{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:35:39Z","timestamp":1791218139402,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate ESAT-6 and CFP-10 (EC) IFN-\u03b3 ELISPOT as a biomarker for treatment efficacy in LTBI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a randomized, blinded, and placebo-controlled trial of INH in EC ELISPOT and Mantoux test positive participants.<\/jats:p>\n                    <jats:p>Measurements and Main Results: Participants received a 6-month course of 900 mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tested for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6 between treatment arms was compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model was fitted to allow for zero inflation and overdispersion of quantitative response. The proportions of EC ELISPOT\u2013positive subjects reduced over time (P &amp;lt; 0.001) but did not differ by study arm (P = 0.36). Median spot-forming units for ESAT-6 and CFP-10 also declined significantly with time (P &amp;lt; 0.001) but did not differ by study arm (P = 0.74 and 0.71, respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In contacts with LTBI, INH therapy plays no role in observed decreases in Mycobacterium tuberculosis antigen\u2013specific T-cell responses over time. IFN-\u03b3 ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT00130325).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201208-1352oc","type":"journal-article","created":{"date-parts":[[2012,12,7]],"date-time":"2012-12-07T03:00:58Z","timestamp":1354849258000},"page":"439-445","source":"Crossref","is-referenced-by-count":49,"title":["Interferon-\u03b3 ELISPOT as a Biomarker of Treatment Efficacy in Latent Tuberculosis Infection"],"prefix":"10.1093","volume":"187","author":[{"given":"Ifedayo M.","family":"Adetifa","sequence":"first","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin O. C.","family":"Ota","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Jeffries","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moses D.","family":"Lugos","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahman S.","family":"Hammond","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Battersby","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick K.","family":"Owiafe","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon D.","family":"Donkor","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Antonio","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah B.","family":"Ibanga","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger H.","family":"Brookes","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Aka","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Walton","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Adegbola","sequence":"additional","affiliation":[{"name":"Medical Research Council Unit, The Gambia, Fajara, The Gambia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip C.","family":"Hill","sequence":"additional","affiliation":[{"name":"Centre for International Health, Department of Preventive and Social Medicine, University of Otago School of Medicine, Dunedin, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,2,15]]},"reference":[{"key":"2026032100523240600_bib1","author":"World Health Organization"},{"key":"2026032100523240600_bib2","article-title":"Joint TDR\/EC expert consultation on biomarkers in tuberculosis-report of the joint TDR\/EC expert consultation to evaluate the potential roles of biomarkers in the management of HIV-infected and HIV-uninfected patients with tuberculosis","author":"World Health Organization"},{"key":"2026032100523240600_bib3","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1046\/j.1365-3083.2003.01328.x","article-title":"Polymorphism in the interferon-gamma receptor-1 gene and susceptibility to pulmonary tuberculosis in the Gambia","volume":"58","author":"Newport","year":"2003","journal-title":"Scand J Immunol"},{"key":"2026032100523240600_bib4","doi-asserted-by":"crossref","first-page":"340","DOI":"10.7326\/0003-4819-146-5-200703060-00006","article-title":"Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research","volume":"146","author":"Menzies","year":"2007","journal-title":"Ann Intern Med"},{"key":"2026032100523240600_bib5","article-title":"Use of tuberculosis interferon-gamma release assay as (IGRAS) in low- and middle-income countries: policy statement","author":"World Health Organization","year":"2011"},{"key":"2026032100523240600_bib6","doi-asserted-by":"crossref","first-page":"e12502","DOI":"10.1371\/journal.pone.0012502","article-title":"Decay kinetics of an interferon gamma release assay with anti-tuberculosis therapy in newly diagnosed tuberculosis cases","volume":"5","author":"Adetifa","year":"2010","journal-title":"PLoS ONE"},{"key":"2026032100523240600_bib7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/1471-2334-6-66","article-title":"Reversion of the ELISPOT test after treatment in Gambian tuberculosis cases","volume":"6","author":"Aiken","year":"2006","journal-title":"BMC Infect Dis"},{"key":"2026032100523240600_bib8","doi-asserted-by":"crossref","first-page":"e1379","DOI":"10.1371\/journal.pone.0001379","article-title":"Incidence of tuberculosis and the predictive value of ELISPOT and Mantoux tests in Gambian case contacts","volume":"3","author":"Hill","year":"2008","journal-title":"PLoS ONE"},{"key":"2026032100523240600_bib9","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1164\/rccm.200608-1109OC","article-title":"Latent tuberculosis infection treatment and T-cell responses to Mycobacterium tuberculosis-specific antigens","volume":"175","author":"Chee","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100523240600_bib10","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.rmed.2009.10.006","article-title":"Serial interferon-gamma release assays after rifampicin prophylaxis in a tuberculosis outbreak","volume":"104","author":"Lee","year":"2010","journal-title":"Respir Med"},{"key":"2026032100523240600_bib11","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1164\/rccm.200511-1783OC","article-title":"Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis","volume":"174","author":"Ewer","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100523240600_bib12","doi-asserted-by":"crossref","first-page":"e192","DOI":"10.1371\/journal.pmed.0040192","article-title":"Longitudinal assessment of an ELISPOT test for Mycobacterium tuberculosis infection","volume":"4","author":"Hill","year":"2007","journal-title":"PLoS Med"},{"key":"2026032100523240600_bib13","first-page":"390","article-title":"Surveillance of drug-resistant Mycobacterium tuberculosis in the Gambia","volume":"7","author":"Adegbola","year":"2003","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100523240600_bib14","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/1471-2334-7-122","article-title":"Comparison of two interferon gamma release assays in the diagnosis of Mycobacterium tuberculosis infection and disease in the Gambia","volume":"7","author":"Adetifa","year":"2007","journal-title":"BMC Infect Dis"},{"key":"2026032100523240600_bib15","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1084\/jem.186.6.859","article-title":"Rapid effector function in CD8+ memory T cells","volume":"186","author":"Lalvani","year":"1997","journal-title":"J Exp Med"},{"key":"2026032100523240600_bib16","first-page":"192","article-title":"Identifying ELISPOT and skin test cut-offs for diagnosis of Mycobacterium tuberculosis infection in the Gambia","volume":"10","author":"Jeffries","year":"2006","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100523240600_bib17","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.rmed.2010.02.001","article-title":"Point-of-care Arkansas method for measuring adherence to treatment with isoniazid","volume":"104","author":"Guerra","year":"2010","journal-title":"Respir Med"},{"key":"2026032100523240600_bib18","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1002\/humu.9438","article-title":"Sub-Saharan African coding sequence variation and haplotype diversity at the NAT2 gene","volume":"27","author":"Patin","year":"2006","journal-title":"Hum Mutat"},{"key":"2026032100523240600_bib19","first-page":"1095","article-title":"Design and implementation of relational databases relevant to the diverse needs of a tuberculosis case contact study in the Gambia","volume":"8","author":"Jeffries","year":"2004","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100523240600_bib20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nri2960","article-title":"Immunological biomarkers of tuberculosis","volume":"11","author":"Walzl","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"2026032100523240600_bib21","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1086\/429245","article-title":"Enzyme-linked immunospot assay responses to early secretory antigenic target 6, culture filtrate protein 10, and purified protein derivative among children with tuberculosis: implications for diagnosis and monitoring of therapy","volume":"40","author":"Nicol","year":"2005","journal-title":"Clin Infect Dis"},{"key":"2026032100523240600_bib22","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1183\/09031936.00151309","article-title":"Tuberculosis treatment effect on T-cell interferon-gamma responses to Mycobacterium tuberculosis-specific antigens","volume":"36","author":"Chee","year":"2010","journal-title":"Eur Respir J"},{"key":"2026032100523240600_bib23","doi-asserted-by":"crossref","first-page":"e5187","DOI":"10.1371\/journal.pone.0005187","article-title":"In vivo and in vitro effects of antituberculosis treatment on Mycobacterial interferon-gamma T cell response","volume":"4","author":"Sauzullo","year":"2009","journal-title":"PLoS ONE"},{"key":"2026032100523240600_bib24","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1086\/499311","article-title":"Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens","volume":"193","author":"Wilkinson","year":"2006","journal-title":"J Infect Dis"},{"key":"2026032100523240600_bib25","doi-asserted-by":"crossref","first-page":"e37436","DOI":"10.1371\/journal.pone.0037436","article-title":"Correlation of Mycobacterium tuberculosis specific and non-specific quantitative Th1 T-cell responses with bacillary load in a high burden setting","volume":"7","author":"Theron","year":"2012","journal-title":"PLoS ONE"},{"key":"2026032100523240600_bib26","first-page":"1021","article-title":"Waning of the specific interferon-gamma response after years of tuberculosis infection","volume":"11","author":"Mori","year":"2007","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100523240600_bib27","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nrmicro2236","article-title":"The spectrum of latent tuberculosis: rethinking the biology and intervention strategies","volume":"7","author":"Barry","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"2026032100523240600_bib28","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1164\/ajrccm\/140.5.1189","article-title":"Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide","volume":"140","author":"Lecoeur","year":"1989","journal-title":"Am Rev Respir Dis"},{"key":"2026032100523240600_bib29","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/87720","article-title":"Memory CD8+ T cell differentiation: Initial antigen encounter triggers a developmental program in naive cells","volume":"2","author":"Kaech","year":"2001","journal-title":"Nat Immunol"},{"key":"2026032100523240600_bib30","first-page":"1","article-title":"Targeted tuberculin testing and treatment of latent tuberculosis infection","volume":"49","author":"American Thoracic Society","year":"2000","journal-title":"MMWR Recomm Rep"},{"key":"2026032100523240600_bib31","first-page":"1232","article-title":"Evaluation of the Arkansas method of urine testing for isoniazid in South Africa","volume":"11","author":"Hanifa","year":"2007","journal-title":"Int J Tuberc Lung Dis"},{"key":"2026032100523240600_bib32","author":"World Health Organization"},{"key":"2026032100523240600_bib33","doi-asserted-by":"crossref","first-page":"e8517","DOI":"10.1371\/journal.pone.0008517","article-title":"Within-subject variability of interferon-g assay results for tuberculosis and boosting effect of tuberculin skin testing: a systematic review","volume":"4","author":"van Zyl-Smit","year":"2009","journal-title":"PLoS ONE"},{"key":"2026032100523240600_bib34","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1097\/INF.0b013e3181cb45da","article-title":"Commercial interferon gamma release assays compared to the tuberculin skin test for diagnosis of latent Mycobacterium tuberculosis infection in childhood contacts in the Gambia","volume":"29","author":"Adetifa","year":"2010","journal-title":"Pediatr Infect Dis J"},{"key":"2026032100523240600_bib35","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1542\/peds.2005-2095","article-title":"Comparison of enzyme-linked immunospot assay and tuberculin skin test in healthy children exposed to Mycobacterium tuberculosis","volume":"117","author":"Hill","year":"2006","journal-title":"Pediatrics"},{"key":"2026032100523240600_bib36","author":"World Health Organization"},{"key":"2026032100523240600_bib37","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1378\/chest.12-0142","article-title":"Relevance of latent TB infection in areas of high TB prevalence","volume":"142","author":"Sharma","year":"2012","journal-title":"Chest"},{"key":"2026032100523240600_bib38","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.cct.2010.12.008","article-title":"Thibela TB: design and methods of a cluster randomised trial of the effect of community-wide isoniazid preventive therapy on tuberculosis amongst gold miners in South Africa","volume":"32","author":"Fielding","year":"2011","journal-title":"Contemp Clin Trials"},{"key":"2026032100523240600_bib39","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S1473-3099(10)70164-X","article-title":"Tuberculosis case-contact research in endemic tropical settings: design, conduct, and relevance to other infectious diseases","volume":"10","author":"Hill","year":"2010","journal-title":"Lancet Infect Dis"},{"key":"2026032100523240600_bib40","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0197-2456(01)00153-2","article-title":"Considerations in the evaluation of surrogate endpoints in clinical trials: summary of a National Institutes of Health workshop","volume":"22","author":"De Gruttola","year":"2001","journal-title":"Control Clin Trials"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/187\/4\/439\/67269051\/ajrccm_187_4_439.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/187\/4\/439\/67269051\/ajrccm_187_4_439.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:53:32Z","timestamp":1774068812000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/187\/4\/439\/8510010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,2,15]]},"published-print":{"date-parts":[[2013,2,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201208-1352oc","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.717969532.793474782","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.717969532.793470477","asserted-by":"object"}]},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,2]]},"published":{"date-parts":[[2013,2]]}}}