title: Tenofovir diphosphate and emtricitabine triphosphate concentrations in blood cells compared with isolated peripheral blood mononuclear cells: a new measure of antiretroviral adherence?
abstract: BACKGROUND
  The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPCs) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence.
  
  
  METHODS
  Ten HIV+ adults with HIV RNA <50 copies/mL on a TDF/FTC-containing regimen provided 5 paired PBMC and ULPC samples over 6 hours. TFV-DP and FTC-TP concentrations were analyzed by liquid chromatography/mass spectrometry. Partial areas under the curve were calculated using noncompartmental methods and Spearman Rank Correlations (rho) between PBMC and ULPC were determined.
  
  
  RESULTS
  The median (25th-75th percentile) concentration of TFV-DP in PBMCs was 143 (103-248) fmol/10(6) cells and in ULPC was 227 (160-394) fmol/10(6) cells (rho = 0.65; P < 0.0001). The concentration of FTC-TP in PBMCs was 6660 (5650-10,000) fmol/10(6) cells and in ULPC was 19.0 (12.0-27.8) fmol/10(6) cells (rho = 0.55; P < 0.0001). Compared to PBMCs, ULPC TFV-DP was 64% higher and FTC-TP was 99.7% lower. ULPC concentrations of TFV-DP and FTC-TP in one additional subject receiving a single dose of TDF/FTC were only 0.05% and 25%, of the other 10 subjects, respectively.
  
  
  CONCLUSIONS
  ULPC concentrations significantly correlated with PBMC concentrations. Preliminary single-dose data suggest some discrimination between intermittent versus consistent dosing. ULPC concentrations of TFV-DP and FTC-TP should be further investigated as a simply collected surrogate measure of ARV adherence.
authors.affiliation: Department of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Adams
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.forename: Prema
authors.initials: P
authors.lastname: Menezes
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.forename: Katrien
authors.initials: K
authors.lastname: Fransen
authors.forename: Tania
authors.initials: T
authors.lastname: Crucitti
authors.forename: Irith
authors.initials: I
authors.lastname: De Baetselier
authors.forename: Lut
authors.initials: L
authors.lastname: Van Damme
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics; D001773:Blood Cells / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011756:Diphosphates / Q000097:blood / Q000493:pharmacokinetics; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D063065:Organophosphonates / Q000097:blood* / Q000493:pharmacokinetics; D011122:Polyphosphates / Q000097:blood / Q000493:pharmacokinetics; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D011756:Diphosphates; D063065:Organophosphonates; D011122:Polyphosphates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine; C005692:triphosphoric acid