{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T07:23:58Z","timestamp":1781594638355,"version":"3.54.5"},"reference-count":38,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,12,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n<jats:p>Early mortality after initiation of antiretroviral therapy (ART) occurs in 9\u201339% of patients in sub-Saharan Africa. A significant proportion of deaths are attributable to tuberculosis (TB). Low baseline CD4 T-cell count and low body mass index (BMI) are strongly associated with early mortality. We hypothesized that initiation of ART concurrent with presumptive anti-TB chemotherapy in high-risk patients would reduce mortality within the first 6 months by treating unrecognized TB. From October 2011 to December 2012, ART-naive, smear-negative participants with a CD4 T-cell count &lt; 50 cells\/\u03bcL and BMI &lt; 18 kg\/m<jats:sup>2<\/jats:sup> were randomly assigned to undergo either empiric four-drug anti-TB treatment followed 2 weeks later by efavirenz-based ART (<jats:italic>N<\/jats:italic> = 23) (ART + TB) or ART only (<jats:italic>N<\/jats:italic> = 20). This open-label, 1:1 randomized, controlled trial took place in Uganda, Mozambique, and Gabon and was stopped prematurely by the sponsor for slow recruitment. Overall, the 43 participants had a median CD4 of 22 (interquartile range [IQR]: 9\u201335) cells\/\u03bcL and a median BMI of 17.5 (IQR: 16.6\u201318.0) kg\/m<jats:sup>2<\/jats:sup>. The mortality was 14% (95% confidence interval [CI]: 5.3\u201327.9); two (10.0%) participants (ART-only group), and four (17.4%; ART + TB group). The associated hazard ratio (HR) for all-cause mortality was 1.6 (95% CI: 0.30\u20138.90). Despite limited enrollment, the study did not suggest that empiric TB treatment in severely immunosuppressed patients with low BMI decreased mortality and, had an HR in the opposite direction than expected. Notably, two participants in the ART + TB group died with autopsy-confirmed drug-induced hepatotoxicity. Improved TB diagnostics sensitive in immunosuppressed patients presenting late to care are urgently needed for more targeted interventions.<\/jats:p>","DOI":"10.4269\/ajtmh.16-0239","type":"journal-article","created":{"date-parts":[[2016,10,18]],"date-time":"2016-10-18T20:13:13Z","timestamp":1476821593000},"page":"1265-1271","source":"Crossref","is-referenced-by-count":13,"title":["Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial"],"prefix":"10.4269","volume":"95","author":[{"given":"Yukari C.","family":"Manabe","sequence":"first","affiliation":[{"name":"Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda."},{"name":"Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Worodria","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"van Leth","sequence":"additional","affiliation":[{"name":"Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands."},{"name":"Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet","family":"Mayanja-Kizza","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda."},{"name":"Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afsatou Ndama","family":"Traore","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9cherches Medicales en Lambar\u00e9n\u00e9 (CERMEL), Albert Schweitzer Hospital, Lambar\u00e9n\u00e9, Gabon."},{"name":"Department of Microbiology, University of Venda, Thohoyandou, South Africa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefo","family":"Ferro","sequence":"additional","affiliation":[{"name":"Catholic University of Mozambique, Beira, Mozambique."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Pakker","sequence":"additional","affiliation":[{"name":"Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands."},{"name":"Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Frank","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9cherches Medicales en Lambar\u00e9n\u00e9 (CERMEL), Albert Schweitzer Hospital, Lambar\u00e9n\u00e9, Gabon."},{"name":"Institute of Tropical Medicine, University of T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin P.","family":"Grobusch","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9cherches Medicales en Lambar\u00e9n\u00e9 (CERMEL), Albert Schweitzer Hospital, Lambar\u00e9n\u00e9, Gabon."},{"name":"Institute of Tropical Medicine, University of T\u00fcbingen, T\u00fcbingen, Germany."},{"name":"Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Colebunders","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine, Antwerp, Belgium."},{"name":"Global Health Institute, University of Antwerp, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Cobelens","sequence":"additional","affiliation":[{"name":"Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands."},{"name":"Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands."},{"name":"KNCV Tuberculosis Foundation, The Hague, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2795","reference":[{"key":"ref1","series-title":"The Gap Report 2014","author":"UNAIDS","year":"2014"},{"key":"ref2","series-title":"PLoS One","first-page":"e28691","article-title":"Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis","volume":"6","author":"Gupta","year":"2011"},{"key":"ref3","series-title":"Lancet","first-page":"817","article-title":"Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries","volume":"367","author":"Braitstein","year":"2006"},{"key":"ref4","series-title":"AIDS","first-page":"1897","article-title":"Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa","volume":"22","author":"Lawn","year":"2008"},{"key":"ref5","series-title":"AIDS","first-page":"1181","article-title":"Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study","volume":"20","author":"Etard","year":"2006"},{"key":"ref6","series-title":"BMC Public Health","first-page":"433","article-title":"Low haemoglobin predicts early mortality among adults starting antiretroviral therapy in an HIV care programme in South Africa: a cohort study","volume":"10","author":"Russell","year":"2010"},{"key":"ref7","series-title":"JAMA","first-page":"782","article-title":"Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes","volume":"296","author":"Stringer","year":"2006"},{"key":"ref8","series-title":"AIDS","first-page":"873","article-title":"Rapid scaling-up of antiretroviral therapy in 10,000 adults in Cote d'Ivoire: 2-year outcomes and determinants","volume":"22","author":"Toure","year":"2008"},{"key":"ref9","series-title":"Lancet","first-page":"1335","article-title":"Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment","volume":"367","author":"Ferradini","year":"2006"},{"key":"ref10","series-title":"AIDS","first-page":"2483","article-title":"Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIV-infected adults in west Africa","volume":"21","author":"Moh","year":"2007"},{"key":"ref11","series-title":"AIDS","first-page":"2355","article-title":"Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi","volume":"20","author":"Zachariah","year":"2006"},{"key":"ref12","series-title":"AIDS","first-page":"713","article-title":"Prevalence, incidence and mortality associated with tuberculosis in HIV-infected patients initiating antiretroviral therapy in rural Uganda","volume":"21","author":"Moore","year":"2007"},{"key":"ref13","series-title":"BMC Infect Dis","first-page":"52","article-title":"Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania","volume":"8","author":"Johannessen","year":"2008"},{"key":"ref14","series-title":"J Acquir Immune Defic Syndr","first-page":"e8","article-title":"Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries","volume":"65","author":"IeDEA and ART Cohort Collaborations","year":"2014"},{"key":"ref15","series-title":"Clin Infect Dis","first-page":"432","article-title":"Advanced HIV disease at entry into HIV care and initiation of antiretroviral therapy during 2006\u20132011: findings from four sub-Saharan African countries","volume":"58","author":"Lahuerta","year":"2014"},{"key":"ref16","series-title":"AIDS","first-page":"2121","article-title":"Reducing deaths from tuberculosis in antiretroviral treatment programmes in sub-Saharan Africa","volume":"26","author":"Lawn","year":"2012"},{"key":"ref17","series-title":"PLoS One","first-page":"e47542","article-title":"Causes of death on antiretroviral therapy: a post-mortem study from South Africa","volume":"7","author":"Wong","year":"2012"},{"key":"ref18","series-title":"PLoS One","first-page":"e33685","article-title":"An autopsy study describing causes of death and comparing clinico-pathological findings among hospitalized patients in Kampala, Uganda","volume":"7","author":"Cox","year":"2012"},{"key":"ref19","series-title":"Lancet","first-page":"1005","article-title":"Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990\u20132013: a systematic analysis for the Global Burden of Disease Study 2013","volume":"384","author":"Murray","year":"2014"},{"key":"ref20","series-title":"AIDS","first-page":"1605","article-title":"Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control","volume":"20","author":"Lawn","year":"2006"},{"key":"ref21","series-title":"PLoS Med","first-page":"e1001270","article-title":"Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and meta-analysis","volume":"9","author":"Suthar","year":"2012"},{"key":"ref22","series-title":"J Infect Dis","first-page":"437","article-title":"Unmasked tuberculosis and tuberculosis immune reconstitution inflammatory disease: a disease spectrum after highly active antiretroviral therapy initiation","volume":"199","author":"Manabe","year":"2008"},{"key":"ref23","series-title":"Clin Infect Dis","first-page":"1500","article-title":"High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania","volume":"40","author":"Mtei","year":"2005"},{"key":"ref24","series-title":"Improving the Diagnosis and Treatment of Smear-Negative Pulmonary and Extrapulmonary Tuberculosis among Adults and Adolescents","author":"WHO","year":"2007"},{"key":"ref25","series-title":"Lancet","first-page":"1198","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"},{"key":"ref26","series-title":"Empirical TB Treatment in Advanced HIV Disease: Results of the TB Fast Track Trial","author":"Grant","year":"2016"},{"key":"ref27","series-title":"J Acquir Immune Defic Syndr","first-page":"297","article-title":"Empiric TB treatment of severely ill patients with HIV and presumed pulmonary TB improves survival","volume":"72","author":"Katagira","year":"2016"},{"key":"ref28","series-title":"Clin Infect Dis","first-page":"965","article-title":"Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban African cohort","volume":"49","author":"Castelnuovo","year":"2009"},{"key":"ref29","series-title":"Int J Tuberc Lung Dis","first-page":"1354","article-title":"Diagnostic yield of tuberculosis using sputum induction in HIV-positive patients before antiretroviral therapy","volume":"16","author":"Lawn","year":"2012"},{"key":"ref30","series-title":"Intensive TB Screening for HIV-Infected Patients Ready to Start ART in Durban, South Africa: Limitations of WHO Guidelines","author":"Bassett","year":"2009"},{"key":"ref31","series-title":"J Acquir Immune Defic Syndr","first-page":"e69","article-title":"Implementation and operational research: integrated pre-antiretroviral therapy screening and treatment for tuberculosis and cryptococcal antigenemia","volume":"68","author":"Pac","year":"2015"},{"key":"ref32","series-title":"Rapid Implementation of the Xpert MTB\/RIF Diagnostic Test: Technical and Operational \u2018How-to\u2019 Practical Considerations","author":"WHO","year":"2011"},{"key":"ref33","series-title":"Lancet","first-page":"1495","article-title":"Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB\/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study","volume":"377","author":"Boehme","year":"2011"},{"key":"ref34","series-title":"AIDS","first-page":"1635","article-title":"Clinical significance of lipoarabinomannan detection in urine using a low-cost point-of-care diagnostic assay for HIV-associated tuberculosis","volume":"26","author":"Lawn","year":"2012"},{"key":"ref35","series-title":"Eur Respir J","first-page":"1211","article-title":"Diagnostic accuracy of a urine lipoarabinomannan strip-test for TB detection in HIV-infected hospitalised patients","volume":"40","author":"Peter","year":"2012"},{"key":"ref36","series-title":"J Acquir Immune Defic Syndr","first-page":"270","article-title":"Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults","volume":"66","author":"Nakiyingi","year":"2014"},{"key":"ref37","article-title":"Xpert MTB\/RIF Ultra: A New Near-Patients TB Test with Sensitivity Equal to Culture","author":"Alland","year":"2015"},{"key":"ref38","series-title":"Lancet","first-page":"1187","article-title":"Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: A pragmatic, parallel-group, multicountry, open-label, randomised controlled trial","volume":"387","author":"Peter","year":"2016"}],"container-title":["The American Society of Tropical Medicine and Hygiene"],"original-title":[],"link":[{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/95\/6\/article-p1265.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/95\/6\/article-p1265.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/95\/6\/article-p1265.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T21:51:56Z","timestamp":1723067516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/95\/6\/article-p1265.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,7]]},"references-count":38,"journal-issue":{"issue":"6"},"URL":"https:\/\/doi.org\/10.4269\/ajtmh.16-0239","relation":{},"ISSN":["0002-9637","1476-1645"],"issn-type":[{"value":"0002-9637","type":"print"},{"value":"1476-1645","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,7]]}}}