Tenofovir/Emtricitabine Metabolites and Endogenous Nucleotide Exposures are associated with p16INK4a Expression in Subjects on Combination Therapy. Issue 5 (July 2016)

• Record Type: Journal Article
• 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
• Is Part Of: Antiviral therapy. Volume 21:Issue 5(2016)
• Page Start: 441
• Page End: 445
• Publication Date: 2016-07
• Subjects: Antiviral agents -- Periodicals; Antiviral Agents -- therapeutic use; Virus Diseases -- therapy; Viruses -- drug effects; Antiviral agents; Periodical; Electronic journals; Periodicals; 616.9106
• DOI: 10.3851/IMP3017
• Languages: English
• ISSNs: 1359-6535

Abstract

Background: 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). Methods: 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. Results: 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. Conclusions: 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.