title: Tenofovir/emtricitabine metabolites and endogenous nucleotide exposures are associated with p16(INK4a) expression in subjects on combination therapy.
abstract: HIV may amplify immunological, physiological and functional changes of ageing. We determined associations of frailty phenotype, a T-cell senescence marker (p16(INK4a) expression), age and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV).
  
  
  
  Plasma and peripheral blood mononuclear cell samples for drug, IM and EN concentrations were collected at four time points in HIV+ adults receiving TFV/FTC with EFV or ATV/RTV. Subjects underwent frailty phenotyping and p16(INK4a) expression analysis. Non-compartmental analysis generated an area under the curve (AUC) for each analyte. Spearman rank correlation and Kruskal-Wallis tests were used to assess associations between AUC, demographics and ageing markers, adjusting for multiple comparisons with the Holm procedure.
  
  
  
  Subjects (n=79) ranged in age from 22-73 years (median 48 years); 48 were African-American, 24 were female, 54 received EFV. Three subjects (range 51-60 years) demonstrated frailty, with 17 subjects (range 26-60 years) demonstrating pre-frailty. Negative associations were observed between p16(INK4a) expression and each of FTC-triphosphate (r=-0.45), deoxyadenosine triphosphate (dATP; r=-0.47) and deoxycytidine triphosphate (dCTP; r=-0.57) AUCs (P-values <0.02). TFV and FTC AUCs were larger among subjects with lower renal function or higher chronological age (P-values ≤0.05). No associations were observed for EFV, ATV or RTV AUCs.
  
  
  
  Associations of IM/EN exposure and p16(INK4a) expression observed here suggest that senescence may alter drug phosphorylation, metabolism or transport. This finding warrants further mechanistic study to ensure optimal treatment in the ageing HIV+ population. Clinicaltrials.gov NCT01180075.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jdumond@unc.edu.
authors.forename: Julie B
authors.initials: JB
authors.lastname: Dumond
authors.forename: Owen
authors.initials: O
authors.lastname: Francis
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Cottrell
authors.forename: Christine
authors.initials: C
authors.lastname: Trezza
authors.forename: Heather Ma
authors.initials: HM
authors.lastname: Prince
authors.forename: Katie
authors.initials: K
authors.lastname: Mollan
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.forename: Chad
authors.initials: C
authors.lastname: Torrice
authors.forename: Nicole
authors.initials: N
authors.lastname: White
authors.forename: Stephanie
authors.initials: S
authors.lastname: Malone
authors.forename: Ruili
authors.initials: R
authors.lastname: Wang
authors.forename: Cornelius
authors.initials: C
authors.lastname: Van Dam
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate / Q000008:administration & dosage; D048588:Benzoxazines / Q000008:administration & dosage; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D000068679:Emtricitabine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009711:Nucleotides / Q000097:blood; D019438:Ritonavir / Q000008:administration & dosage; D000068698:Tenofovir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003521:Cyclopropanes; D009711:Nucleotides; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; D000068679:Emtricitabine; C098320:efavirenz; D019438:Ritonavir