URIDINE FOR THE TREATMENT OF HAART-

ASSOCIATED LIPODYSTROPHY

- a randomized, double-blind, placebo-controlled trial

BACKGROUND

• No pharmacological therapy has proven effective in the treatment of lipoatrophy under unchanged HAART.

• The role of stavudine/zidovudine in the development of lipoatrophy.

– mitochondrial toxicity leading to decreased de novo synthesis of pyrimidines (?)

BACKGROUND

• Uridine is a precursor for pyrimidine nucleotides.

• Uridine prevents and reverts stavudine/zidovudine -induced ”lipoatrophy” in vitro.

• NucleomaxX® has high bioavailability of uridine.

Walker et al Antivir Ther in press, Venhoff et al AIDS 2005

AIM OF THE STUDY

• To determine if uridine increases the amount of peripheral subcutaneous fat during unchanged HAART containing stavudine or zidovudine.

• The effects of uridine on features of insulin resistance.

• The safety of uridine in patients receiving HAART.

METHODS: study design

• A randomized, double-blind, placebo-controlled trial for 3 months.

• NucleomaxX® 36 g 3 times a day for 10 consecutive days each month.

• Both NucleomaxX® and placebo contained identical amount of calories (1660 kJ/100g).

0 1 2 3 months

Body composition, HOMA (insulin resistance), lipids, blood gas analysis, lactate

Complete blood count, alanine aminotransferase, creatinine, potassium, sodium

HIV-PCR

METHODS: study design

= period of consumption of NucleomaxXHOMA-insulin resistance index: fasting glucose (mmol/l) x insulin (mU/l) /22.5

METHODS: patients

• INCLUSION CRITERIA:

• stable HIV-infection• > 18 years• HAART > 18 months• current use of stavudine

or zidovudine• lipoatrophy

• EXCLUSION CRITERIA:

• allergy to milk proteins

• current use of didanosine

• pregnancy or lactation

METHODS: body composition

• Dual Energy X-ray absorptiometry (DEXA)

– limb and total fat

• MRI (16 scans)

– intra-abdominal fat

• Proton spectroscopy

– liver fat

DEXA

MRI

RESULTS

• 20 patients were randomized.

• One discontinued due to taste of the product (NucleomaxX) and one died from myocardial infarction (placebo).

• 18 patients completed the study.

• Background medication of all patients remained unchanged during the study period.

Baseline characteristics

NucleomaxX

(n=9)

Placebo (n=9)

p-value

Age (y) 47 ± 2 47 ± 5 1.0

Male / female 8 / 1 7 / 2

Weight (kg) 77.8 ± 5.1 69.4 ± 3.4 0.2

Total limb fat (g) 3370 ± 890 3110 ± 900 0.8

Intra-abdominal fat (cm3) 2320 ± 320 2030 ± 500 0.6

Total fat (g) 14410 ± 2700 12040 ± 2340 0.5

Liver fat content (%) 6.4 ± 3.1 12.8 ± 5.2 0.3

Data are mean ± SEM

HIV characteristics

Data are mean ± SEM.

NucleomaxX®

(n=9)Placebo(n=9)

p-value

Duration of HIV-infection (y) 11.8 ± 1.5 8.7 ± 1.5 0.2

Duration of antiviral therapy (y) 6.1 ± 0.7 6.3 ± 0.6 0.9

N of patients VL <50 cop/ml 8 7

CD4 count (x106/l) 611 ± 88 485 ± 91 0.3

N of patients using d4T 4 4

N of patients using ZDV 5 5

N of patients using PI 9 9

N of patients using NNRTI 2 1

RESULTS: body composition

Mean change from baseline (error bars represent SEM).

P-value in red for comparison of the change in the NucleomaxX vs. placebo, P in green for comparison between baseline and 3 months in each arm.

-500

0

500

1000

1500

NucleomaxX Placebo

p<0.001

p<0.05

Lim

b f

at

(g)

0

500

1000

1500

2000

2500

NucleomaxX Placebo

p<0.001

p<0.01

To

tal b

od

y f

at

(g

)

-400

-200

0

200

400

NucleomaxX Placebo

p<0.05

p<0.05

Intr

a-a

bd

om

ina

l fa

t(c

m3)

• The proportion of limb fat to total fat

– increased from 19% to 25% in the NucleomaxX (p<0.05) group

– remained stable in the placebo group (from 23% to 25%, p=0.4)

• No significant change in subjective assessment of lipoatrophy.

• Liver fat content did not change.

RESULTS: body composition

RESULTS: laboratory results

NucleomaxX® (n=9)

Baseline 3 months

P Placebo (n=9)

Baseline 3 months

P

*

P

HOMA (insulin resistance)

3.0 ± 1.0 3.2 ± 1.5 2.3 ± 0.6 2.0 ± 0.6

Triglycerides (mmol/l)

2.8 ± 0.5 3.0 ± 0.4 3.5 ± 0.9 3.0 ± 0.9

HDL cholesterol (mmol/l)

1.24 ± 0.10

1.15 ± 0.08

1.13 ± 0.06

1.22 ±0.09

<0.05

ALT (U/l) 33 ± 5 42 ± 12 39 ± 9 32 ± 8

Venous blood pH

7.33 ± 0.01

7.36 ± 0.01

<0.05 7.34 ± 0.01

7.35 ± 0.01

Venous blood base excess

-0.2 ± 0.3 1.1 ± 0.3 <0.05 0.0 ± 0.6 0.1 ± 0.3

Data are mean ± SEM. P-value in red for comparison of the change in the NucleomaxX vs. placebo, P-value in green for comparison between baseline and 3 months in each arm.

NucleomaxX® (n=9) Baseline 3 months

Placebo (n=9) Baseline 3 months

N of patients with VL <50

8 8 7 7

CD4 106/l 611 ± 88 613 ± 92 485 ± 91 503 ± 93

• No change in complete blood count, creatinine,

sodium, potassium or lactate concentrations.

• One discontinuation due to taste of NucleomaxX, no other side effects reported.

RESULTS: safety

RESULTS: serum uridine

NucleomaxX

Placebo

P-value in red for comparison of the change in the NucleomaxX vs. placebo group, P-value in green for comparison between baseline and day 71 in each arm.

0

10

20

Ser

um

uri

din

eco

nce

ntr

atio

n (

um

ol/

l)

Day 0 Day 71 Day 0 Day 71

p<0.001

p<0.001

CONCLUSION

• NucleomaxX during 3 month treatment of HAART-associated lipoatrophy

– increased significantly and predominantly the amount of subcutaneous fat

– did not affect markers of insulin resistance or liver fat content

• decrease in HDL-cholesterol

– was well tolerated and safe

• Limitations of the study: small sample size.

ACKNOWLEDGEMENTS

• Helsinki University Central Hospital, Finland– Jussi Sutinen, Ksenia Sevastianova, Anna-Maija

Häkkinen, Matti Ristola, Katja Tuominen, Hannele Yki-Järvinen

• Medizinische Universitätsklinik, Freiburg, Germany– Ulrich A. Walker

• Medizinische Klinik Würzburg, Germany- Hartwig Klinker

• Patients

UAW has applied for a patent for the use of pyrimidine precursors to treat lipoatrophy