{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T21:23:00Z","timestamp":1750368180125,"version":"3.37.3"},"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000864","name":"British HIV Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000864","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BMS, Gilead Sciences, Janssen, MSD and ViiV Healthcare","award":["2012-003581-40"],"award-info":[{"award-number":["2012-003581-40"]}]},{"name":"National Institute for Health Research (NIHR) Biomedical Research Centre"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objectives<\/jats:title>\n<jats:p>To investigate the associations of plasma lamivudine (3TC), abacavir (ABC), emtricitabine (FTC) and tenofovir (TFV) concentrations with cognitive function in a cohort of treated people with HIV (PWH).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Pharmacokinetics (PK) and cognitive function (Cogstate, six domains) data were obtained from PWH recruited in the POPPY study on either 3TC\/ABC or FTC\/tenofovir disoproxil fumarate (TDF)-containing regimens. Association between PK parameters (AUC<jats:sub>0-24<\/jats:sub>: area under the concentration-time curve over 24 hours, C<jats:sub>max<\/jats:sub>: maximum concentration and C<jats:sub>trough<\/jats:sub>: trough concentration) and cognitive scores (standardized into z-scores) were evaluated using rank regression adjusting for potential confounders.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Median (IQR) global cognitive z-scores in the 83 PWH on 3TC\/ABC and 471 PWH on FTC\/TDF were 0.14 (-0.27, 0.38) and 0.09 (-0.28, 0.42), respectively. Higher 3TC AUC<jats:sub>0-24<\/jats:sub> and C<jats:sub>trough<\/jats:sub> were associated with better global z-scores [<jats:italic>rho<\/jats:italic> = 0.29 (p = 0.02) and 0.27 (p = 0.04), respectively], whereas higher 3TC C<jats:sub>max<\/jats:sub> was associated with poorer z-scores [<jats:italic>rho<\/jats:italic> = -0.31 (p&lt;0.01)], independently of ABC concentrations. Associations of ABC PK parameters with global and domain z-scores were non-significant after adjustment for confounders and 3TC concentrations (all p\u2019s&gt;0.05). None of the FTC and TFV PK parameters were associated with global or domain cognitive scores.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Whilst we found no evidence of either detrimental or beneficial effects of ABC, FTC and TFV plasma exposure on cognitive function of PWH, higher plasma 3TC exposures were generally associated with better cognitive performance although higher peak concentrations were associated with poorer performance.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0253861","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T17:35:07Z","timestamp":1626888907000},"page":"e0253861","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Associations between plasma nucleoside reverse transcriptase inhibitors concentrations and cognitive function in people with HIV"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6185-0514","authenticated-orcid":true,"given":"Davide","family":"De Francesco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinzhu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Dickinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6963-2821","authenticated-orcid":true,"given":"Jonathan","family":"Underwood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanouil","family":"Bagkeris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daphne S.","family":"Babalis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick W. G.","family":"Mallon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank A.","family":"Post","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime H.","family":"Vera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Memory","family":"Sachikonye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saye","family":"Khoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline A.","family":"Sabin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-8416","authenticated-orcid":true,"given":"Alan","family":"Winston","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Boffito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the Pharmacokinetic and Clinical Observations in PeoPle Over fiftY (POPPY) study","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"issue":"23","key":"pone.0253861.ref001","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1212\/WNL.0b013e318200d727","article-title":"HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy CHARTER Study","volume":"75","author":"RK Heaton","year":"2010","journal-title":"Neurology"},{"issue":"2","key":"pone.0253861.ref002","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s11065-009-9095-0","article-title":"Functional consequences of HIV-associated neuropsychological impairment","volume":"19","author":"AA Gorman","year":"2009","journal-title":"Neuropsychology review"},{"key":"pone.0253861.ref003","article-title":"Neuropsychological impairment in human immunodeficiency virus-infection: implications for employment","author":"RK Heaton","year":"1994","journal-title":"Psychosomatic Medicine"},{"issue":"5","key":"pone.0253861.ref004","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1212\/WNL.0b013e3181ab2b3b","article-title":"Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy","volume":"73","author":"LA Cysique","year":"2009","journal-title":"Neurology"},{"issue":"6","key":"pone.0253861.ref005","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1017\/S1355617711000968","article-title":"Does antiretroviral therapy improve HIV-associated cognitive impairment? A quantitative review of the literature","volume":"17","author":"T Al-Khindi","year":"2011","journal-title":"Journal of the International Neuropsychological Society"},{"issue":"1","key":"pone.0253861.ref006","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/bmb\/ldy019","article-title":"Cognitive impairment in people living with HIV in the ART era: a review","volume":"127","author":"K Alford","year":"2018","journal-title":"British medical bulletin"},{"issue":"3","key":"pone.0253861.ref007","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/QAD.0000000000000538","article-title":"Could antiretroviral neurotoxicity play a role in the pathogenesis of cognitive impairment in treated HIV disease?","volume":"29","author":"J Underwood","year":"2015","journal-title":"Aids"},{"key":"pone.0253861.ref008","first-page":"1","article-title":"Cerebral Vascular Toxicity of Antiretroviral Therapy","author":"L Bertrand","year":"2019","journal-title":"Journal of Neuroimmune Pharmacology"},{"issue":"3","key":"pone.0253861.ref009","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1136\/sti.77.3.158","article-title":"Mitochondrial toxicity and HIV therapy","volume":"77","author":"AJ White","year":"2001","journal-title":"Sex Transm Infect"},{"key":"pone.0253861.ref010","first-page":"dyy072","article-title":"Cohort profile: The Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study","author":"E Bagkeris","year":"2018","journal-title":"International Journal of Epidemiology"},{"issue":"3","key":"pone.0253861.ref011","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1097\/FTD.0000000000000286","article-title":"A validated method for quantification of dolutegravir using ultra performance liquid chromatography coupled with UV detection","volume":"38","author":"X Wang","year":"2016","journal-title":"Therapeutic drug monitoring"},{"issue":"3","key":"pone.0253861.ref012","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1093\/jac\/dkz479","article-title":"Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate\/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001\/ANRS143 randomized trial","volume":"75","author":"L Dickinson","year":"2020","journal-title":"Journal of Antimicrobial Chemotherapy"},{"issue":"5","key":"pone.0253861.ref013","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1097\/QAD.0000000000002479","article-title":"Plasma nucleotide reverse transcriptase inhibitor concentration and their associations with liver and renal parameters in people living with HIV","volume":"34","author":"X Wang","year":"2020","journal-title":"Aids"},{"issue":"4","key":"pone.0253861.ref014","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/hiv.12714","article-title":"Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV\u2010negative controls","volume":"20","author":"D De Francesco","year":"2019","journal-title":"HIV medicine"},{"issue":"9","key":"pone.0253861.ref015","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate","volume":"150","author":"AS Levey","year":"2009","journal-title":"Annals of internal medicine"},{"issue":"9","key":"pone.0253861.ref016","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1046\/j.1525-1497.2001.016009606.x","article-title":"The PHQ-9","volume":"16","author":"K Kroenke","year":"2001","journal-title":"Journal of General Internal Medicine"},{"issue":"3","key":"pone.0253861.ref017","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1097\/QAD.0b013e32834171f8","article-title":"Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort","volume":"25","author":"M Smurzynski","year":"2011","journal-title":"AIDS (London, England)"},{"issue":"3","key":"pone.0253861.ref018","article-title":"Factors in AIDS dementia complex trial design: results and lessons from the abacavir trial","volume":"2","author":"BJ Brew","year":"2007","journal-title":"PLoS clinical trials"},{"issue":"5","key":"pone.0253861.ref019","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1093\/infdis\/171.5.1166","article-title":"Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase I\/II study","volume":"171","author":"R van Leeuwen","year":"1995","journal-title":"Journal of Infectious Diseases"},{"issue":"4","key":"pone.0253861.ref020","first-page":"137","article-title":"Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder","volume":"19","author":"S Letendre","year":"2011","journal-title":"Topics in antiviral medicine"},{"issue":"9","key":"pone.0253861.ref021","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s40262-018-0632-y","article-title":"Clinical pharmacokinetics and pharmacodynamics of drugs in the central nervous system","volume":"57","author":"N Srinivas","year":"2018","journal-title":"Clinical pharmacokinetics"},{"issue":"1","key":"pone.0253861.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1743-8454-3-1","article-title":"The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses","volume":"3","author":"C Anthonypillai","year":"2006","journal-title":"Cerebrospinal fluid research"},{"key":"pone.0253861.ref023","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1097\/01.qai.0000137001.40505.56","article-title":"Pharmacokinetic properties of nucleoside\/nucleotide reverse transcriptase inhibitors","volume":"37","author":"PJ Piliero","year":"2004","journal-title":"JAIDS Journal of Acquired Immune Deficiency Syndromes"},{"issue":"1","key":"pone.0253861.ref024","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/hiv.12534","article-title":"Nucleoside reverse transcriptase inhibitor\u2010reducing strategies in HIV treatment: assessing the evidence.","volume":"19","author":"C Orkin","year":"2018","journal-title":"HIV medicine"},{"issue":"4","key":"pone.0253861.ref025","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1093\/cid\/ciz926","article-title":"Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid","volume":"71","author":"Q Ma","year":"2020","journal-title":"Clinical Infectious Diseases"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0253861","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T17:35:35Z","timestamp":1626888935000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0253861"}},"subtitle":[],"editor":[{"given":"Andrea","family":"Calcagno","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":25,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0253861","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2021,7,21]]}}}