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).

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 NucleomaxX HOMA-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 ± 247 ± Male / female8 / 17 / 2 Weight (kg)77.8 ± ± Total limb fat (g)3370 ± ± Intra-abdominal fat (cm 3 )2320 ± ± Total fat (g)14410 ± ± Liver fat content (%)6.4 ± ± Data are mean ± SEM

HIV characteristics Data are mean ± SEM.

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.

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 PPlacebo (n=9) Baseline 3 months P*P* P HOMA (insulin resistance) 3.0 ± ± ± ± 0.6 Triglycerides (mmol/l) 2.8 ± ± ± ± 0.9 HDL cholesterol (mmol/l) 1.24 ± ± ± ±0.09 <0.05 ALT (U/l)33 ± 542 ± 1239 ± 932 ± 8 Venous blood pH 7.33 ± ± 0.01 < ± ± 0.01 Venous blood base excess -0.2 ± ± 0.3< ± ± 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.

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.

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