title: Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine.
abstract: Tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC), two nucleos(t)ide analogs (NA), are coformulated as an anti-HIV combination tablet for treatment and preexposure prophylaxis (PrEP). TDF/FTC may have effects on the deoxynucleoside triphosphate (dNTP) pool due to their similar structures and similar metabolic pathways. We carried out a comprehensive clinical study to characterize the effects of TDF/FTC on the endogenous dNTP pool, from baseline to 30 days of TDF/FTC therapy, in both treatment-naive HIV-positive and HIV-negative individuals. dATP, dCTP, dGTP, and TTP were quantified in peripheral blood mononuclear cells (PBMC) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. Forty individuals (19 HIV-positive) were enrolled and underwent a baseline visit and then received TDF/FTC for at least 30 days. Longitudinal measurements were analyzed using mixed-model segmented linear regression analysis. The dNTPs were reduced by 14% to 37% relative to the baseline level within 3 days in both HIV-negative and HIV-positive individuals (P ≤ 0.003). These reductions persisted to various degrees at day 30. These findings indicate that dNTP pools are influenced by TDF/FTC therapy. This may alter cellular homeostasis and could increase the antiviral effect through a more favorable analog/dNTP ratio. Further work is needed to elucidate mechanisms, to evaluate the clinical significance of these findings, and to further probe differences between HIV-negative and HIV-positive individuals. (This study has been registered at ClinicalTrials.gov under identifier NCT01040091.).
authors.affiliation: University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Chen
authors.affiliation: University of Colorado, School of Medicine, Division of Infectious Diseases, Aurora, Colorado, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Castillo-Mancilla
authors.affiliation: University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Seifert
authors.affiliation: University of Colorado, School of Medicine, Aurora, Colorado, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: McAllister
authors.affiliation: University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: University of Colorado, Colorado School of Public Health, Department of Biostatistics and Informatics, Aurora, Colorado, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: MaWhinney
authors.affiliation: University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Aurora, Colorado, USA Peter.Anderson@ucdenver.edu.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D003838:Deoxyadenine Nucleotides / Q000037:antagonists & inhibitors / Q000097:blood*; D003845:Deoxycytosine Nucleotides / Q000037:antagonists & inhibitors / Q000097:blood*; D003848:Deoxyguanine Nucleotides / Q000037:antagonists & inhibitors / Q000097:blood*; D000068679:Emtricitabine / Q000494:pharmacology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D016014:Linear Models; D008297:Male; D000068698:Tenofovir / Q000494:pharmacology*; D013942:Thymine Nucleotides / Q000037:antagonists & inhibitors / Q000097:blood*
chemical_list: D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D003848:Deoxyguanine Nucleotides; D013942:Thymine Nucleotides; C024107:2'-deoxycytidine 5'-triphosphate; C029603:deoxyguanosine triphosphate; D000068698:Tenofovir; D000068679:Emtricitabine; C026600:2'-deoxyadenosine triphosphate; C024157:thymidine 5'-triphosphate