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Observational Study
. 2016;21(5):441-5.
doi: 10.3851/IMP3017. Epub 2016 Jan 5.

Tenofovir/emtricitabine Metabolites and Endogenous Nucleotide Exposures Are Associated With p16(INK4a) Expression in Subjects on Combination Therapy

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Free PMC article
Observational Study

Tenofovir/emtricitabine Metabolites and Endogenous Nucleotide Exposures Are Associated With p16(INK4a) Expression in Subjects on Combination Therapy

Julie B Dumond et al. Antivir Ther. .
Free PMC article

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.

Figures

Figure 1a–h
Figure 1a–h
Scatter plots of tenofovir disphosphate (TFV-tp), emtricitabine triphosphate (FTC-tp), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP) area under the curve (AUC) values vs. log2p16INK4a (log2p16) expression (a–d); TFV and FTC AUC values vs. age (e, f); and TFV and FTC AUC values vs. creatinine clearance (CrCL; g,h), by regimen. Subjects receiving TFV/FTC with efavirenz are shown in the open circles; those receiving TFV/FTC with atazanavir/ritonavir are shown in the closed circles.

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