A randomized open study comparing the impact of reducing stavudine dose vs. switching to tenofovir...

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

[email protected]

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


LDL-Cholesterol6

-mo

nth

∆

LD

L-C

hl

(mg

/dL

) Global p-value=0.078

Baseline

-12

-10

-8

-6

-4

-2

0


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


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


Change in mean CD4 cell countChange in mean CD4 cell count


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


p-value=0.134

p-value=0.764p-value=0.328

-400

-300

-200

-100

0

100

200

300

400

500


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


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


Total fat∆

w

eig

ht

6- m

on

th (

g)


Baseline

-6

-4

-2

0

2

4

6

8

10

12


Total fat6-

mo

nth

med

ian

∆ (

%)


Baseline

-3

-2,5

-2

-1,5

-1

-0,5

0

0,5

1

1,5


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


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


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


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


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


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


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


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


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


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


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.

A randomized open study comparing the impact of reducing stavudine dose vs. switching to tenofovir...

Documents

Transcript of A randomized open study comparing the impact of reducing stavudine dose vs. switching to tenofovir...