Effects of Uridine Supplementation on Metabolic Side Effects of Stavudine and Zidovudine

Treatment of HIV infection with nucleoside analogue reverse transcriptase inhibitors (NRTIs)
has been associated with numerous toxicities that have been attributed to impaired
mitochondrial function secondary to a reduction in the levels of mitochondrial DNA (mtDNA).
Abnormalities in mitochondrial function have been implicated in the development of insulin
resistance in patients with HIV infection and have also been hypothesized to underlie many of
the pathophysiologic features of type 2 diabetes mellitus in non-HIV infected individuals.

Uridine, a pyrimidine nucleoside that plays an essential role in the synthesis of RNA and
other key physiologic processes, has been proposed as a therapy for NRTI-induced
mitochondrial dysfunction. Uridine supplementation protected bone marrow cells from the
toxicity of zidovudine, normalized the growth of neurons exposed to NRTIs, and abrogated
mitochondrial toxicity of NRTIs in HepG2 cells in vitro. A food supplement called
NucleomaxX®, extracted from the stem of sugar cane, raises plasma uridine concentrations to
levels known to prevent mitochondrial toxicity in vitro. In a recent case report, oral
administration of uridine, given in the form of NucleomaxX®, ameliorated the mitochondrial
toxicity caused by stavudine and led to improvements in myalgias and liver and muscle
enzymes, despite continuing treatment with stavudine. In a clinical study of 14 HIV-infected
patients treated with stavudine or zidovudine, NucleomaxX® led to improved hepatic
mitochondrial function as assessed by the 13C-methionine breath test.

We will perform a randomized double-blind placebo-controlled study in 20 HIV-positive
subjects who are currently undergoing treatment with antiretroviral regimens containing
stavudine or zidovudine and who have evidence of impaired mitochondrial function and insulin
resistance. Subjects will be hospitalized in the SFGH CTSI Clinical Research Center (CCRC)
for 6 days to undergo comprehensive metabolic studies. Subjects will then be randomized, in a
1:1 fashion, to receive either NucleomaxX® or placebo for two months, after which they will
repeat the 6-day CCRC-based assessments. This study is designed to test the hypothesis that,
in comparison to placebo, uridine supplementation will enhance mitochondrial function, and
this will be associated with concomitant improvements in glucose and lipid metabolism.

Inclusion Criteria:

- Confirmed HIV-1 infection

- HIV-1 RNA <10,000 copies/mL within 30 days of study entry

- Treatment with stavudine or zidovudine for at least 12 months prior to entry and no
plan to discontinue for the duration of the study

- Stable antiretroviral regimen for at least 3 months prior to entry and no plan to
change antiretroviral therapy for the duration of the study

- Mitochondrial dysfunction as evidenced by a fasting plasma lactate level > 1.5 mmol/L

- Insulin resistance as evidenced by a HOMA-IR > 2.77 as calculated from fasting blood
samples (for glucose and insulin) obtained during the screening visit

- Karnofsky performance score >= 80

- Women who are on stable regimens of hormonal contraceptives or hormone replacement
therapy for at least 6 months prior to enrollment may participate

- Men who are on stable doses of testosterone replacement therapy for 6 months prior to
enrollment may participate

- Subjects on a stable dose of lipid lowering agents for 6 months prior to enrollment
may participate

Exclusion Criteria:

- Serum creatinine and blood urea nitrogen > 1.5 upper limit of normal (ULN)

- Direct bilirubin >2 X ULN

- AST (SGOT) or ALT (SGPT) >5 x ULN

- Hgb < 8.5 g/dL

- Abnormal hepatitis B or C serology

- A clinical diagnosis of diabetes mellitus or a fasting glucose > 126 mg/dl

- Physical or functional obstruction to food intake or impaired absorption

- A clinically suspected concomitant treatable infection that has not yet been treated

- An opportunistic infection within the preceding 30 days

- Ascites

- Pregnancy

- Treatment with growth hormone, anabolic steroids (including supraphysiologic doses of
testosterone), glucocorticoids, insulin, sulfonylureas, metformin, thiazolidinediones,
or appetite stimulants within preceding 6 months

- Dementia, active drug or alcohol abuse or dependence, or other conditions that would
preclude adherence to the protocol or the ability to provide informed consent.

- Any other condition that, in the opinion of the investigators, would put the subject
at risk