{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:17:03Z","timestamp":1787008623881,"version":"build-2736575974"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of British Columbia Clinician-Investigator Program"},{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Research British Columbia Health Professional Investigator Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Recent studies suggest that triple-dose rifampin (TDR; \u226530\u2005mg\/kg\/d) may be unsafe. We updated a systematic review to investigate the safety and efficacy of TDR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We searched Embase, MEDLINE, Cochrane CENTRAL, Cochrane Database for Systematic Reviews, and clinicaltrials.gov for randomized, controlled trials from 1 January 1965 to 10 February 2024 that compared standard-dose rifampin (SDR) with TDR and\/or double-dose rifampin (DDR) in human tuberculosis treatment. The primary outcome was pooled incidence rate ratio (IRR) of severe adverse events (SevAEs) between participants who received TDR and those who received SDR. Pooled relative risk (RR) of death was a key secondary outcome. Meta-analysis was performed using the inverse variance method. Heterogeneity was assessed using I2, and bias was assessed using Cochrane Risk of Bias 2. The protocol was prospectively registered (osf.io\/kfn5a).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of the 11 315 articles identified, 17 met inclusion criteria, enrolling 2313 SDR participants (17 studies), 2238 receiving DDR (12 studies), and 1199 receiving TDR (11 studies). Six studies had a high risk of bias. There was an increase in pooled SevAEs among participants who received TDR compared with those who received SDR (IRR, 1.48; 95% confidence interval [CI], 1.12\u20131.96; I2, 23%), driven by hepatic events (IRR, 1.96; 95% CI, 1.21\u20133.18). Death did not differ between participants who received TDR and SDR (RR, 1.19; 95% CI, .71\u20131.99). One limitation is that only 2 included studies were blinded.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Regimens that used TDR were associated with an increase in SevAEs, raising concerns regarding safety of TDR regimens.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciaf004","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T23:16:26Z","timestamp":1735946186000},"page":"119-128","source":"Crossref","is-referenced-by-count":7,"title":["Safety of Triple-Dose Rifampin in Tuberculosis Treatment: A Systematic Review and Meta-Analysis"],"prefix":"10.1093","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6024-9030","authenticated-orcid":false,"given":"Omri A","family":"Arbiv","sequence":"first","affiliation":[{"name":"Faculty of Medicine, University of Toronto , Toronto, Ontario ,","place":["Canada"]},{"name":"Institute of Health Policy, Management, and Evaluation, Dalla Lana School of Public Health, University of Toronto , Toronto, Ontario ,","place":["Canada"]},{"name":"Clinician-Investigator Program, University of British Columbia , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Holmes","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland , Dublin ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie JeongMin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of British Columbia, Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of British Columbia, Vancouver, British Columbia ,","place":["Canada"]},{"name":"Provincial TB Services, BC Centre for Disease Control , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7027-3579","authenticated-orcid":false,"given":"Kamila","family":"Romanowski","sequence":"additional","affiliation":[{"name":"Provincial TB Services, BC Centre for Disease Control , Vancouver, British Columbia ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-6368","authenticated-orcid":false,"given":"Sarah K","family":"Brode","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Toronto , Toronto, Ontario ,","place":["Canada"]},{"name":"Division of Respirology, University Health Network , Toronto, Ontario ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6982-1825","authenticated-orcid":false,"given":"William J","family":"Burman","sequence":"additional","affiliation":[{"name":"Public Health Institute at Denver Health , Denver, Colorado ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1601-4514","authenticated-orcid":false,"given":"Dick","family":"Menzies","sequence":"additional","affiliation":[{"name":"McGill International TB Centre, McGill University , Montreal, Quebec ,","place":["Canada"]},{"name":"Department of Epidemiology, Biostatistics and Occupational Health, McGill University , Quebec ,","place":["Canada"]},{"name":"Montreal Chest Institute, McGill University Health Centre , Montreal, Quebec ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8879-4989","authenticated-orcid":false,"given":"James C","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of British Columbia, Vancouver, British Columbia ,","place":["Canada"]},{"name":"Provincial TB Services, BC Centre for Disease Control , Vancouver, British Columbia ,","place":["Canada"]},{"name":"McGill International TB Centre, McGill University , Montreal, Quebec ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"2025080104320147700_ciaf004-B1","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1093\/cid\/ciw376","article-title":"Official American Thoracic Society\/Centers for Disease Control and Prevention\/Infectious Diseases Society of America clinical practice guidelines: treatment of drug-susceptible tuberculosis","volume":"63","author":"Nahid","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2025080104320147700_ciaf004-B2","doi-asserted-by":"crossref","first-page":"e194","DOI":"10.1093\/cid\/cir184","article-title":"Why do we use 600\u2005mg of rifampicin in tuberculosis treatment","volume":"52","author":"van Ingen","year":"2011","journal-title":"Clin Infect Dis"},{"key":"2025080104320147700_ciaf004-B3","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1128\/AAC.01533-06","article-title":"Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin","volume":"51","author":"Gumbo","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"2025080104320147700_ciaf004-B4","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1136\/thoraxjnl-2020-216497","article-title":"High-dose rifamycins in the treatment of TB: a systematic review and meta-analysis","volume":"77","author":"Arbiv","year":"2022","journal-title":"Thorax"},{"key":"2025080104320147700_ciaf004-B5","author":"World Health Organization"},{"key":"2025080104320147700_ciaf004-B6","doi-asserted-by":"crossref","first-page":"2000955","DOI":"10.1183\/13993003.00955-2020","article-title":"Increased bactericidal activity but dose-limiting intolerability at 50\u2005mg\u00b7kg\u22121 rifampicin","volume":"58","author":"Te Brake","year":"2021","journal-title":"Eur Respir J"},{"key":"2025080104320147700_ciaf004-B7","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1056\/NEJMoa2212537","article-title":"Treatment strategy for rifampin-susceptible tuberculosis","volume":"388","author":"Paton","year":"2023","journal-title":"N Engl J Med"},{"key":"2025080104320147700_ciaf004-B8","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ijid.2023.05.002","article-title":"High rate of adverse drug reactions with a novel tuberculosis re-treatment regimen combining triple doses of both isoniazid and rifampicin","volume":"133","author":"Souleymane","year":"2023","journal-title":"Int J Infect Dis"},{"key":"2025080104320147700_ciaf004-B9","author":"Sanchez-Montalva"},{"key":"2025080104320147700_ciaf004-B10"},{"key":"2025080104320147700_ciaf004-B11","author":"Arbiv"},{"key":"2025080104320147700_ciaf004-B12","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"2025080104320147700_ciaf004-B13","author":"US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation, and Research (CDER), Center for Biologics Evaluation and Research (CBER)"},{"key":"2025080104320147700_ciaf004-B14","author":"Higgins"},{"key":"2025080104320147700_ciaf004-B15","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat Med"},{"key":"2025080104320147700_ciaf004-B16","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1093\/oxfordjournals.aje.a116237","article-title":"Methods for trend estimation from summarized dose-response data, with applications to meta-analysis","volume":"135","author":"Greenland","year":"1992","journal-title":"Am J Epidemiol"},{"key":"2025080104320147700_ciaf004-B17","doi-asserted-by":"crossref","first-page":"d4002","DOI":"10.1136\/bmj.d4002","article-title":"Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials","volume":"343","author":"Sterne","year":"2011","journal-title":"BMJ"},{"key":"2025080104320147700_ciaf004-B18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1136\/ebmental-2019-300117","article-title":"How to perform a meta-analysis with R: a practical tutorial","volume":"22","author":"Balduzzi","year":"2019","journal-title":"Evid Based Ment Health"},{"key":"2025080104320147700_ciaf004-B19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v072.c01","article-title":"Multivariate dose-response meta-analysis: the dosresmeta R package","volume":"72","author":"Crippa","year":"2016","journal-title":"J Stat Softw"},{"key":"2025080104320147700_ciaf004-B20","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1093\/cid\/ciac932","article-title":"A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus-associated tuberculous meningitis: the LASER-TBM trial","volume":"76","author":"Davis","year":"2023","journal-title":"Clin Infect Dis"},{"key":"2025080104320147700_ciaf004-B21","doi-asserted-by":"crossref","first-page":"EVIDoa2300054","DOI":"10.1056\/EVIDoa2300054","article-title":"Four-month high-dose rifampicin regimens for pulmonary tuberculosis","volume":"2","author":"Jindani","year":"2023","journal-title":"NEJM Evid"},{"key":"2025080104320147700_ciaf004-B22","doi-asserted-by":"crossref","first-page":"e910","DOI":"10.1093\/cid\/ciac585","article-title":"Decreased dolutegravir and efavirenz concentrations with preserved virological suppression in patients with tuberculosis and human immunodeficiency virus receiving high-dose rifampicin","volume":"76","author":"Sekaggya-Wiltshire","year":"2023","journal-title":"Clin Infect Dis"},{"key":"2025080104320147700_ciaf004-B23","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/cid\/ciac208","article-title":"Randomized clinical trial of high-dose rifampicin with or without levofloxacin versus standard of care for pediatric tuberculous meningitis: the TBM-KIDS trial","volume":"75","author":"Paradkar","year":"2022","journal-title":"Clin Infect Dis"},{"key":"2025080104320147700_ciaf004-B24","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1093\/cid\/ciab162","article-title":"High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly human immunodeficiency virus (HIV)-positive Ugandan adults: a phase II open-label randomized controlled trial","volume":"73","author":"Cresswell","year":"2021","journal-title":"Clin Infect Dis"},{"key":"2025080104320147700_ciaf004-B25","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1093\/jac\/dkz557","article-title":"Effect of high-dose rifampicin on efavirenz pharmacokinetics: drug-drug interaction randomized trial","volume":"75","author":"Atwine","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2025080104320147700_ciaf004-B26","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1473-3099(16)30274-2","article-title":"High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial","volume":"17","author":"Boeree","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"2025080104320147700_ciaf004-B27","doi-asserted-by":"crossref","first-page":"e01014-18","DOI":"10.1128\/AAC.01014-18","article-title":"Double-blind, randomized, placebo-controlled phase II dose-finding study to evaluate high-dose rifampin for tuberculous meningitis","volume":"62","author":"Dian","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2025080104320147700_ciaf004-B28","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1056\/NEJMoa1507062","article-title":"Intensified antituberculosis therapy in adults with tuberculous meningitis","volume":"374","author":"Heemskerk","year":"2016","journal-title":"N Engl J Med"},{"key":"2025080104320147700_ciaf004-B29","doi-asserted-by":"crossref","first-page":"499","DOI":"10.5588\/ijtld.19.0063","article-title":"First-line tuberculosis treatment with double-dose rifampicin is well tolerated","volume":"24","author":"Maug","year":"2020","journal-title":"Int J Tuberc Lung Dis"},{"key":"2025080104320147700_ciaf004-B30","doi-asserted-by":"crossref","first-page":"ofae034","DOI":"10.1093\/ofid\/ofae034","article-title":"Safety and efficacy of 25\u2005mg\/kg and 35\u2005mg\/kg vs 10\u2005mg\/kg rifampicin in pulmonary TB: a phase IIb randomized controlled trial","volume":"11","author":"Kannabiran","year":"2024","journal-title":"Open Forum Infect Dis"},{"key":"2025080104320147700_ciaf004-B31","doi-asserted-by":"crossref","first-page":"e01054","DOI":"10.1128\/AAC.01054-17","article-title":"Pharmacokinetics, tolerability, and bacteriological response of rifampin administered at 600, 900, and 1,200 milligrams daily in patients with pulmonary tuberculosis","volume":"61","author":"Aarnoutse","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2025080104320147700_ciaf004-B32","doi-asserted-by":"crossref","first-page":"832","DOI":"10.5588\/ijtld.15.0577","article-title":"A randomised phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis","volume":"20","author":"Jindani","year":"2016","journal-title":"Int J Tuberc Lung Dis"},{"key":"2025080104320147700_ciaf004-B33","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/S2213-2600(24)00076-6","article-title":"High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial","volume":"12","author":"Ruslami","year":"2024","journal-title":"Lancet Respir Med"},{"key":"2025080104320147700_ciaf004-B34","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1164\/rccm.201712-2524OC","article-title":"Efficacy and safety of high-dose rifampin in pulmonary tuberculosis. A randomized controlled trial","volume":"198","author":"Vel\u00e1squez","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"2025080104320147700_ciaf004-B35","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0140-6736(04)17670-8","article-title":"External validity of randomised controlled trials: \u201cto whom do the results of this trial apply?\u201d","volume":"365","author":"Rothwell","year":"2005","journal-title":"Lancet"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciaf004\/61402000\/ciaf004.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/81\/1\/119\/61402000\/ciaf004.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/81\/1\/119\/61402000\/ciaf004.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T08:32:25Z","timestamp":1754037145000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/81\/1\/119\/7950941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,9]]},"published-print":{"date-parts":[[2025,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciaf004","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,7,15]]},"published":{"date-parts":[[2025,1,9]]}}}