 17 (100%) 17 (100%)
Baseline laboratory datesBaseline laboratory datesBaseline laboratory datesBaseline laboratory dates
D4T-40 (n=22)D4T-40 (n=22) D4T-30 (n=19)D4T-30 (n=19) TDF (n=17) TDF (n=17) P P
Tgl (mg/dL)Tgl (mg/dL) 141 ±116 207 ± 189141 ±116 207 ± 189 242 ± 234 0,15 242 ± 234 0,15
Chl total (mg/dL) Chl total (mg/dL) 222 ± 35 227 ± 40 222 ± 35 227 ± 40 205± 49 0,96 205± 49 0,96
LDL-Chl (mg/dL) LDL-Chl (mg/dL) 142 ± 29142 ± 29 141 ± 33 137 ± 29 0,87 141 ± 33 137 ± 29 0,87HDL-Chl (mg/dL) HDL-Chl (mg/dL) 48 ± 1148 ± 11 47 ±15 47 ±15 47 ± 9 0,65 47 ± 9 0,65
LactateLactate (mg/dL) (mg/dL) 13 ± 513 ± 5 15 ±3 15 ±3 13 ±5 0,89 13 ±5 0,89
Baseline fat mass(DEXA)Baseline fat mass(DEXA)Baseline fat mass(DEXA)Baseline fat mass(DEXA)
D4T-40 (n=22)D4T-40 (n=22) D4T-30 (n=19)D4T-30 (n=19) TDF (n=17) TDF (n=17) P P Peripheral (g)Peripheral (g)MedianMedian 3204 3295 44383204 3295 4438 0,57 0,57 IQR IQR 2238-4797 2785-4351 2585-5619 2238-4797 2785-4351 2585-5619
Truncal (g)Truncal (g)Median Median 7510 8220 9107 7510 8220 9107 0,27 0,27IQRIQR 5742-10375 6833- 12090 7769-118505742-10375 6833- 12090 7769-11850
Total (g)Total (g)MedianMedian 11843 11459 1400011843 11459 14000 0,31 0,31IQR 8674-15061 9851-16990 10673-18848IQR 8674-15061 9851-16990 10673-18848
Baseline lean mass(DEXA)Baseline lean mass(DEXA)Baseline lean mass(DEXA)Baseline lean mass(DEXA)
D4T-40 (n=22)D4T-40 (n=22) D4T-30 (n=19)D4T-30 (n=19) TDF (n=17) TDF (n=17) P P Peripheral (g)Peripheral (g) MedianMedian 25218 24331 25212 0,38 25218 24331 25212 0,38 IQRIQR 22088-2928522088-29285 21945-29121 23110-2714321945-29121 23110-27143
Truncal (g)Truncal (g) Median Median 25184 26205 26652 0,55 25184 26205 26652 0,55IQR 23035-28547 24495-28146 25238-28591IQR 23035-28547 24495-28146 25238-28591
Total (g)Total (g) MedianMedian 55008 53896 5613455008 53896 56134 0,750,75IQRIQR 48792-62588 52531-59918 53129-59874 48792-62588 52531-59918 53129-59874
-40
-30
-20
-10
0
10
20
30
Baseline 1 Mo 3 Mo 6 Mo
Triglycerides Triglycerides Percentage of change from baselinePercentage of change from baseline
%%d4T 40d4T 40d4T 30d4T 30TDFTDF
At 6 Mo: 30 vs.40:p-value=0.638 30 vs.TDF:p-value=0.152* * 40 vs. TDF=0.0390
At 1 Mo:p-value=0.133
At 3 Mo:p-value=0.093
-10
-5
0
5
10
15
20
25
d4T 30mg TDF 300mgd4T 40mg
Cholesterol
6 -m
on
th ∆
Ch
l (m
g/d
L) 30 vs. 40: p-value=0.939
30 vs. TDF: p-value=0.073*40 vs. TDF: p-value=0.020
Baseline
-25
-20
-15
-10
-5
0
5
10
d4T 30mg TDF 300mgd4T 40mg
LDL-Cholesterol6
-mo
nth
∆
LD
L-C
hl
(mg
/dL
) Global p-value=0.078
Baseline
-12
-10
-8
-6
-4
-2
0
d4T 30mg TDF 300mgd4T 40mg
HDL-Cholesterol6-
mo
nth
∆ H
DL
-Ch
l (m
g/d
L)
Global p-value=0.788
Baseline
-30
-25
-20
-15
-10
-5
0
5
10
15
20
Baseline 1 Mo 3 Mo 6 Mo
Lactate Lactate Percentage of change from baselinePercentage of change from baseline
%%
d4T 40d4T 40d4T 30d4T 30TDFTDF
At 3 Mo: 30 vs.40:p-value=0.466 30 vs.TDF:p-value=0.344* * 40 vs. TDF=0.015
**
**
At 6 Mo: p-value=0.159At 1 Mo: p-value=0.326
0
100
200
300
400
500
600
700
800
900
Baseline 1 Mo 3 Mo 6 Mo
Change in mean CD4 cell countChange in mean CD4 cell count
d4T 40d4T 40d4T 30d4T 30TDFTDF
CD
4 ce
ll (
cell
s/m
m3
)
p-value=0.134 p-value=0.762 p-value=0.620
% of patients with HIV-1 RNA<20
0
20
40
60
80
100
120
Baseline study 1 Mo 3 Mo 6 Mo
d4T 40d4T 40d4T 30d4T 30TDFTDF
p-value=0.134
p-value=0.764p-value=0.328
-400
-300
-200
-100
0
100
200
300
400
500
d4T 30mg TDF 300mgd4T 40mg
Peripheral fat∆
wei
gh
t 6-
mo
nth
(g
)
30 vs. 40: p-value=0.124 30 vs. TDF: p-value=0.902 *40 vs. TDF: p-value=0.003
Baseline
-15
-10
-5
0
5
10
15
d4T 30mg TDF 300mgd4T 40mg
Peripheral fat 6
-mo
nth
∆
med
ian
(%
) 30 vs. 40: p-value=0.09730 vs. 40: p-value=0.097 30 vs. TDF: p-value=0.768 30 vs. TDF: p-value=0.768 *40 vs. TDF: p-value=0.003*40 vs. TDF: p-value=0.003
Baseline
-600-400-200
0200400600800
1000120014001600
d4T 30mg TDF 300mgd4T 40mg
Total fat∆
w
eig
ht
6- m
on
th (
g)
30 vs. 40: p-value=0.168 30 vs. TDF: p-value=0.998 *40 vs. TDF: p-value=0.032
Baseline
-6
-4
-2
0
2
4
6
8
10
12
d4T 30mg TDF 300mgd4T 40mg
Total fat6-
mo
nth
med
ian
∆ (
%)
30 vs. 40: p-value=0.179 30 vs. TDF: p-value=0.988 *40 vs. TDF: p-value=0.029
Baseline
-3
-2,5
-2
-1,5
-1
-0,5
0
0,5
1
1,5
d4T 30mg TDF 300mgd4T 40mg
Total lean mass6-
mo
nth
med
ian
∆ (
%)
*40 vs. TDF: p-value=0.016*30 vs. TDF: p-value=0.008 30 vs. 40: p-value=1.000
Baseline
-2000
-1500
-1000
-500
0
500
1000
d4T 30mg TDF 300mgd4T 40mg
Total lean mass∆
wei
gh
t 6-
mo
nth
(g
)
30 vs. 40: p-value=0.995 *40 vs. TDF: p-value=0.013 *30 vs. TDF: p-value=0.007
Baseline
Mitochondrial functionMitochondrial function
0 1 2 3 4 5 60.0
0.5
1.0
1.5
2.0
2.5
d4T (40 mg)d4T (30 mg)TDF
Months
mtD
NA
/ n
DN
A(N
D2/
18S
rR
NA
)
0 1 2 3 4 5 60
20
40
60
80
100
120
d4T (40 mg)d4T (30 mg)TDF
Months
Cit
rate
syn
thas
e ac
tivi
ty
(nm
ol/m
in/m
g)
0 1 2 3 4 5 60
1
2
3
4
5
6
7
8
9
10
d4T (40 mg)d4T (30 mg)TDF
Months
Sp
on
tan
eo
us
ce
llu
lar
ox
ida
tio
n
(nm
ol O
2/min
/mg)
Mitochondrial function Mitochondrial function
0 1 2 3 4 5 60
50
100
150
200
250
300
d4T (40 mg)d4T (30 mg)TDF
Months
Co
mp
lex
III
act
ivit
y
(nm
ol/m
in/m
g)
0 1 2 3 4 5 60
10
20
30
40
50
60
d4T (40 mg)d4T (30 mg)TDF
Months
Co
mp
lex
IV
ac
tiv
ity
(nm
ol/m
in/m
g)
Complex III activity
0 1 2 3 4 5 60
20
40
60
80
100
120
140
160
d4T (40 mg)d4T (30 mg)TDF
Months
Per
cen
tag
e re
spec
t to
bas
elin
e(1
00%
)
Complex IV activity
0 1 2 3 4 5 60
20
40
60
80
100
120
140
160
d4T (40 mg)d4T (30 mg)TDF
Months
Per
cen
tag
e re
spec
t to
bas
elin
e(1
00%
)
Mitochondrial functionMitochondrial functionMitochondrial mass
(CS activity)
0 1 2 3 4 5 60
20
40
60
80
100
120
140
160
d4T (40 mg)d4T (30 mg)TDF
Months
Per
cen
tag
e re
spec
t to
bas
elin
e(1
00%
)
mtDNA content
0 1 2 3 4 5 60
20
40
60
80
100
120
140
160
d4T (40 mg)d4T (30 mg)TDF
Months
Per
cen
tag
e re
spec
t to
bas
elin
e(1
00%
)
Spontaneouscellular oxidation
0 1 2 3 4 5 60
20
40
60
80
100
120
140
160
d4T (40 mg)d4T (30 mg)TDF
Months
Per
cen
tag
e re
spec
t to
bas
elin
e(1
00%
)
ResultsResults
Virological safety and Adverse events•Virological rebounds: 2 patient in d4T 40 arm•No significant changes in CD4 cell count•2 cases of symptomatic hyperlactatemia in d4T 40 arm
•1case at baseline visit, another after 6 months.
Reasons for discontinuation:•Pregnancy -1patient•Lost to follow up-2 patients•Poor adherence-1 patient
Virological safety and Adverse events•Virological rebounds: 2 patient in d4T 40 arm•No significant changes in CD4 cell count•2 cases of symptomatic hyperlactatemia in d4T 40 arm
•1case at baseline visit, another after 6 months.
Reasons for discontinuation:•Pregnancy -1patient•Lost to follow up-2 patients•Poor adherence-1 patient
ConclusionsConclusions
In patients receiving d4T 40 mg bid containing antiviral
therapy and HIV-1 RNA<20 copies/mL:•Switching from d4T 40 bid to TNF was associated with
significant improvement in triglycerides, cholesterol and
body fat at 6 months.•Reduction in d4T 40 bid to d4T 30 mg bid was associated
with an improvement in triglycerides, cholesterol and body
fat at 6 months although the differences did not reached
statistical significant.•Both switch arms were at least as virologically effective as
d4T 40 arm.
In patients receiving d4T 40 mg bid containing antiviral
therapy and HIV-1 RNA<20 copies/mL:•Switching from d4T 40 bid to TNF was associated with
significant improvement in triglycerides, cholesterol and
body fat at 6 months.•Reduction in d4T 40 bid to d4T 30 mg bid was associated
with an improvement in triglycerides, cholesterol and body
fat at 6 months although the differences did not reached
statistical significant.•Both switch arms were at least as virologically effective as
d4T 40 arm.
ConclusionsConclusions
•No mitochondrial parameter from PBMCs studied differed
among groups either at baseline or at 6 months suggesting
either that fat and plasma lipid effects are not mediated via
mitochondria, or if mediated by mitochondria not by those
from PBMCs, or the mitochondrial tests used are not
sensible enough to detect potentially mitochondria-
mediated changes.
•No mitochondrial parameter from PBMCs studied differed
among groups either at baseline or at 6 months suggesting
either that fat and plasma lipid effects are not mediated via
mitochondria, or if mediated by mitochondria not by those
from PBMCs, or the mitochondrial tests used are not
sensible enough to detect potentially mitochondria-
mediated changes.
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