Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial
Summary Background Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculos...
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| Veröffentlicht in: | The Lancet (British edition) 2016-03, Vol.387 (10024), p.1198-1209 |
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| creator | Hosseinipour, Mina C, Prof Bisson, Gregory P, MD Miyahara, Sachiko, PhD Sun, Xin, MS Moses, Agnes, MMED Riviere, Cynthia, MD Kirui, Fredrick K, MMED Badal-Faesen, Sharlaa, MBBCh Lagat, David, MBChB Nyirenda, Mulinda, MMED Naidoo, Kogieleum, MBChB Hakim, James, Prof Mugyenyi, Peter, Prof Henostroza, German, MD Leger, Paul D, MD Lama, Javier R, MD Mohapi, Lerato, MBBCh Alave, Jorge, MD Mave, Vidya, MD Veloso, Valdilea G, MD Pillay, Sandy, MBChB Kumarasamy, Nagalingeswaran, PhD Bao, Jing, MD Hogg, Evelyn, BA Jones, Lynne, MT ASCP Zolopa, Andrew, Prof Kumwenda, Johnstone, Prof Gupta, Amita, MD |
| description | Summary Background Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. Methods We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov , number NCT01380080. Findings Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9–32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5–7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4–7·8); absolute risk difference of −0·06% (95% CI −3·05 to 2·94). Grade 3 or 4 signs or symp |
| doi_str_mv | 10.1016/S0140-6736(16)00546-8 |
| format | Article |
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Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. Methods We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov , number NCT01380080. Findings Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9–32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5–7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4–7·8); absolute risk difference of −0·06% (95% CI −3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. Interpretation Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. Funding National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(16)00546-8</identifier><identifier>PMID: 27025337</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adult ; AIDS-Related Opportunistic Infections - immunology ; AIDS-Related Opportunistic Infections - prevention & control ; Allergies ; Ambulatory Care Facilities ; Anti-HIV Agents - therapeutic use ; Antiretroviral agents ; Antiretroviral drugs ; Antitubercular Agents - therapeutic use ; CD4 Lymphocyte Count ; Clinical trials ; Drug therapy ; Female ; HIV ; HIV Infections - drug therapy ; HIV Infections - immunology ; Human immunodeficiency virus ; Humans ; Infectious diseases ; Internal Medicine ; Isoniazid - therapeutic use ; Kaplan-Meier Estimate ; Male ; Mortality ; Mycobacterium ; Preventive medicine ; Treatment Outcome ; Tuberculosis ; Tuberculosis - immunology ; Tuberculosis - prevention & control</subject><ispartof>The Lancet (British edition), 2016-03, Vol.387 (10024), p.1198-1209</ispartof><rights>Elsevier Ltd</rights><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Mar 19, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c528t-3857293e2280f01cf8f6db01032a4b5988d961df51846117bc85905f0c8f64a03</citedby><cites>FETCH-LOGICAL-c528t-3857293e2280f01cf8f6db01032a4b5988d961df51846117bc85905f0c8f64a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1775104114?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976,64364,64366,64368,72218</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27025337$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hosseinipour, Mina C, Prof</creatorcontrib><creatorcontrib>Bisson, Gregory P, MD</creatorcontrib><creatorcontrib>Miyahara, Sachiko, PhD</creatorcontrib><creatorcontrib>Sun, Xin, MS</creatorcontrib><creatorcontrib>Moses, Agnes, MMED</creatorcontrib><creatorcontrib>Riviere, Cynthia, MD</creatorcontrib><creatorcontrib>Kirui, Fredrick K, MMED</creatorcontrib><creatorcontrib>Badal-Faesen, Sharlaa, MBBCh</creatorcontrib><creatorcontrib>Lagat, David, MBChB</creatorcontrib><creatorcontrib>Nyirenda, Mulinda, MMED</creatorcontrib><creatorcontrib>Naidoo, Kogieleum, MBChB</creatorcontrib><creatorcontrib>Hakim, James, Prof</creatorcontrib><creatorcontrib>Mugyenyi, Peter, Prof</creatorcontrib><creatorcontrib>Henostroza, German, MD</creatorcontrib><creatorcontrib>Leger, Paul D, MD</creatorcontrib><creatorcontrib>Lama, Javier R, MD</creatorcontrib><creatorcontrib>Mohapi, Lerato, MBBCh</creatorcontrib><creatorcontrib>Alave, Jorge, MD</creatorcontrib><creatorcontrib>Mave, Vidya, MD</creatorcontrib><creatorcontrib>Veloso, Valdilea G, MD</creatorcontrib><creatorcontrib>Pillay, Sandy, MBChB</creatorcontrib><creatorcontrib>Kumarasamy, Nagalingeswaran, PhD</creatorcontrib><creatorcontrib>Bao, Jing, MD</creatorcontrib><creatorcontrib>Hogg, Evelyn, BA</creatorcontrib><creatorcontrib>Jones, Lynne, MT ASCP</creatorcontrib><creatorcontrib>Zolopa, Andrew, Prof</creatorcontrib><creatorcontrib>Kumwenda, Johnstone, Prof</creatorcontrib><creatorcontrib>Gupta, Amita, MD</creatorcontrib><creatorcontrib>Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team</creatorcontrib><title>Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Summary Background Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. Methods We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov , number NCT01380080. Findings Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9–32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5–7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4–7·8); absolute risk difference of −0·06% (95% CI −3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. Interpretation Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. Funding National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.</description><subject>Adult</subject><subject>AIDS-Related Opportunistic Infections - immunology</subject><subject>AIDS-Related Opportunistic Infections - prevention & control</subject><subject>Allergies</subject><subject>Ambulatory Care Facilities</subject><subject>Anti-HIV Agents - therapeutic use</subject><subject>Antiretroviral agents</subject><subject>Antiretroviral drugs</subject><subject>Antitubercular Agents - therapeutic use</subject><subject>CD4 Lymphocyte Count</subject><subject>Clinical trials</subject><subject>Drug therapy</subject><subject>Female</subject><subject>HIV</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - immunology</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Internal Medicine</subject><subject>Isoniazid - therapeutic use</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Mortality</subject><subject>Mycobacterium</subject><subject>Preventive medicine</subject><subject>Treatment Outcome</subject><subject>Tuberculosis</subject><subject>Tuberculosis - immunology</subject><subject>Tuberculosis - prevention & 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tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial</title><author>Hosseinipour, Mina C, Prof ; Bisson, Gregory P, MD ; Miyahara, Sachiko, PhD ; Sun, Xin, MS ; Moses, Agnes, MMED ; Riviere, Cynthia, MD ; Kirui, Fredrick K, MMED ; Badal-Faesen, Sharlaa, MBBCh ; Lagat, David, MBChB ; Nyirenda, Mulinda, MMED ; Naidoo, Kogieleum, MBChB ; Hakim, James, Prof ; Mugyenyi, Peter, Prof ; Henostroza, German, MD ; Leger, Paul D, MD ; Lama, Javier R, MD ; Mohapi, Lerato, MBBCh ; Alave, Jorge, MD ; Mave, Vidya, MD ; Veloso, Valdilea G, MD ; Pillay, Sandy, MBChB ; Kumarasamy, Nagalingeswaran, PhD ; Bao, Jing, MD ; Hogg, Evelyn, BA ; Jones, Lynne, MT ASCP ; Zolopa, Andrew, Prof ; Kumwenda, Johnstone, Prof ; Gupta, Amita, MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c528t-3857293e2280f01cf8f6db01032a4b5988d961df51846117bc85905f0c8f64a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>AIDS-Related Opportunistic Infections - immunology</topic><topic>AIDS-Related Opportunistic Infections - prevention & control</topic><topic>Allergies</topic><topic>Ambulatory Care Facilities</topic><topic>Anti-HIV Agents - therapeutic use</topic><topic>Antiretroviral agents</topic><topic>Antiretroviral drugs</topic><topic>Antitubercular Agents - therapeutic use</topic><topic>CD4 Lymphocyte Count</topic><topic>Clinical trials</topic><topic>Drug therapy</topic><topic>Female</topic><topic>HIV</topic><topic>HIV Infections - drug therapy</topic><topic>HIV Infections - immunology</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Internal Medicine</topic><topic>Isoniazid - therapeutic use</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Mortality</topic><topic>Mycobacterium</topic><topic>Preventive medicine</topic><topic>Treatment Outcome</topic><topic>Tuberculosis</topic><topic>Tuberculosis - immunology</topic><topic>Tuberculosis - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hosseinipour, Mina C, Prof</creatorcontrib><creatorcontrib>Bisson, Gregory P, MD</creatorcontrib><creatorcontrib>Miyahara, Sachiko, PhD</creatorcontrib><creatorcontrib>Sun, Xin, MS</creatorcontrib><creatorcontrib>Moses, Agnes, MMED</creatorcontrib><creatorcontrib>Riviere, Cynthia, MD</creatorcontrib><creatorcontrib>Kirui, Fredrick K, MMED</creatorcontrib><creatorcontrib>Badal-Faesen, Sharlaa, MBBCh</creatorcontrib><creatorcontrib>Lagat, David, MBChB</creatorcontrib><creatorcontrib>Nyirenda, Mulinda, MMED</creatorcontrib><creatorcontrib>Naidoo, Kogieleum, MBChB</creatorcontrib><creatorcontrib>Hakim, James, Prof</creatorcontrib><creatorcontrib>Mugyenyi, Peter, Prof</creatorcontrib><creatorcontrib>Henostroza, German, MD</creatorcontrib><creatorcontrib>Leger, Paul D, MD</creatorcontrib><creatorcontrib>Lama, Javier R, MD</creatorcontrib><creatorcontrib>Mohapi, Lerato, MBBCh</creatorcontrib><creatorcontrib>Alave, Jorge, MD</creatorcontrib><creatorcontrib>Mave, Vidya, MD</creatorcontrib><creatorcontrib>Veloso, Valdilea G, MD</creatorcontrib><creatorcontrib>Pillay, Sandy, MBChB</creatorcontrib><creatorcontrib>Kumarasamy, Nagalingeswaran, PhD</creatorcontrib><creatorcontrib>Bao, Jing, MD</creatorcontrib><creatorcontrib>Hogg, Evelyn, BA</creatorcontrib><creatorcontrib>Jones, Lynne, MT ASCP</creatorcontrib><creatorcontrib>Zolopa, Andrew, Prof</creatorcontrib><creatorcontrib>Kumwenda, Johnstone, Prof</creatorcontrib><creatorcontrib>Gupta, Amita, MD</creatorcontrib><creatorcontrib>Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>News PRO</collection><collection>Pharma and Biotech Premium PRO</collection><collection>Global News & ABI/Inform Professional</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni 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Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>The Lancet (British edition)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hosseinipour, Mina C, Prof</au><au>Bisson, Gregory P, MD</au><au>Miyahara, Sachiko, PhD</au><au>Sun, Xin, MS</au><au>Moses, Agnes, MMED</au><au>Riviere, Cynthia, MD</au><au>Kirui, Fredrick K, MMED</au><au>Badal-Faesen, Sharlaa, MBBCh</au><au>Lagat, David, MBChB</au><au>Nyirenda, Mulinda, MMED</au><au>Naidoo, Kogieleum, MBChB</au><au>Hakim, James, Prof</au><au>Mugyenyi, Peter, Prof</au><au>Henostroza, German, MD</au><au>Leger, Paul D, MD</au><au>Lama, Javier R, MD</au><au>Mohapi, Lerato, MBBCh</au><au>Alave, Jorge, MD</au><au>Mave, Vidya, MD</au><au>Veloso, Valdilea G, MD</au><au>Pillay, Sandy, MBChB</au><au>Kumarasamy, Nagalingeswaran, PhD</au><au>Bao, Jing, MD</au><au>Hogg, Evelyn, BA</au><au>Jones, Lynne, MT ASCP</au><au>Zolopa, Andrew, Prof</au><au>Kumwenda, Johnstone, Prof</au><au>Gupta, Amita, MD</au><aucorp>Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2016-03-19</date><risdate>2016</risdate><volume>387</volume><issue>10024</issue><spage>1198</spage><epage>1209</epage><pages>1198-1209</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Summary Background Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. Methods We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov , number NCT01380080. Findings Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9–32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5–7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4–7·8); absolute risk difference of −0·06% (95% CI −3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. Interpretation Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. Funding National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27025337</pmid><doi>10.1016/S0140-6736(16)00546-8</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2016-03, Vol.387 (10024), p.1198-1209 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1777485700 |
| source | MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central UK/Ireland |
| subjects | Adult AIDS-Related Opportunistic Infections - immunology AIDS-Related Opportunistic Infections - prevention & control Allergies Ambulatory Care Facilities Anti-HIV Agents - therapeutic use Antiretroviral agents Antiretroviral drugs Antitubercular Agents - therapeutic use CD4 Lymphocyte Count Clinical trials Drug therapy Female HIV HIV Infections - drug therapy HIV Infections - immunology Human immunodeficiency virus Humans Infectious diseases Internal Medicine Isoniazid - therapeutic use Kaplan-Meier Estimate Male Mortality Mycobacterium Preventive medicine Treatment Outcome Tuberculosis Tuberculosis - immunology Tuberculosis - prevention & control |
| title | Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial |
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