{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:44:10Z","timestamp":1773881050858,"version":"3.50.1"},"reference-count":19,"publisher":"International Union Against Tuberculosis and Lung Disease","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJTLD Open"],"accepted":{"date-parts":[[2025,10,9]]},"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>The REMEMBER (A5274) study found that the four-drug TB preventive regimen did not reduce mortality compared to isoniazid-only, raising adherence concerns. Using drug measurements and pharmacometrics, we assessed adherence in the four-drug arm by comparing participants who developed TB (cases) to those who did not (controls).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Using a 1:4 matched case-control design, we analysed stored blood samples at weeks 2, 4, and 8 since treatment start. Rifampicin and pyrazinamide were measured, and adherence was assessed using two thresholds: i) lower limit of quantification (LLOQ) and ii) personalised thresholds derived from pharmacokinetic simulations. Population pharmacokinetic models and Monte Carlo simulations were used to predict individualised thresholds assuming 100% adherence. Conditional logistic regression compared non-adherence between cases and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Among 28 cases and 112 controls, the proportion of samples &lt;LLOQ was 52% (cases) versus 45% (controls) for rifampicin and 20% (cases) versus 14% (controls) for pyrazinamide. Non-adherence was significantly higher in cases compared to controls for two pyrazinamide metrics: the week 4 LLOQ (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.050) and the week 2 2.5th percentile personalised threshold (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.023).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Poor adherence may have contributed to TB incidence in REMEMBER. While not definitive, personalised thresholds from model-based simulations remain useful for adherence assessment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.5588\/ijtldopen.25.0467","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:54:16Z","timestamp":1771926856000},"page":"77-83","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacokinetic modelling as a tool to assess TB treatment adherence: application to the REMEMBER study"],"prefix":"10.5588","volume":"3","author":[{"given":"N.","family":"Abdelgawad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Chirehwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"McIlleron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Kanyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Mwelase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Naidoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Kumwenda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Nyirenda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.P.","family":"Samaneka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.R.","family":"Lama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Mohapi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.","family":"Mave","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.G.","family":"Veloso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Valencia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.C.","family":"Hosseinipour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.","family":"Scarsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Denti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"3554","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"2026031812064707000_3.2.77.1","doi-asserted-by":"crossref","unstructured":"World Health Organization . WHO consolidated guidelines on tuberculosis. Module 1: prevention. Tuberculosis preventive treatment. Geneva: WHO, 2021.","DOI":"10.30978\/TB2021-2-86"},{"key":"2026031812064707000_3.2.77.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028691"},{"key":"2026031812064707000_3.2.77.3","unstructured":"World Health Organization . WHO operational handbook on tuberculosis. Module 1: prevention - tuberculosis preventive treatment. 2nd ed. Geneva: WHO, 2020."},{"issue":"10024","key":"2026031812064707000_3.2.77.4","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/S0140-6736(16)00546-8","article-title":"Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial","volume":"387","author":"Hosseinipour","year":"2016","journal-title":"Lancet"},{"issue":"Suppl 12","key":"2026031812064707000_3.2.77.5","first-page":"s231","article-title":"The importance of treatment adherence in HIV","volume":"19","author":"Schaecher","year":"2013","journal-title":"Am J Manag Care"},{"key":"2026031812064707000_3.2.77.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jash.2011.01.001"},{"key":"2026031812064707000_3.2.77.7","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.96.09102026"},{"key":"2026031812064707000_3.2.77.8","doi-asserted-by":"publisher","DOI":"10.1007\/s11606-021-06648-1"},{"key":"2026031812064707000_3.2.77.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(99)80026-5"},{"key":"2026031812064707000_3.2.77.10","doi-asserted-by":"publisher","DOI":"10.1007\/BF00558302"},{"key":"2026031812064707000_3.2.77.11","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01830-15"},{"key":"2026031812064707000_3.2.77.12","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/5.Supplement_3.S428"},{"issue":"8","key":"2026031812064707000_3.2.77.13","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1128\/AAC.00490-17","article-title":"Pharmacokinetics of pyrazinamide and optimal dosing regimens for drug-sensitive and -resistant tuberculosis","volume":"61","author":"Chirehwa","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2026031812064707000_3.2.77.14","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200544100-00004"},{"issue":"6","key":"2026031812064707000_3.2.77.15","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/psp4.12790","article-title":"A quantitative approach to the choice of number of samples for percentile estimation in bootstrap and visual predictive check analyses","volume":"11","author":"Jonsson","year":"2022","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2026031812064707000_3.2.77.16","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e318225c1de"},{"issue":"8","key":"2026031812064707000_3.2.77.17","doi-asserted-by":"crossref","first-page":"362","DOI":"10.5588\/ijtld.24.0610","article-title":"Model-based evaluation of adherence to bedaquiline and clofazimine in adults with drug-resistant TB","volume":"29","author":"Resendiz-Galvan","year":"2025","journal-title":"Int J Tuberc Lung Dis"},{"issue":"4","key":"2026031812064707000_3.2.77.18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1097\/FTD.0b013e31825c6067","article-title":"Population pharmacokinetic model for adherence evaluation using lamivudine concentration monitoring","volume":"34","author":"Zhang","year":"2012","journal-title":"Ther Drug Monit"},{"issue":"1","key":"2026031812064707000_3.2.77.19","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1093\/jac\/dkae404","article-title":"Saliva-based point-of-care assay to measure the concentration of pyrazinamide using a mobile UV spectrophotometer","volume":"80","author":"Chen","year":"2025","journal-title":"J Antimicrob Chemother"}],"container-title":["IJTLD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.5588\/ijtldopen.25.0467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T19:07:17Z","timestamp":1773860837000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.theunion.org\/lookup\/doi\/10.5588\/ijtldopen.25.0467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":19,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2,1]]},"published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.5588\/ijtldopen.25.0467"],"URL":"https:\/\/doi.org\/10.5588\/ijtldopen.25.0467","relation":{},"ISSN":["3005-7590"],"issn-type":[{"value":"3005-7590","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]}}}