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

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

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.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aging / genetics
  • Aging / metabolism
  • 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*
  • 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

Substances

  • Anti-HIV Agents
  • Benzoxazines
  • Cyclin-Dependent Kinase Inhibitor p16
  • Nucleotides
  • P16 protein, human
  • Atazanavir Sulfate
  • Tenofovir
  • Emtricitabine
  • efavirenz
  • Ritonavir

Associated data

  • ClinicalTrials.gov/NCT01180075