title: Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir.
abstract: BACKGROUND
  Lipoatrophy modestly improves when the thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) is removed. In vitro, uridine (NucleomaxX(®); Pharma Nord, Vojens, Denmark) reversed tNRTI mitochondrial toxicity.
  
  
  METHODS
  All patients had lipoatrophy on a tNRTI-containing regimen with HIV RNA<400 copies/ml. A randomized 48-week study switched patients from tNRTI to tenofovir (TDF) or added uridine (continuing tNRTI). End points were changes in limb fat (DEXA), subcutaneous abdominal fat mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), inflammation markers (soluble tumour necrosis factor receptors, high-sensitivity C reactive protein [hsCRP], interleukin-6 [IL-6], soluble vascular cell adhesion molecule 1), bone mineral density (BMD) of the hip and spine, HIV-1 RNA, CD4(+) T-cells and fasting metabolic parameters.
  
  
  RESULTS
  Fifty patients were enrolled (n=24 TDF switch; n=26 uridine); median age 48 years; 54% white; 86% male; limb fat 4,494 g. Baseline characteristics were similar between groups. In the NucleomaxX(®) arm, mtRNA increased (all P<0.001), hsCRP and IL-6 increased (both P=0.02), whereas fat mtDNA decreased without changes in limb fat. In the TDF-switch arm, fat mtDNA and inflammation markers did not change; however, significant increases in mtRNAs (P<0.001), limb fat (409 g; IQR -59-1,155) and CD4(+) T-cell count (P=0.03), and decreases in total and hip BMD (median -3.3%; IQR -5.1-0; P=0.005) were observed. Between-group changes were significant for fat mtDNA, hsCRP, IL-6, limb fat and hip BMD. No correlation was found between changes in limb fat and those of fat mtRNA, inflammation markers or protease inhibitor duration.
  
  
  CONCLUSIONS
  In HIV lipoatrophy, NucleomaxX(®) improved mtRNA, but worsened inflammation markers and fat mtDNA without changes in limb fat. Switching from a tNRTI to TDF for 48 weeks increased limb fat and fat mtRNA. Large decreases in total and hip BMD were seen after TDF switch. ClinicalTrials.gov identifier: NCT00119379.
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA. mccomsey.grace@clevelandactu.org
authors.forename: Grace A
authors.initials: GA
authors.lastname: McComsey
authors.forename: MaryAnn
authors.initials: M
authors.lastname: O'Riordan
authors.forename: Julia
authors.initials: J
authors.lastname: Choi
authors.forename: Daniel
authors.initials: D
authors.lastname: Libutti
authors.forename: David
authors.initials: D
authors.lastname: Rowe
authors.forename: Norma
authors.initials: N
authors.lastname: Storer
authors.forename: Danielle
authors.initials: D
authors.lastname: Harrill
authors.forename: Mariana
authors.initials: M
authors.lastname: Gerschenson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017667:Adipocytes / Q000473:pathology; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015519:Bone Density; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D039682:HIV-Associated Lipodystrophy Syndrome / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D012313:RNA / Q000032:analysis / Q000235:genetics; D000077278:RNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects; D000068698:Tenofovir; D014529:Uridine / Q000494:pharmacology* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D000077278:RNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D012313:RNA; D000068698:Tenofovir; D000225:Adenine; D014529:Uridine