Effects of Uridine Supplementation on Metabolic Side Effects of Stavudine and Zidovudine
Condition: HIV Infections; Insulin Resistance; Hyperlactatemia
MeSH terms: Insulin Resistance; Hyperlactatemia
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether uridine supplementation will improve
      insulin sensitivity and overall carbohydrate metabolism in 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.
    

Detailed description: 
      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.
    

Intervention name(s): NucleomaxX (contains uridine)
Intervention type(s): Drug
Intervention description(s): Escalated doses of NucleomaxX tid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: HIV; AIDS; uridine; mitochondria; insulin resistance; Treatment Experienced