title: The early effects of stavudine compared with tenofovir on adipocyte gene expression, mitochondrial DNA copy number and metabolic parameters in South African HIV-infected patients: a randomized trial.
abstract: OBJECTIVE
  Stavudine is being phased out because of its mitochondrial toxicity and tenofovir (TDF) is recommended as part of first-line highly active antiretroviral therapy (HAART) in South Africa. A prospective, open-label, randomized controlled trial comparing standard- and low-dose stavudine with TDF was performed to assess early differences in adipocyte mtDNA copy number, gene expression and metabolic parameters in Black South African HIV-infected patients.
  
  
  METHODS
  Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or TDF (300 mg) each combined with lamivudine and efavirenz. Subcutaneous fat biopsies were obtained at weeks 0 and 4. Adipocyte mtDNA copies/cell and gene expression were measured using quantitative polymerase chain reaction (qPCR). Markers of inflammation and lipid and glucose metabolism were also assessed.
  
  
  RESULTS
  A 29% and 32% decrease in the mean mtDNA copies/cell was noted in the standard-dose (P < 0.05) and low-dose stavudine (P < 0.005) arms, respectively, when compared with TDF at 4 weeks. Nuclear respiratory factor-1 (NRF1) and mitochondrial cytochrome B (MTCYB) gene expression levels were affected by stavudine, with a significantly (P < 0.05) greater fall in expression observed with the standard, but not the low dose compared with TDF. No significant differences were observed in markers of inflammation and lipid and glucose metabolism.
  
  
  CONCLUSIONS
  These results demonstrate early mitochondrial depletion among Black South African patients receiving low and standard doses of stavudine, with preservation of gene expression levels, except for NRF1 and MTCYB, when compared with patients on TDF.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. colin.menezes@wits.ac.za
authors.forename: C N
authors.initials: CN
authors.lastname: Menezes
authors.forename: R
authors.initials: R
authors.lastname: Duarte
authors.forename: C
authors.initials: C
authors.lastname: Dickens
authors.forename: T
authors.initials: T
authors.lastname: Dix-Peek
authors.forename: D
authors.initials: D
authors.lastname: Van Amsterdam
authors.forename: M-A
authors.initials: MA
authors.lastname: John
authors.forename: P
authors.initials: P
authors.lastname: Ive
authors.forename: M
authors.initials: M
authors.lastname: Maskew
authors.forename: P
authors.initials: P
authors.lastname: Macphail
authors.forename: M P
authors.initials: MP
authors.lastname: Fox
authors.forename: F
authors.initials: F
authors.lastname: Raal
authors.forename: I
authors.initials: I
authors.lastname: Sanne
authors.forename: N J
authors.initials: NJ
authors.lastname: Crowther
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000627:therapeutic use*; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D013019:South Africa; D018119:Stavudine / Q000627:therapeutic use*; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D018119:Stavudine; D005947:Glucose; D000225:Adenine