{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:32:26Z","timestamp":1790937146838,"version":"4.1.0"},"reference-count":21,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T00:00:00Z","timestamp":1521504000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["110179"],"award-info":[{"award-number":["110179"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:\u00a0<\/ns4:bold>\n                    Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C\/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy.\u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:\u00a0<\/ns4:bold>\n                    We will perform a parallel group, randomised (1:1), double blind, placebo-controlled,\u00a0 multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV).\u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Discussion:\u00a0<\/ns4:bold>\n                    Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C\/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14007.1","type":"journal-article","created":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T11:32:34Z","timestamp":1521545554000},"page":"32","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":54,"title":["Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial"],"prefix":"10.12688","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-336X","authenticated-orcid":false,"given":"Joseph","family":"Donovan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Hoan","family":"Phu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9661-6835","authenticated-orcid":false,"given":"Le Thi Phuong","family":"Thao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Huu","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Thi Hoang","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Thi Mai","family":"Trang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Thi Thu","family":"Hiep","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Bao","family":"Nhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bui Thi Bich","family":"Hanh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vu Thi Phuong","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Duc","family":"Bang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Chau","family":"Giang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dang Thi Minh","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-6280","authenticated-orcid":false,"given":"Jeremy","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen TT","family":"Thuong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Nang","family":"Vien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2740-3155","authenticated-orcid":false,"given":"Ronald B.","family":"Geskus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2383-4791","authenticated-orcid":false,"given":"Tran Tinh","family":"Hien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5728-0918","authenticated-orcid":false,"given":"Evelyne","family":"Kestelyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Wolbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Van Vinh","family":"Chau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-2087","authenticated-orcid":false,"given":"Guy E.","family":"Thwaites","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2018,3,20]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"295-300","DOI":"10.1097\/WCO.0b013e3283602814","article-title":"Advances in the diagnosis and treatment of tuberculous meningitis.","volume":"26","author":"G Thwaites","year":"2013","journal-title":"Curr Opin Neurol."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"CD002244","DOI":"10.1002\/14651858.CD002244.pub4","article-title":"Corticosteroids for managing tuberculous meningitis.","volume":"4","author":"K Prasad","year":"2016","journal-title":"Cochrane Database Syst Rev."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"999-1010","DOI":"10.1016\/S1474-4422(13)70168-6","article-title":"Tuberculous meningitis: more questions, still too few answers.","volume":"12","author":"G Thwaites","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"124-34","DOI":"10.1056\/NEJMoa1507062","article-title":"Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis.","volume":"374","author":"A Heemskerk","year":"2016","journal-title":"N Engl J Med."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"434-46","DOI":"10.1016\/j.cell.2011.12.023","article-title":"Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.","volume":"148","author":"D Tobin","year":"2012","journal-title":"Cell."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"717-30","DOI":"10.1016\/j.cell.2010.02.013","article-title":"The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans.","volume":"140","author":"D Tobin","year":"2010","journal-title":"Cell."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"1741-51","DOI":"10.1056\/NEJMoa040573","article-title":"Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults.","volume":"351","author":"G Thwaites","year":"2004","journal-title":"N Engl J Med."},{"key":"ref-8","doi-asserted-by":"crossref","first-page":"XX","DOI":"10.12688\/wellcomeopenres.14006.2","article-title":"Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): study protocol for a randomised controlled trial. [version 1; referees: awaiting peer review].","volume":"3","author":"J Donovan","year":"2018","journal-title":"Wellcome Open Res."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"1308-11","DOI":"10.1093\/cid\/ciu094","article-title":"Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America.","volume":"58","author":"H Masur","year":"2014","journal-title":"Clin Infect Dis."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"1092-7","DOI":"10.1111\/j.1440-1843.2010.01798.x","article-title":"Risk of hepatitis B virus reactivation in patients with asthma or chronic obstructive pulmonary disease treated with corticosteroids.","volume":"15","author":"T Kim","year":"2010","journal-title":"Respirology."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"1017-8","DOI":"10.1111\/j.1440-1843.2010.01822.x","article-title":"Systemic corticosteroid and reactivation of chronic hepatitis B.","volume":"15","author":"C Lai","year":"2010","journal-title":"Respirology."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"124-8","DOI":"10.1186\/2197-425X-3-S1-A919","article-title":"Nurse-delivered focused echocardiography to determine intravascular volume status in a deployed maritime critical care unit.","volume":"101","author":"S Hutchings","year":"2015","journal-title":"J R Nav Med Serv."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"329-37","DOI":"10.1177\/0885066609340640","article-title":"Techniques for assessment of intravascular volume in critically ill patients.","volume":"24","author":"P Marik","year":"2009","journal-title":"J Intensive Care Mede."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"963-7","DOI":"10.1016\/j.ajem.2016.02.012","article-title":"Bedside sonographic measurement of optic nerve sheath diameter as a predictor of intracranial pressure in ED.","volume":"34","author":"E Komut","year":"2016","journal-title":"Am J Emerg Med."},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"563-7","DOI":"10.4103\/0976-3147.165347","article-title":"Optic nerve sonography: A noninvasive means of detecting raised intracranial pressure in a resource-limited setting.","volume":"6","author":"O Aduayi","year":"2015","journal-title":"J Neurosci Rural Pract."},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"5019-23","DOI":"10.1200\/JCO.2007.11.8711","article-title":"Randomized clinical trial design for assessing noninferiority when superiority is expected.","volume":"25","author":"B Freidlin","year":"2007","journal-title":"J Clin Oncol."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"647-56","DOI":"10.1016\/j.cct.2010.08.011","article-title":"Adjusted significance levels for subgroup analyses in clinical trials.","volume":"31","author":"B Spiessens","year":"2010","journal-title":"Contemp Clin Trials."},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"1374-83","DOI":"10.1093\/cid\/cir230","article-title":"Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis.","volume":"52","author":"M Torok","year":"2011","journal-title":"Clin Infect Dis."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"3244-53","DOI":"10.1128\/AAC.00064-11","article-title":"Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis.","volume":"55","author":"G Thwaites","year":"2011","journal-title":"Antimicrob Agents Chemother."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"803-12","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: a uniform case definition for use in clinical research.","volume":"10","author":"S Marais","year":"2010","journal-title":"Lancet Infect Dis."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"422-8","DOI":"10.1111\/j.1541-0420.2007.00707.x","article-title":"Cox regression methods for two-stage randomization designs.","volume":"63","author":"Y Lokhnygina","year":"2007","journal-title":"Biometrics."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,12,23]],"date-time":"2018-12-23T22:20:11Z","timestamp":1545603611000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,20]]},"references-count":21,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.14007.1","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.15224.r32233","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.15224.r34043","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.15224.r34043","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.15224.r32233","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,20]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.15224.r32233, Ravindra K Garg, Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India, 26 Mar 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1#referee-response-32233","order":0,"name":"referee-response-32233","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15224.r34043, Katalin A. Wilkinson, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa, 10 Oct 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1#referee-response-34043","order":1,"name":"referee-response-34043","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Joseph Donovan<\/b>; \n<i>Posted: 24 Oct 2018<\/i>; Dear Dr Wilkinson,Many thanks for your comments.I have included replies to each of your points as below:&nbsp;1. Related to ancillary study 1 (management strategies in response to DILI): the numbers anticipated in the HIV-uninfected patients is n~70, to be analysed according to the 3 strategies. This may mean that the numbers in these analyses might be relatively low. Since the DILI strategy study will also be run in the ACT-HIV study, where anticipated numbers are n~100, will the two groups be potentially combined for analysis? It is acknowledged that this will present a number of limitations with respect to drug interactions when considering ART in the HIV-infected patients.\n<u>Author reply<\/u>These two DILI patient groups (from LAST ACT and from ACT HIV) will be analysed together (and a separate analysis will be performed stratified by HIV status). When anti-TB drugs are stopped because of DILI, the use and cessation of other potentially hepatotoxic (and DILI-causing) drugs will also be recorded, including ART.&nbsp;2. Related to ancillary study 2: will genetic variants associated with development of DILI be examined related to the host or bacteria, or both?\n<u>Author reply<\/u>Host only&nbsp;3. Related to ancillary study 3: the influence of dexamethasone on the resolution of inflammatory markers in the CSF will be examined. This should be done in parallel with blood, although I see no blood collection for such studies in Table 3.\n<u>Author reply<\/u>Only CSF inflammatory markers will be analysed at this time&nbsp;4. Considering that there is no LTAH4 genotyping at weekends, and a patient recruited on a Friday may have been already on anti-TB treatment for 5 days with adjunctive dexamethasone. Therefore, by the time the genotyping result is returned on Monday with a CC genotype, the patient already received 8 days of potentially harmful dexamethasone. Assuming that this patient is randomised to placebo, the harm is potentially already done, therefore having a negative effect on the placebo arm. Is there a way to control for this, by potentially not recruiting on a Friday or introducing weekend genotyping for the duration of the trial.\n<u>Author reply<\/u>The number of days of dexamethasone received will be recorded, including any days given whilst waiting for the LTA4H result to return. The effect of dexamethasone on individuals randomised to placebo will be factored in to the analysis. Genotyping is now available on one day over the weekend which will reduce this effect.&nbsp;5. HIV testing is done at baseline: would there be benefit in further HIV testing at 3 and\/or 6 months?\n<u>Author reply<\/u>Additional HIV testing was considered, however a decision was made to only perform this if clinically indicated, rather than as part of the trial.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-32\/v1#referee-comment-3721","order":2,"name":"referee-comment-3721","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The trial is supported by the Wellcome Trust [110179], an Investigator Award to Professor Guy Thwaites. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}