Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies

Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of...

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Vydáno v:The lancet respiratory medicine Ročník 3; číslo 3; s. 201 - 209
Hlavní autoři: Kurbatova, Ekaterina V, Cegielski, J Peter, Lienhardt, Christian, Akksilp, Rattanawadee, Bayona, Jaime, Becerra, Mercedes C, Caoili, Janice, Contreras, Carmen, Dalton, Tracy, Danilovits, Manfred, Demikhova, Olga V, Ershova, Julia, Gammino, Victoria M, Gelmanova, Irina, Heilig, Charles M, Jou, Ruwen, Kazennyy, Boris, Keshavjee, Salmaan, Kim, Hee Jin, Kliiman, Kai, Kvasnovsky, Charlotte, Leimane, Vaira, Mitnick, Carole D, Quelapio, Imelda, Riekstina, Vija, Smith, Sarah E, Tupasi, Thelma, van der Walt, Martie, Vasilyeva, Irina A, Via, Laura E, Viiklepp, Piret, Volchenkov, Grigory, Walker, Allison Taylor, Wolfgang, Melanie, Yagui, Martin, Zignol, Matteo
Médium: Journal Article
Jazyk:angličtina
Vydáno: England 01.03.2015
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ISSN:2213-2619
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Abstract Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment. Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
AbstractList BACKGROUNDSputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis.METHODSWe analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling.FINDINGSWe assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment.INTERPRETATIONTime to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis.FUNDINGUS Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment. Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
Author Gelmanova, Irina
Bayona, Jaime
Jou, Ruwen
Kliiman, Kai
Gammino, Victoria M
Quelapio, Imelda
Wolfgang, Melanie
Kvasnovsky, Charlotte
Kim, Hee Jin
Lienhardt, Christian
Kazennyy, Boris
Yagui, Martin
Dalton, Tracy
Ershova, Julia
Via, Laura E
Keshavjee, Salmaan
Smith, Sarah E
Viiklepp, Piret
Demikhova, Olga V
Heilig, Charles M
Kurbatova, Ekaterina V
Volchenkov, Grigory
Akksilp, Rattanawadee
Caoili, Janice
Walker, Allison Taylor
Danilovits, Manfred
Cegielski, J Peter
Becerra, Mercedes C
van der Walt, Martie
Leimane, Vaira
Vasilyeva, Irina A
Riekstina, Vija
Tupasi, Thelma
Contreras, Carmen
Mitnick, Carole D
Zignol, Matteo
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  givenname: J Peter
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  fullname: Cegielski, J Peter
  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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  organization: WHO, Geneva, Switzerland
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  organization: Harvard Medical School and Partners In Health, Boston, MA, USA
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  organization: Harvard Medical School and Partners In Health, Boston, MA, USA
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  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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  organization: Tartu University Hospital, Tartu, Estonia
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  organization: Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia
– sequence: 12
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  fullname: Ershova, Julia
  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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  surname: Gammino
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  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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  organization: Harvard Medical School and Partners In Health, Boston, MA, USA
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  surname: Heilig
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  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
– sequence: 16
  givenname: Ruwen
  surname: Jou
  fullname: Jou, Ruwen
  organization: Reference Laboratory of Mycobacteriology, Taiwan Centers for Disease Control, Taipei, Taiwan
– sequence: 17
  givenname: Boris
  surname: Kazennyy
  fullname: Kazennyy, Boris
  organization: Orel Oblast Tuberculosis Dispensary, Orel, Russia
– sequence: 18
  givenname: Salmaan
  surname: Keshavjee
  fullname: Keshavjee, Salmaan
  organization: Harvard Medical School and Partners In Health, Boston, MA, USA
– sequence: 19
  givenname: Hee Jin
  surname: Kim
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  organization: Korean Institute of Tuberculosis, Seoul, South Korea
– sequence: 20
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  surname: Kliiman
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  organization: Tartu University Hospital, Tartu, Estonia
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  surname: Kvasnovsky
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  organization: Riga East University Hospital, Tuberculosis and Lung Disease Center, Riga, Latvia
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  organization: Harvard Medical School and Partners In Health, Boston, MA, USA
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  organization: Tropical Disease Foundation, Manila, Philippines
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  organization: Riga East University Hospital, Tuberculosis and Lung Disease Center, Riga, Latvia
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  givenname: Sarah E
  surname: Smith
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  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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  givenname: Thelma
  surname: Tupasi
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  organization: Tropical Disease Foundation, Manila, Philippines
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  surname: van der Walt
  fullname: van der Walt, Martie
  organization: Medical Research Council, Pretoria, South Africa
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  givenname: Irina A
  surname: Vasilyeva
  fullname: Vasilyeva, Irina A
  organization: Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia
– sequence: 30
  givenname: Laura E
  surname: Via
  fullname: Via, Laura E
  organization: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
– sequence: 31
  givenname: Piret
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  organization: National Tuberculosis Registry, National Institute for Health Development, Tallinn, Estonia
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  surname: Volchenkov
  fullname: Volchenkov, Grigory
  organization: Vladimir Oblast Tuberculosis Dispensary, Vladimir, Russia
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  organization: Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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  organization: National Institute of Health, Lima, Peru
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  givenname: Matteo
  surname: Zignol
  fullname: Zignol, Matteo
  organization: WHO, Geneva, Switzerland
BackLink https://www.ncbi.nlm.nih.gov/pubmed/25726085$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright Copyright © 2015 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.
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GrantInformation US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
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PublicationTitle The lancet respiratory medicine
PublicationTitleAlternate Lancet Respir Med
PublicationYear 2015
References 25726087 - Lancet Respir Med. 2015 Mar;3(3):174-5. doi: 10.1016/S2213-2600(15)00058-2.
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Snippet Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed...
BACKGROUNDSputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its...
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SubjectTerms Adolescent
Adult
Aged
Humans
Middle Aged
Mycobacterium tuberculosis - isolation & purification
Prospective Studies
Sputum - microbiology
Treatment Outcome
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Pulmonary - drug therapy
Young Adult
Title Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies
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