{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:55:09Z","timestamp":1777452909372,"version":"3.51.4"},"reference-count":20,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antiviral Therapy"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      HIV may amplify immunological, physiological and functional changes of ageing. We determined associations of frailty phenotype, a T-cell senescence marker (p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      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).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>INK4a<\/jats:sup>\n                      expression analysis. Non-compartmental analysis generated an area under the curve (AUC) for each analyte. Spearman rank correlation and Kruskal\u2013Wallis tests were used to assess associations between AUC, demographics and ageing markers, adjusting for multiple comparisons with the Holm procedure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Subjects ( n=79) ranged in age from 22\u201373 years (median 48 years); 48 were African-American, 24 were female, 54 received EFV. Three subjects (range 51\u201360 years) demonstrated frailty, with 17 subjects (range 26\u201360 years) demonstrating pre-frailty. Negative associations were observed between p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      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 \u22640.02). TFV and FTC AUCs were larger among subjects with lower renal function or higher chronological age ( P-values \u22640.05). No associations were observed for EFV, ATV or RTV AUCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Associations of IM\/EN exposure and p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3851\/imp3017","type":"journal-article","created":{"date-parts":[[2016,1,5]],"date-time":"2016-01-05T11:46:03Z","timestamp":1451994363000},"page":"441-445","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Tenofovir\/Emtricitabine Metabolites and Endogenous Nucleotide Exposures are associated with p16\n                    <sup>INK4a<\/sup>\n                    Expression in Subjects on Combination Therapy"],"prefix":"10.1177","volume":"21","author":[{"given":"Julie B","family":"Dumond","sequence":"first","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Owen","family":"Francis","sequence":"additional","affiliation":[{"name":"Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mackenzie","family":"Cottrell","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Trezza","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather MA","family":"Prince","sequence":"additional","affiliation":[{"name":"School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Mollan","sequence":"additional","affiliation":[{"name":"School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig","family":"Sykes","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad","family":"Torrice","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"White","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Malone","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruili","family":"Wang","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelius","family":"Van Dam","sequence":"additional","affiliation":[{"name":"Regional Center for Infectious Diseases, Cone Health, Greensboro, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristine B","family":"Patterson","sequence":"additional","affiliation":[{"name":"School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael G","family":"Hudgens","sequence":"additional","affiliation":[{"name":"Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norman E","family":"Sharpless","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Forrest","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2015,7,1]]},"reference":[{"key":"bibr1-IMP3017","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir626"},{"key":"bibr2-IMP3017","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir627"},{"key":"bibr3-IMP3017","unstructured":"Margolick J., Li X., Detels R. Earlier occurrence of the frailty phenotype in HIV+ men than in HIV- men: The MACS Cohort.\n                      18th Conference on Retroviruses and Opportunistic Infections\n                      . 27 February\u20132 March 2011, Boston, MA, USA. Abstract 794."},{"key":"bibr4-IMP3017","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/62.11.1279"},{"key":"bibr5-IMP3017","unstructured":"Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 8, 2015, Department of Health and Human Services. (Accessed 18 August 2015.) Available from https:\/\/aidsinfo.nih.gov\/guidelines\/html\/1\/adult-and-adolescent-treatment-guidelines\/0."},{"key":"bibr6-IMP3017","doi-asserted-by":"publisher","DOI":"10.1086\/381678"},{"key":"bibr7-IMP3017","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2012.11.010"},{"key":"bibr8-IMP3017","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00311-11"},{"key":"bibr9-IMP3017","doi-asserted-by":"publisher","DOI":"10.1111\/hiv.12017"},{"key":"bibr10-IMP3017","doi-asserted-by":"publisher","DOI":"10.1159\/000180580"},{"key":"bibr11-IMP3017","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/56.3.M146"},{"key":"bibr12-IMP3017","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2005.06.019"},{"key":"bibr13-IMP3017","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2004.03.002"},{"key":"bibr14-IMP3017","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2012.00856.x"},{"key":"bibr15-IMP3017","volume-title":"Full US Prescribing Information","author":"Truvada (emtricitabne\/tenofovir)","year":"2009"},{"key":"bibr16-IMP3017","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.044461"},{"key":"bibr17-IMP3017","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004006"},{"key":"bibr18-IMP3017","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000659"},{"key":"bibr19-IMP3017","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1399"},{"key":"bibr20-IMP3017","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e31815e7478"}],"container-title":["Antiviral Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3851\/IMP3017","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3851\/IMP3017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T12:52:35Z","timestamp":1777380755000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.3851\/IMP3017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,1]]},"references-count":20,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,7]]}},"alternative-id":["10.3851\/IMP3017"],"URL":"https:\/\/doi.org\/10.3851\/imp3017","relation":{},"ISSN":["1359-6535","2040-2058"],"issn-type":[{"value":"1359-6535","type":"print"},{"value":"2040-2058","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7,1]]}}}