{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T06:51:21Z","timestamp":1787899881242,"version":"build-2784847793"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.14006.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2018,6,20]],"date-time":"2018-06-20T00:00:00Z","timestamp":1529452800000}}],"reference-count":24,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,6,20]],"date-time":"2018-06-20T00:00:00Z","timestamp":1529452800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust","award":["110179"],"award-info":[{"award-number":["110179"]}]}],"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                    Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients 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 multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT).\u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Discussion:\u00a0<\/ns4:bold>\n                    Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14006.2","type":"journal-article","created":{"date-parts":[[2018,6,20]],"date-time":"2018-06-20T06:05:43Z","timestamp":1529474743000},"page":"31","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled 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 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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"}]},{"given":"Marcel","family":"Wolbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5007-7896","authenticated-orcid":false,"given":"Raph L","family":"Hamers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6233-6410","authenticated-orcid":false,"given":"Reinout","family":"van 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T20:42:14Z","timestamp":1661460134000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,20]]},"references-count":24,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.14006.2","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.15979.r33350","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.15979.r33814","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.15979.r33814","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.15979.r33350","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,20]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.15222.r32220, Ravindra Kumar Garg, Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India, 26 Mar 2018, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v1#referee-response-32220","order":0,"name":"referee-response-32220","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15979.r33350, Rohit Bhatia, Manish Modi, Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi, Delhi, India, 17 Jul 2018, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2#referee-response-33350","order":1,"name":"referee-response-33350","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Joseph Donovan<\/b>; <i>Posted: 25 Jul 2018<\/i>; <u>Question 1<\/u>We feel we have already addressed this question and no further details are given as to why there are safety concerns regarding arm 1 of the DILI sub-study. There is no evidence to suggest that DILI arm 1 is unsafe, and the purpose of clinical research such as this is to produce high quality evidence to support our clinical treatment. We do not know that it is safer to stop essential first line anti-tuberculous drugs at an ALT threshold of &gt;5x ULN, and change to less effective anti-tuberculous therapy. This is frequently done but we do not know it is the safer approach in TBM. As previously explained, it is anticipated that arm 1 (continue all 4 first line anti-TB drugs) and arm 2 (stop only pyrazinamide) of the DILI study will result in less adverse events due to the continuation of the best and most appropriate anti-TB drugs. There are clear safety thresholds where a patient in DILI arms 1 or 2 moves to arm 3. Patients are reviewed daily and LFTs, including INR, are checked regularly. This trial has received ethical approval from the Oxford Tropical Research Ethics Committee, the Ethics Committees of the Hospital for Tropical Diseases and Pham Ngoc Thach Hospital, the Vietnam Ministry of Health, and Faculty of Medicine University of Indonesia. An independent data monitoring committee will review unblinded trial data at interim analysis points and advise on any safety issues. We believe the DILI sub-study is important, and there is no evidence base to say that arm 1 is unsafe.&nbsp; <u>Question 2<\/u>CT or MRI brain imaging can be important in the management of a patient with TBM, but it is not always available. It may be ideal to have imaging for every patient we treat but this is not always possible in all settings. Clinical trials cannot only be performed in sites where gold standard level testing is available for every patient. Where availability of imaging is limited, imaging must be done on a case-by-case basis where it is required.&nbsp; <u>Question 3<\/u>The experience of the reviewers suggests that most patients would be on anti-retroviral treatment at the time of presentation with TBM, however this is not the case in our setting. We do not believe that corticosteroid therapy will worsen HIV infection, and corticosteroids are often given to HIV co-infected individuals for a multitude of reasons. Furthermore, this is a double blind trial and physicians will not know who is treated with dexamethasone. The reviewers say that \u201cthe best evidence from the previous trial and recommendations of experts should be taken to decide about the best time to start ART in this trial\u201d. Our protocol states that ART in both Ho Chi Minh City and Jakarta is often commenced 6\u20138 weeks after the start of anti-tuberculosis treatment, \u201cwith the precise timing left to the discretion of the attending physician\u201d. Our trial physicians also follow local expert guidelines. We do not believe that in the absence of additional clinical trial data further expert guidance is needed.&nbsp;Yours Sincerely&nbsp;&nbsp;Professor Guy Thwaites (Senior author and study Chief Investigator)&nbsp;Dr Joseph Donovan (First author and Research Fellow)","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2#referee-comment-3656","order":2,"name":"referee-comment-3656","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15979.r33814, Ira Shah, Srushti Gandhi, Department of Paediatrics, HOD Pediatric Infectious Diseases, Incharge, Pediatric HIV and TB clinic, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India, 17 Sep 2018, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2#referee-response-33814","order":3,"name":"referee-response-33814","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Joseph Donovan<\/b>; <i>Posted: 18 Sep 2018<\/i>; Dear Dr Gandhi and Dr Shah,Thank you for your reply.I will address each of your points individually.&nbsp;1. It would help to mention an interval of how many hours-days is required to be eligible for the study in case the person has received any of the afore-mentioned drugs prior to the study. <u>Author reply<\/u>Whilst this clarification did not appear in the protocol, this was clarified subsequently in trial procedures. The term \u2018immediately before\u2019 was defined as \u2018within the 14 day period before\u2019&nbsp;2. Does the inclusion criteria include persons with TBM as a part of disseminated TB?&nbsp; <u>Author reply<\/u>Yes these patients can be included. Included patients must have a clinical diagnosis of TBM (\u22655 days of meningitis symptoms, and CSF abnormalities) and anti-tuberculosis chemotherapy either planned or started by the attending physician. If patients have other disseminated TB disease they can still enter the study.&nbsp; <i>3. The Ancillary study 6:&nbsp;Pathophysiology and treatment of hyponatraemia and raised intracranial pressure <\/i>does not specify what modalities will be used to determine the best method of treatment. <u>Author reply<\/u>Treatment will be decided by the treating physician and will be based on serum sodium and relevant study measurements and tests (serial fluid balance, urinary sodium, paired serum and urine osmolality, and intravascular volume measurements by Doppler ultrasound assessment of inferior vena cava collapsibility index). Local and national guidelines will be used.4. Will the ART be modified if the patient develops DILI? <u>Author reply<\/u>As stated in the protocol, \u201cIf DILI develops ART should not be stopped until all other management has been tried (including interrupting anti-tuberculosis drugs according to the randomised schedule). HIV specialists and liver specialists should be consulted at this point\u201d. Modification of ART may be necessary and specialists will be consulted in this instance.5. Interactions with Rifampicin and EFV are also seen. Are you going to monitor the TDM of efavirenz when using rifampicin in these patients? <u>Author reply<\/u>No this does not form part of our study protocol&nbsp;6. What about co-infection with HBV and HCV? Are you going to include these patients? It is not mentioned in the inclusion or exclusion criteria. <u>Author reply<\/u>Patients with HBV and HCV remain eligible to enter the DILI sub-study unless they meet the stated exclusion criteria. Those with HBV or HCV, plus signs of chronic liver disease of any cause, will be excluded.&nbsp;7. Other co-infections in HIV infected (which are non-neurological) is also not mentioned. Some patients do have systemic fungal infections such as esophageal candidiasis and histoplasmosis. Giving dexamethasone in these patients will be a problem. Are you going to include these patients as well as? <u>Author reply<\/u>These patients will not be excluded unless corticosteroids are considered contraindicated by the treating physician. Patients will be closely monitored, including for AIDS related disease. If a study participant was found to have a co-infection or other condition where corticosteroids were considered to do harm, then study drug would be discontinued.&nbsp;8. Survival in HIV infected patients with TBM will also depend on baseline CD4 count and HIV viral load. So that may be a confounding factor when analysing the data. This issue needs to be addressed. <u>Author reply<\/u>Sub group analyses include ART status at enrolment (ART naive, \u22643 months of ART, &gt;3 months of ART), and CD4 cell count at enrolment&nbsp;9. In case of DILI in the intensive phase, a regime of Lfx, E and aminoglycoside may not be enough. Would you consider addition of Linezolid or any other drug that is not hepatotoxic and does not have interaction with the ART. <u>Author reply<\/u>This treatment follows in-country and international guidelines. In cases where this therapy is considered inadequate, decisions would be made on a case-by-case basis. Linezolid is not widely available at our study sites.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-31\/v2#referee-comment-3696","order":4,"name":"referee-comment-3696","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":5,"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"}]}}