Tenofovir/emtricitabine metabolites and endogenous nucleotide exposures are associated with p16(INK4a) expression in subjects on combination therapy

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/e...

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Bibliographic Details
Published in:Antiviral therapy 2016, Vol.21 (5), p.441
Main Authors: Dumond, Julie B, Francis, Owen, Cottrell, Mackenzie, Trezza, Christine, Prince, Heather Ma, Mollan, Katie, Sykes, Craig, Torrice, Chad, White, Nicole, Malone, Stephanie, Wang, Ruili, Van Dam, Cornelius, Patterson, Kristine B, Hudgens, Michael G, Sharpless, Norman E, Forrest, Alan
Format: Article
Language:English
Subjects:
Adult
Aged
Aging - genetics
Aging - metabolism
Alkynes
Anti-HIV Agents - administration & dosage
Anti-HIV Agents - blood
Anti-HIV Agents - pharmacokinetics
Atazanavir Sulfate - administration & dosage
Benzoxazines - administration & dosage
Cyclin-Dependent Kinase Inhibitor p16 - genetics
Cyclopropanes
Drug Therapy, Combination
Emtricitabine - administration & dosage
Emtricitabine - blood
Emtricitabine - pharmacokinetics
Female
Gene Expression
HIV Infections - blood
HIV Infections - drug therapy
HIV Infections - genetics
Humans
Male
Middle Aged
Nucleotides - blood
Ritonavir - administration & dosage
Tenofovir - administration & dosage
Tenofovir - blood
Tenofovir - pharmacokinetics
Young Adult
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Summary: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
ISSN:2040-2058
DOI:10.3851/IMP3017